The therapeutic logic of an ADC is elegantly simple on paper. Each molecule combines three components: a monoclonal antibody that recognizes an antigen displayed on the surface of tumor cells, a chemical linker that holds the assembly together, and a cytotoxic payload far too potent to administer as a conventional drug. After infusion, the ADC circulates in the bloodstream, docks onto its target antigen, and is swallowed whole by the cancer cell through antigen-mediated endocytosis. Inside endosomes and lysosomes, the linker is cleaved and the payload is released, where it kills the cell by disrupting DNA replication or crippling microtubule function. The design goal is selective eradication—chemotherapy-grade killing delivered only to cells bearing the right molecular address, sparing normal tissue from the collateral damage that has defined cytotoxic therapy for decades.

Clinical reality has largely vindicated that concept, at least for a growing list of tumors. Since the U.S. Food and Drug Administration approved the first ADC, gemtuzumab ozogamicin (Mylotarg), in 2000, the field has progressed through three recognizable generations. First-generation conjugates from 2000 to 2012 relied on non-selective linkers and conventional payloads with limited efficacy. The second generation, spanning 2013 to 2019, introduced the linker and payload chemistry that made agents such as trastuzumab emtansine and trastuzumab deruxtecan clinically meaningful. The third generation, from 2020 onward, adds site-specific conjugation, bispecific antibody designs, and immunomodulatory payloads. The pace of approvals has accelerated sharply, and the authors anticipate a continued expansion that will keep reshaping the oncology formulary.

Yet the review is unsparing about who actually benefits. Clinically established ADC targets in solid tumors remain confined to a narrow set of molecules—HER2, TROP2, Nectin-4, folate receptor alpha, tissue factor, and c-MET, with Claudin 18.2-directed agents still investigational. Many membrane proteins and mutated subtypes prevalent in refractory gastrointestinal cancers remain unexplored; KRAS mutations, common in colorectal and pancreatic cancer and associated with poor prognosis, still have no approved ADC directed at them. Compounding the target scarcity is the pronounced intratumoral heterogeneity of solid tumors: within a single lesion, some cell subpopulations express the target abundantly while others show little or none. A single-target ADC may therefore eradicate only a fraction of the tumor, leaving target-negative subclones to seed relapse—and therapeutic pressure actively selects for resistant clones that have downregulated or lost the antigen altogether.

The biomarker problem is, if anything, more disorienting. In theory, the level of target antigen expression should predict response, and in some settings it does: trastuzumab emtansine works best in HER2-high breast cancer, and mirvetuximab soravtansine shows superior efficacy in folate receptor alpha-high, platinum-resistant ovarian cancer. But the correlation repeatedly breaks down. Trastuzumab deruxtecan benefits not only HER2-high patients but also those with HER2-low and, in the defined hormone receptor-positive population, even HER2-ultralow expression. Sacituzumab govitecan and other approved ADCs produce response rates that do not track cleanly with target levels. The authors argue that efficacy is governed by a far more complex biology—epitope accessibility, internalization and recycling kinetics, stromal composition, hypoxia, immune infiltration—and they point to emerging solutions ranging from genomic and transcriptomic profiling to patient-derived organoid assays and machine-learning models that integrate multimodal biomarker data for patient stratification.

Two engineering strategies dominate the search for solutions. The first is multispecificity: bispecific ADCs that recognize two distinct antigens, or two epitopes on the same antigen, can in principle sweep up heterogeneous tumor populations and exploit differential expression between malignant and healthy tissue to concentrate payload at the tumor site. Examples include ZW49, a HER2 biparatopic ADC that has completed a phase I study, and M1231, a MUC1×EGFR bispecific that achieved complete tumor regression in patient-derived xenograft models of non-small cell lung cancer and esophageal cancer. The second is payload diversification. Immune-stimulating antibody conjugates deliver small-molecule agonists—such as activators of the STING pathway—directly to the tumor microenvironment, aiming to ignite local innate immunity while avoiding the systemic toxicity that doomed earlier attempts with TLR7/8 agonists. The review highlights work combining STING activation with TGF-β and PD-L1 blockade, as well as dual-payload ADCs designed to produce additive or synergistic killing from a single molecule.

Sequencing and combination questions are becoming urgent as more patients cycle through multiple ADCs. Four ADCs are now FDA-approved for breast cancer: trastuzumab emtansine, trastuzumab deruxtecan, sacituzumab govitecan, and datopotamab deruxtecan. Some share antibody backbones, others share payload mechanisms—trastuzumab deruxtecan and sacituzumab govitecan both rely on topoisomerase I inhibition—and accumulating evidence suggests payload-mediated cross-resistance may be a dominant mechanism of acquired resistance. The Translational Breast Cancer Research Consortium is running one prospective registry study and three phase II trials to settle the question. Meanwhile, ADC–immunotherapy combinations have already produced an approved first-line regimen for metastatic urothelial carcinoma, but the disappointing results of pairing trastuzumab deruxtecan with immunotherapy show that rational combination design still requires a much deeper understanding of how individual ADCs remodel the tumor microenvironment.

Safety is the review’s most sobering chapter. A pooled meta-analysis cited by the authors found that treatment-related adverse events occur in more than 90 percent of ADC-treated patients, with 46 percent reaching grade 3 or higher—profiles comparable to, or worse than, conventional chemotherapy. Three agents—belantamab mafodotin, tisotumab vedotin, and mirvetuximab soravtansine—carry FDA boxed warnings for ocular toxicity. In the InnovaTV 204 trial of tisotumab vedotin in cervical cancer, roughly 53 percent of 101 patients experienced ocular adverse events, mostly low-grade conjunctivitis, dry eye, and keratitis, but two developed ulcerative keratitis requiring discontinuation and 22 percent needed dose reductions. Real-world data suggest belantamab-associated ocular toxicity may reach 90 percent in myeloma. The proposed mechanism is unsettling in its simplicity: ADCs accumulate in tears and corneal tissue through Fcγ receptor-mediated uptake by corneal epithelial and limbal stem cells, and the ocular surface’s poor drainage prolongs exposure.

Interstitial lung disease is the other defining hazard. Reported incidence for trastuzumab deruxtecan ranges from 7.6 to 26.4 percent, with some cases progressing to fatal pulmonary injury, and the HER2-targeted candidate ARX788 has shown rates as high as 32.7 percent. No validated pharmacologic prophylaxis exists; management rests on treatment interruption and prompt corticosteroids, with grade 2 or higher pneumonitis mandating permanent discontinuation of trastuzumab deruxtecan. The authors’ own prior work offers a mechanistic clue: alveolar macrophages internalize and process ADCs via Fcγ receptor-mediated phagocytosis, triggering local lung inflammation—an off-target, off-tumor pathway that engineering strategies such as site-specific conjugation, linker stabilization, and antibody masking have so far failed to translate into substantial clinical improvement. ADC development, they note, still leans on trial and error rather than mechanism-guided optimization.

The review closes on a note of ambition rather than resignation. China, which accounts for roughly 43.8 percent of global esophageal cancer cases and 37 percent of gastric cancer cases—against a backdrop of about 4.82 million new cancer diagnoses and 2.57 million cancer deaths in 2022—now hosts the world’s largest clinical pipeline of bispecific ADCs. BL-B01D1, an EGFR×HER3 bispecific developed by Sichuan Baili Pharmaceutical, achieved confirmed objective response rates of 44.1 percent in urothelial carcinoma; Jacobio Pharma’s HER2-targeted STING-agonist conjugate JAB-BX467 is in IND preparation; and Kanghong’s KH815, a dual-payload TROP2-directed ADC delivering both a topoisomerase I and an RNA polymerase II inhibitor, is in first-in-human testing. For the authors, these programs mark China’s transition from fast follower to innovator—and, more broadly, signal that the next generation of ADCs will be judged not by their ability to hit a single target, but by how intelligently they navigate the heterogeneity, biomarker uncertainty, and toxicity that the first two decades of the technology have laid bare.

Subject of Research: Antibody–drug conjugates for solid tumors: mechanisms, clinical landscape, and safety challenges

Article Title: Antibody–drug conjugates in solid tumors: current landscape, challenges, and future directions

Article References: Yang, T., Shimura, T., Wei, Q., & Cheng, X. (2026). Antibody–drug conjugates in solid tumors: current landscape, challenges, and future directions. Holistic Integrative Oncology, 5(1), Article 83. https://doi.org/10.1007/s44178-026-00304-6

Image Credits: AI Generated

DOI: 10.1007/s44178-026-00304-6

Keywords: antibody-drug conjugates, solid tumors, targeted therapy, HER2, interstitial lung disease, ocular toxicity, bispecific antibodies, biomarkers, cancer immunotherapy, payload diversification, China oncology pipeline, drug resistance

The research team, led by Eilidh M. Duncan of Myeloma Patients Europe in Brussels, brought together an unusually diverse group of 38 participants to tackle the problem. Rather than consulting only clinicians or researchers, the investigators recruited patients with direct experience of CAR-T or bispecific antibody treatment, informal family carers, patient advocates from myeloma, lymphoma, and leukaemia communities, academic researchers, trialists, pharmaceutical industry representatives, and officials from regulatory and health technology assessment bodies, including the FDA and EMA. Data came from 14 one-to-one interviews with 16 participants and two online focus groups involving 15 and 19 participants respectively. Transcripts were analysed using a deductive-inductive thematic approach with double coding by independent researchers, a methodological rigor that strengthens the credibility of the resulting themes.

The technical context makes the challenge clear. CAR-T therapy involves engineering a patient’s own T cells to recognise cancer cells, while bispecific antibodies, or BsAbs, are laboratory-made molecules that physically link T cells to malignant cells. Both can trigger cytokine release syndrome, an immune overreaction causing fever, nausea, headache, low blood pressure, and potentially multi-organ failure. They can also cause immune effector cell-associated neurotoxicity syndrome, or ICANS, a neuropsychiatric condition ranging from mild tremor and confusion to haemorrhage, coma, and death. According to the study, CRS occurs in roughly 87 percent of CAR-T patients and 67 percent of those receiving BsAbs, while neurotoxicity affects 40 to 64 percent of CAR-T recipients, with 27 percent requiring intensive care admission. These acute toxicities typically emerge within one to four weeks after treatment, yet longer-term experiences are rarely assessed or reported.

One of the most striking findings concerns the logistical maze surrounding CAR-T treatment. Because the therapy is only available at specialised centres, patients frequently travel more than 100 kilometres for infusion and hospitalisation, then return to local providers for follow-up. This fragmentation across multiple treatment sites complicates PROM data capture and contributes to missing data. Participants also highlighted a sobering measurement paradox: patients experiencing the worst toxicities, such as cognitive impairment from ICANS or severe CRS, are often too unwell to complete questionnaires at all. As one researcher explained, the data dip between pre-lymphodepletion and week two captures only the sick patients who are still fit enough to fill out forms, not the sickest ones, making the reasons for missing data critically important to understand.

Bispecific antibodies present their own distinct measurement headache. Unlike CAR-T, which is a fixed-duration treatment, BsAbs involve continuous administration with a wide variety of side effects occurring over different time periods. Participants described agents such as talquetamab, a GPRC5D-targeting bispecific, which produces gastrointestinal effects, skin toxicity, complete taste loss, falling nails, itchy rashes, and weight loss. Some symptoms resolve over several months while others, like taste changes and weight loss, persist indefinitely. These treatment-specific domains fall outside the scope of generic instruments such as the EORTC QLQ-C30, which was designed for broad applicability rather than therapy-specific sensitivity. A recent review found 15 distinct PROMs used within just 16 CAR-T studies, highlighting the heterogeneity that undermines evidence synthesis across trials.

The timing of assessments emerged as a central controversy. Participants broadly agreed that baseline measurements for CAR-T and BsAbs trials should occur earlier than for older anticancer therapies, yet uncertainty persists about what baseline actually means. Because the CAR-T process spans several weeks, including leukapheresis, bridging therapies, and hospitalisation, a patient’s disease status and quality of life can shift dramatically between initial stages and infusion. Several researchers argued that future analyses should include two baselines, one right before lymphodepletion and one at the time of apheresis. Health technology assessment representatives insisted that baseline should mean study baseline, tied to treatment decision or randomisation, not any later time point.

Follow-up timing proved equally contentious. Participants suggested assessments as early as one week after infusion could serve as a crucial anchor point to capture the frequency, intensity, severity, and resolution of side effects. Industry representatives acknowledged the feasibility challenges, noting that patients are often hospitalised and facing severe complications like CRS shortly after infusion. For BsAbs with step-up dosing, where patients receive three doses during week one, some argued quality of life and toxicity should be explored after each individual dose. A regulatory representative called for weekly assessments during the first two months after CAR-T administration, using an item library to select really important symptoms such as headache and fatigue, alongside physical functioning measured on a high-frequency basis.

Perhaps the most emotionally resonant finding concerns what current PROMs systematically miss. Patients described the intense mental strain of waiting for CAR-T, including fear that their health would deteriorate during the manufacturing interval and render them ineligible. One patient recounted that doctors and nurses focused on physical side effects while never asking about the mental part, which was the most difficult aspect, and that her doctor essentially told her the mental part was hers to handle alone. Participants also flagged emerging concepts like time toxicity, meaning the time patients spend managing treatment and its effects, along with the burden on family carers, financial strain, and the psychological weight of living with an immunocompromised state. None of the three commonly used PROMs in trials, the EORTC QLQ-C30, MDASI-CAR, and PRO-CTCAE, capture waiting anxiety, logistical burden, caregiver burden, or treatment-free survival.

The study’s recommendations form a concrete blueprint for reform. The authors propose a dual-baseline strategy appropriate for rapid clinical changes preceding CAR-T infusion, mandated early high-frequency assessments, meaning weekly for the first four weeks, systematic inclusion of patient-important domains currently under-captured such as emotional well-being and time toxicity, continued PRO data collection beyond clinical progression, and transparent, comprehensive reporting of PRO findings. They also endorse interim strategies like combining instruments, adding PRO-CTCAE items to primary measures, and incorporating qualitative interviews or free-text responses. Longer-term, they support developing new treatment-specific PROMs, potentially with a modular core-plus-supplement design, alongside computerised adaptive testing to tailor questionnaires to individuals and reduce respondent burden.

The stakes extend far beyond academic measurement. CAR-T and BsAbs are high-cost therapies whose cost-effectiveness for health systems remains controversial, and PROM data directly informs reimbursement decisions. Under-reporting PRO data, the authors argue, is not just a concern for research validity but an unethical waste of patients’ time and energy, breaking the implicit agreement that patients’ contributions will meaningfully inform knowledge generation. Patients were willing to complete PROMs when they understood how their data would be used and felt confident it would not be wasted. As these immunotherapies continue to expand across haematological malignancies, the gap between what patients endure and what trials record can no longer be ignored. Clearer guidance from regulators and payers on instrument selection, assessment schedules, and reporting would substantially improve the quality and patient-centredness of evidence in this rapidly evolving field.

Subject of Research: Optimisation of patient-reported outcome measures for haematological cancer patients receiving CAR-T and bispecific antibody immunotherapies

Article Title: Optimisation of patient-reported outcome measurement for haematological cancer patients receiving novel immunotherapies: perspectives of multi-stakeholders

Article References: Duncan, E. M., Salviano, J., Kyriakou, C., Nier, S., Oerlemans, S., Salek, S., Morgan, K., & Joyner, K. (2026). Optimisation of patient-reported outcome measurement for haematological cancer patients receiving novel immunotherapies: perspectives of multi-stakeholders. Frontiers in Hematology, 5, Article 1800304. https://doi.org/10.3389/frhem.2026.1800304

Image Credits: AI Generated

DOI: 10.3389/frhem.2026.1800304

Keywords: CAR-T therapy, bispecific antibodies, patient-reported outcomes, PROMs, haematological malignancies, cytokine release syndrome, ICANS, quality of life, clinical trials, time toxicity, regulatory guidance, survivorship

Now a comprehensive review published in Molecular Cancer by Le-Le Zhang, Yi Wang, Yuqi Fu and colleagues, spanning institutions from Chengdu University to the University of Macau and the Hangzhou Institute of Medicine of the Chinese Academy of Sciences, delivers the most systematic account yet of how this checkpoint operates across the entire arc of tumor evolution—and what a new generation of therapeutics must do to outflank it. The work arrives at a moment when the field is shifting from broad blockade toward precision immunotherapy, and its integrated framework is already being described as strategic guidance for the next wave of checkpoint inhibitors.

The mechanistic core of the review is unflinching in its detail. The authors trace how the PD-1/PD-L1 axis drives T cell exhaustion, the progressive dysfunction state in which chronically stimulated T cells lose their ability to proliferate, produce effector cytokines and kill tumor targets. Beyond exhausting the cytotoxic arm of the immune system, the axis impairs antigen presentation—the process by which tumor cells display fragments of their abnormal proteins for immune recognition—and actively reshapes the immunosuppressive tumor microenvironment, recruiting regulatory T cells, tumor-associated macrophages and other suppressive populations that cement an anti-inflammatory fortress around the malignancy.

Perhaps most provocatively, the review catalogues how PD-L1 signaling feeds directly into tumor biology rather than merely hiding from immunity. The axis promotes epithelial–mesenchymal transition, the developmental program through which epithelial cancer cells acquire motility, invasiveness and stem-like properties, thereby enabling metastatic spread. This positions PD-L1 not as a passive shield but as an active participant in tumor initiation, disease progression and immune escape throughout tumor evolution—a reframing with direct consequences for how clinicians interpret PD-L1 expression as a biomarker and how drug developers think about blocking it.

On the therapeutic front, the review maps an expanding arsenal. Monoclonal antibodies remain the backbone, but the field is rapidly diversifying into bispecific molecules capable of engaging two targets simultaneously, and Fc-optimized biologics engineered to fine-tune the antibody’s effector functions—modulating how the constant region recruits immune cells or avoids unwanted depletion of therapeutic cells themselves. These design refinements aim to improve tissue penetration, extend half-life and reduce the off-target toxicities that have constrained first-generation agents.

More radical are the novel synthetic modalities the authors catalogue: RNA interference to silence PD-L1 transcripts, CRISPR-based gene editing to disrupt checkpoint expression at the genomic level, antisense oligonucleotides to block translation, and mRNA platforms that can either encode therapeutic antibodies or deliver instructions for in vivo production of checkpoint-targeting agents. These approaches represent a conceptual leap from blocking a protein-protein interaction to rewriting the genetic and transcriptomic instructions that produce it, offering potential solutions for tumors that have evolved to downregulate antigen presentation or upregulate alternative checkpoints.

Small-molecule inhibitors occupy a parallel and rapidly maturing track. The review evaluates emerging compounds designed to directly disrupt the PD-1/PD-L1 engagement at the interface itself, to modulate checkpoint expression transcriptionally or post-translationally, and to reprogram the oncogenic, metabolic and epigenetic circuits that tumors use to circumvent checkpoint blockade. By targeting the transcription factors, metabolic enzymes and chromatin modifiers that govern PD-L1 expression, these agents aim to dismantle the resistance architecture rather than simply blocking the checkpoint’s binding surface.

A dedicated focus of the review is the resistance problem itself. The authors dissect adaptive and intrinsic mechanisms, including PD-L1 re-induction after treatment withdrawal, persistent T cell dysfunction, deficits in antigen presentation that render tumor cells invisible to immune surveillance, and compensatory upregulation of alternative immune checkpoints such as LAG-3, TIM-3 and TIGIT. These escape routes explain why responses are heterogeneous and why tumors that initially regress often rebound with a new immunosuppressive phenotype. Understanding these routes is essential for designing rational combinations rather than empirical ones.

Indeed, the review advances rationale-driven combination approaches that integrate checkpoint inhibitors with targeted agents, chemotherapy, metabolic modulators and epigenetic drugs to amplify antitumor immunity. By pairing PD-1/PD-L1 blockade with agents that increase antigen release, reverse T cell exhaustion, normalize tumor metabolism or open chromatin to restore tumor-suppressor programs, these combinations aim to convert cold, immunologically silent tumors into inflamed ones that respond to checkpoint release. The strategic logic is that resistance is a moving target, and combinations must anticipate the escape routes rather than chase them after the fact.

Taken together, the review proposes an integrated framework for understanding the diverse roles of the PD-1/PD-L1 axis in tumor–immune interactions and offers strategic guidance for developing next-generation checkpoint inhibitors and precision immunotherapy approaches. As the field moves beyond the first decade of checkpoint blockade, the message is clear: the axis is not a single switch but a dynamic, multifunctional circuit that tumors exploit at every stage of their evolution, and only a correspondingly multifaceted therapeutic strategy—one that combines mechanistic insight, synthetic biology, small-molecule chemistry and rational combination design—will be sufficient to turn the promise of immunotherapy into durable clinical benefit for the majority of patients who currently do not respond.

Subject of Research: Cancer Immunotherapy

Article Title: The PD-1/PD-L1 axis in cancer: from immune evasion mechanisms to next-generation therapeutics

Article References: Zhang, L.-L., Wang, Y., Fu, Y., Li, H., Ma, X., Huang, M.-Y., Tang, Z., Qin, J.-J., & Li, T. (2026). The PD-1/PD-L1 axis in cancer: from immune evasion mechanisms to next-generation therapeutics. Molecular Cancer. https://doi.org/10.1186/s12943-026-02790-8

Image Credits: AI Generated

DOI: 10.1186/s12943-026-02790-8

Keywords: PD-1, PD-L1, immune checkpoint inhibitors, cancer immunotherapy, T cell exhaustion, drug resistance, bispecific antibodies, tumor microenvironment, CRISPR, mRNA therapeutics, axis, cancer

The core concept behind an ADC is deceptively simple, and reviewers often describe it as a guided missile. The drug consists of three covalently joined components: a monoclonal antibody that recognizes a tumor-associated antigen, a chemical linker that holds the assembly together in the bloodstream, and a cytotoxic payload far too potent to be given as a conventional chemotherapy. The antibody does the navigation; it binds cells displaying the right surface marker and, through antigen-mediated internalization, delivers the poison selectively to the interior of the cancer cell. The theoretical payoff is a dramatic widening of the therapeutic window, since maximal damage is concentrated on tumor tissue while healthy cells are largely spared. In practice, as the review makes clear, that selectivity is never perfect, and the gap between concept and clinic has shaped the entire development history of the field.

That history spans three generations of chemistry. Early ADCs, built on murine antibodies and labile linkers, produced such heavy off-target toxicity that several were abandoned. The current era belongs to agents such as trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd), and sacituzumab govitecan (SG), which pair humanized antibodies with cleavable or stable linkers and payloads including auristatin derivatives such as monomethyl auristatin E (MMAE) and topoisomerase I inhibitors. Payload choice matters enormously: topoisomerase I inhibitors exhibit what researchers call bystander killing, in which membrane-permeable drug released from a dying tumor cell diffuses into neighboring malignant cells that express little or none of the target antigen. This property helps explain why T-DXd and SG have produced striking responses in tumors with heterogeneous antigen expression, including triple-negative breast cancer, non-small cell lung cancer, metastatic urothelial carcinoma, and HER2-low breast cancers that were previously ineligible for HER2-directed therapy.

Beyond simple payload delivery, a modern ADC is expected to do several jobs at once. The antibody component retains its natural immune functions, recruiting effector cells through antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC). Linker stability determines how much free drug leaks into circulation, which in turn drives systemic side effects such as neutropenia and interstitial lung disease. The review emphasizes that optimizing all three modules simultaneously, antigen selection, linker chemistry, and payload, is a multi-variable engineering problem rather than a linear design task, and that this complexity explains why clinically successful ADCs remain outnumbered by the many candidates that have failed in trials.

Clinically, ADCs have become an established option for patients who have exhausted traditional treatments or developed resistance to earlier lines of therapy. The review systematically walks through the FDA-approved agents in solid tumors, highlighting overall response rates (ORR) and the therapeutic niches each drug has carved out, from HER2-positive and HER2-low breast cancer to urothelial carcinoma and lung cancer, alongside applications in hematological malignancies. The picture that emerges is one of genuine clinical transformation: diseases once treated only with blunt cytotoxic chemotherapy now have therapies that combine molecular precision with lethal payload delivery. Yet the review is equally candid that efficacy is frequently incomplete, with many patients deriving only transient benefit before disease progression.

That incomplete benefit points to the review’s central concern: acquired drug resistance. Tumors are Evolving systems, and the review organizes the escape routes cancer cells take into several mechanistic categories. Changes in the target antigen itself, through downregulation, mutation, or loss of surface expression, can starve the ADC of its docking site. Alterations in the internalization and trafficking machinery prevent the conjugate from reaching the lysosomal compartments where the linker is meant to be cleaved. Upregulation of drug efflux pumps can expel released payloads before they act, a mechanism long familiar from conventional chemotherapy. And changes in the payload’s downstream vulnerabilities, such as modifications in the DNA damage response (DDR) pathways targeted by topoisomerase I inhibitors or alterations in glutathione peroxidase 4 (GPX4) linked to ferroptosis sensitivity, can blunt the lethal effect even after successful delivery.

Just as consequential, the review argues, is the tumor microenvironment (TME), the crowded ecosystem of stromal and immune cells that surrounds a malignancy. Cancer-associated fibroblasts (CAFs), including the adipose-derived subtype (adCAFs), can form physical and biochemical barriers that shield tumor cells from circulating antibody. Myeloid-derived suppressor cells (MDSCs) dampen the immune effector functions that the antibody arm of an ADC is meant to recruit. Poorly vascularized and hypoxic regions limit drug penetration deep into tumor masses, meaning that even a perfectly designed conjugate may only reach the outer shell of a lesion. The review frames these microenvironmental factors not as secondary details but as first-order determinants of whether an ADC works, and as targets for rational combination strategies.

On that front, the review surveys a growing arsenal of next-generation designs. Bispecific antibodies (BsAbs) can bind two antigens at once, improving tumor specificity and compensating for heterogeneous expression. Immune-stimulating antibody conjugates (ISACs) replace or augment the cytotoxic payload with immune agonists, converting the delivery platform into a vaccine-like stimulus. Degrader-antibody conjugates (DACs) piggyback on PROTAC technology, protein degradation targeting chimeras, to deliver molecular glues or degraders that eliminate intracellular oncoproteins previously considered undruggable. Dual-payload ADCs carry two mechanistically distinct toxins in one molecule, attacking multiple vulnerabilities simultaneously and complicating the tumor’s escape routes. Each of these platforms addresses a specific failure mode identified in the resistance analysis, reflecting a maturing, mechanism-driven design philosophy.

Combination therapy emerges as another major theme. Because ADC resistance often converges on pathways that other drug classes already target, the review explores rational pairings with tyrosine kinase inhibitors (TKIs), DNA damage response modulators, and immune checkpoint inhibitors (ICIs). The immunological logic is particularly attractive: ADC-induced tumor cell death releases antigens that can prime antitumor immune responses, while checkpoint blockade removes the brakes on the T cells that response activates. In hematological malignancies, the review also discusses ADC use in minimal residual disease (MRD) settings and around hematopoietic stem cell transplantation (HSCT), where their selectivity could help eradicate residual clones, though it notes the need to manage risks such as cytokine release syndrome (CRS) when ADCs are combined with other immune-directed agents.

The review closes with a sober but optimistic outlook. ADCs have already demonstrated, in the words of the clinical record, that precision-targeted cytotoxicity can rescue patients who have failed traditional treatment, and the pace of approvals across breast, lung, and urothelial cancers shows no sign of slowing. But the same analysis shows that the field’s future depends on solving the resistance puzzle at every level, from linker chemistry and bystander payload design to microenvironment remodeling and immune synergy. With the authors supported by Guangdong provincial and national Chinese research funding, the work consolidates a decade of clinical learning into a design manual for what may come next. If the next generation of conjugates delivers on the strategies outlined here, the guided missile metaphor may finally describe what these drugs actually do for the majority of patients, not just the fortunate few.

Subject of Research: Antibody-drug conjugate mechanisms, resistance, and next-generation strategies in cancer targeted therapy

Article Title: Antibody-drug conjugates: mechanism, progress and future directions of cancer targeted therapy

Article References: Li, M., Wu, G., Chen, B., Zheng, Z., Ning, X., Li, J., Zeng, D., Li, J., & Song, J. (2026). Antibody-drug conjugates: mechanism, progress and future directions of cancer targeted therapy. Molecular Cancer. https://doi.org/10.1186/s12943-026-02817-0

Image Credits: AI Generated

DOI: 10.1186/s12943-026-02817-0

Keywords: antibody-drug conjugates, targeted cancer therapy, drug resistance, monoclonal antibodies, cancer drug delivery, trastuzumab deruxtecan, tumor microenvironment, bispecific antibodies, immune checkpoint inhibitors, topoisomerase I inhibitors, triple-negative breast cancer, combination therapy

The central premise of the collection is that understanding lymphoma biology at the molecular level is the key to improving outcomes. Despite a decade of progress, low-grade lymphomas remain incurable with conventional approaches for most patients, and disease heterogeneity, therapeutic resistance, and relapse continue to frustrate clinicians. The six contributions, three focused on low-grade lymphomas and three on aggressive subtypes, share a common objective: deepening the mechanistic understanding of these cancers in ways that translate directly into individualized therapeutic interventions. The breadth of topics covered illustrates how many different layers of biology, from epigenetics to inflammation, must be understood before personalized treatment can become routine.

One of the most technically intriguing contributions is an original research article investigating dual targeting of EZH2 and PD-L1 in Burkitt’s lymphoma. EZH2 is a histone methyltransferase, an enzyme that chemically modifies histone proteins around which DNA is wound, thereby controlling which genes are accessible for transcription. In many B-cell malignancies, EZH2 activity is dysregulated, locking cells into abnormal gene-expression programs that promote survival and proliferation. PD-L1, meanwhile, is an immune checkpoint molecule that tumor cells display to suppress T-cell activity, effectively camouflaging the cancer from the immune system. The researchers demonstrated that inhibiting both targets simultaneously produces synergistic antitumor activity: apoptosis, or programmed cell death, increases within the tumor, while immune activation is restored. Although Burkitt lymphoma is an aggressive disease rather than a low-grade subtype, the underlying mechanism is broadly applicable across low-grade B-cell lymphomas. The findings lend strong support to the concept that epigenetic remodeling can enhance immune-mediated tumor elimination, providing a rationale for combining targeted epigenetic drugs with immunotherapy.

Waldenström macroglobulinemia, an indolent B-cell malignancy, serves as a striking example of how precision medicine is already changing clinical practice. A review article on relapsed or refractory disease summarizes how treatment selection increasingly depends on the molecular profile of the tumor, particularly mutations in MYD88 and CXCR4, two genes that drive signaling through the B-cell receptor pathway and related networks. Patients harboring different mutational patterns respond differently to available drugs, making genetic testing central to therapeutic planning. The review surveys an expanding armamentarium: next-generation Bruton tyrosine kinase inhibitors designed to improve on first-generation covalent BTK blockers, BCL2 inhibition that targets the anti-apoptotic machinery keeping lymphoma cells alive, CXCR4-targeted agents, bispecific antibodies that bridge immune cells to tumor cells, antibody-drug conjugates that deliver cytotoxic payloads selectively, and chimeric antigen receptor T-cell therapy. Beyond cataloguing these drugs, the authors emphasize individualized treatment selection, therapeutic sequencing, and biomarker-guided decision-making, reflecting the growing complexity of managing indolent B-cell cancers.

The clinical potential of innovative immunotherapy combinations is illustrated in a case report describing a patient with relapsed or refractory central nervous system lymphoma successfully treated with glofitamab combined with lenalidomide. Glofitamab is a CD20×CD3 bispecific antibody, a engineered molecule with one arm binding the CD20 protein on B cells and the other binding CD3 on T cells, physically bringing cytotoxic T lymphocytes into contact with malignant cells. Lenalidomide is an immunomodulatory agent that alters the tumor microenvironment and enhances immune function. Lymphoma relapsing in the central nervous system is particularly difficult to treat, as many drugs fail to cross the blood-brain barrier and intensive chemotherapy carries substantial toxicity. The favorable response observed, though based on limited clinical experience, demonstrates the promise of chemotherapy-free strategies that engage the immune system to achieve durable disease control while potentially sparing patients the burden of toxic regimens. The report provides valuable preliminary evidence supporting formal clinical evaluation of bispecific antibody-based combinations.

Treatment resistance remains one of the greatest barriers to successful targeted therapy, and a mini-review on kinase inhibitor resistance in subtypes of cutaneous T-cell lymphoma confronts this problem directly. Kinase inhibitors block specific signaling enzymes that lymphoma cells depend on, but tumors frequently find ways around them. The review describes how genetic mutations, activation of compensatory signaling pathways that bypass the blocked enzyme, epigenetic alterations that reprogram gene expression, and changes within the tumor microenvironment collectively contribute to therapeutic failure. The authors argue that understanding these resistance mechanisms is essential for designing rational combination therapies capable of restoring treatment sensitivity. Although focused on a T-cell malignancy, the concepts have broad relevance across lymphoma subtypes and underscore resistance biology as a critical frontier in precision hematology, where the sequence and combination of drugs must anticipate the escape routes available to the tumor.

Personalized medicine extends beyond treatment to diagnosis and clinical evaluation, as highlighted by an unusual case report of synchronous mucosa-associated lymphoid tissue lymphoma occurring in a married couple. MALT lymphoma arises in lymphoid tissue associated with mucosal surfaces and is often linked to chronic inflammation or infection. The simultaneous development of this rare lymphoma in spouses cannot establish causality, but it raises intriguing questions about shared environmental exposures, infectious agents, or other common risk factors that might contribute to lymphoma pathogenesis. The report also emphasizes the importance of comprehensive diagnostic assessment in atypical clinical presentations and demonstrates how rare observations can generate hypotheses that stimulate future biological and epidemiological research, a reminder that careful clinical documentation remains a source of scientific discovery.

Accurate prognostic assessment forms another essential pillar of personalized care. A study addressing grade 1–3a follicular lymphoma integrated the systemic immune-inflammation index, a blood-based measure derived from routine counts of immune cells that reflects the balance of systemic inflammation, with the established Follicular Lymphoma International Prognostic Index. The investigators proposed a novel combined model, FLIPI-SII, that improves prediction of POD24, meaning progression of disease within 24 months of treatment, as well as long-term survival. POD24 is a clinically meaningful milestone, because patients who progress early fare substantially worse and may benefit from different surveillance intensity or earlier therapeutic intervention. By demonstrating the value of combining host inflammatory biomarkers with established clinical prognostic factors, the study shows how cheap, widely available measures can refine risk stratification and individualize follow-up strategies without requiring expensive genomic testing in every patient.

Collectively, the six articles reveal overarching themes that are defining the future of lymphoma research. Molecular characterization is becoming fundamental to clinical decision-making, enabling therapies to be matched to specific biological alterations. Immunotherapy continues to expand beyond conventional monoclonal antibodies through immune checkpoint inhibitors, bispecific antibodies, immunomodulatory drugs, and cellular therapies. Understanding the biological mechanisms responsible for therapeutic resistance is essential for designing more durable treatment strategies. And advances in prognostic biomarkers and predictive models are improving clinicians’ ability to tailor both treatment and follow-up to patient-specific risk. Substantial challenges remain, however: many promising molecular targets require validation in prospective multicenter studies, and predictive biomarkers must demonstrate reproducibility across diverse patient populations before they can guide care.

The path forward will depend on continued collaboration between basic scientists, translational investigators, and clinicians, and on the integration of comprehensive molecular profiling, multi-omic technologies, artificial intelligence, and biomarker-driven clinical trial designs. As precision hematology continues to evolve, the identification of novel molecular targets, validated biomarkers, and effective combination therapies will be instrumental in achieving more durable responses and better outcomes for patients with low-grade non-Hodgkin lymphoma. What the Research Topic makes clear is that personalized treatment is no longer a distant aspiration but an emerging reality, built study by study, target by target, and patient by patient.

Subject of Research: Molecular targets and personalized therapy for low-grade non-Hodgkin lymphoma

Article Title: Editorial: New molecular targets for personalized treatment for low-grade non-hodgkin lymphoma

Article References: Visentin, A. (2026). Editorial: New molecular targets for personalized treatment for low-grade non-hodgkin lymphoma. Frontiers in Hematology, 5, Article 1959952. https://doi.org/10.3389/frhem.2026.1959952

Image Credits: AI Generated

DOI: 10.3389/frhem.2026.1959952

Keywords: low-grade non-Hodgkin lymphoma, precision medicine, EZH2, PD-L1, Waldenström macroglobulinemia, bispecific antibodies, glofitamab, MYD88, CXCR4, drug resistance, follicular lymphoma, prognostic biomarkers

The research, led by Anna Wec and colleagues, began with a large-scale search for new neutralizing antibodies. Using high-throughput screening approaches, the team isolated several antibody candidates from llamas, animals whose immune systems are well known in the biotechnology field for producing single-domain antibodies, sometimes called nanobodies, that are smaller and structurally distinct from conventional human antibodies. These llama-derived candidates showed the ability to neutralize two of the most immune-evasive Omicron subvariants identified to date, XBB.1.5 and JN.1, both of which carried dense clusters of spike mutations that had disabled most previously authorized antibody therapeutics. The identification of antibodies capable of recognizing these heavily mutated variants provided the raw material for a more ambitious engineering effort aimed at durability rather than just potency.

From these lead candidates, the researchers constructed bispecific antibodies, engineered molecules that combine the targeting regions of two different antibodies into a single therapeutic protein. The strategic logic behind bispecific design is straightforward: if a therapeutic antibody binds to two separate sites on the viral spike protein simultaneously, the virus must acquire mutations at both locations at once to escape neutralization. The probability of such a combined mutational event occurring without compromising the virus’s fitness is far lower than the probability of escape from a single-site antibody. In effect, bispecific antibodies raise the genetic barrier to resistance, forcing the virus into a corner where the mutations needed for escape come at a cost to its own replication or transmission. This principle has long been appreciated in antiviral drug design, where combination therapies have proven essential for controlling rapidly evolving pathogens such as HIV.

However, bispecific antibodies have historically been difficult and expensive to manufacture. Producing them requires co-expressing two different antibody chains in the same cell and ensuring they assemble correctly into the intended molecule, a process that generates manufacturing complexity and cost far exceeding that of conventional monoclonal antibodies. These burdens have slowed the clinical deployment of bispecific formats, particularly in infectious disease applications where large quantities of drug may be needed and where rapid response to emerging variants is essential. The new study addressed this bottleneck directly by introducing structural modifications that allow multiple bispecific antibodies to be delivered in tandem through a single mRNA construct, sidestepping much of the traditional manufacturing challenge.

The mRNA approach represents a conceptual inversion of how antibody therapies have traditionally been produced. Rather than manufacturing antibodies in bioreactors, purifying them, and infusing the finished proteins into patients, mRNA therapy delivers the genetic instructions for the antibodies in the form of messenger RNA. Once the mRNA enters cells, the patients’ own cellular machinery translates the genetic code and produces the therapeutic antibodies in situ, releasing them into the bloodstream. This platform proved its worth during the pandemic in the vaccine context, and its application to antibody delivery offers several advantages: the same lipid nanoparticle manufacturing process can be used for virtually any antibody sequence, new variants can be countered by simply updating the encoded sequence, and multiple antibody specificities can be packaged together in a single formulation.

A key technical hurdle in multiplexed mRNA delivery is ensuring that co-delivered antibody components do not interfere with one another. Antibody heavy chains and light chains from different specificities can mispair when expressed in the same cell, generating a mixture of nonfunctional or unpredictable molecules. The researchers solved this problem through what they describe as orthogonal Fc engineering, a set of structural modifications to the antibody constant region that ensures each antibody component assembles only with its intended partner. This orthogonal design principle, borrowed in spirit from genetic code expansion and synthetic biology, allows several distinct bispecific antibodies to be encoded and expressed simultaneously from a single mRNA dose without cross-reactivity, maximizing the breadth of viral coverage that can be achieved with one therapeutic product.

The performance of the engineered platform in laboratory testing was notable. In serum neutralization assays, the mRNA-encoded bispecific antibody cocktail neutralized a broad range of both historical and currently circulating SARS-CoV-2 variants, spanning the evolutionary distance from early pandemic isolates to the latest immune-evasive Omicron descendants. This breadth reflects the combined targeting of multiple conserved and semi-conserved epitopes on the spike protein, a coverage profile that no single conventional antibody has been able to achieve against this virus. In animal studies, the therapy protected mice against infection with the XBB.1.5 variant, providing direct evidence that the mRNA-delivered antibodies reach protective concentrations in vivo and function against a variant that has evaded nearly all previous antibody drugs.

Beyond the immediate application to COVID-19, the structural template established in this work has implications that extend across antiviral medicine and beyond. The authors note that the platform may have applications in other therapeutic areas in which broad antigen coverage, resistance to escape, or simultaneous engagement of multiple disease-associated targets is desirable. Rapidly mutating RNA viruses such as influenza, respiratory syncytial virus, and HIV all present the same fundamental challenge that SARS-CoV-2 has posed: the target is a moving one, and single-target therapeutics are quickly rendered obsolete. A modular platform in which new antibody combinations can be encoded, updated, and delivered via mRNA offers a path toward therapies that evolve in step with their targets, much as seasonal vaccine formulations are updated each year.

The convergence of llama-derived antibody discovery, bispecific engineering, orthogonal assembly design, and mRNA delivery in a single therapeutic platform illustrates how lessons from the pandemic era are being consolidated into next-generation tools. For immunocompromised patients who remain unable to benefit fully from vaccination, the prospect of a durable, broadly neutralizing, and rapidly updatable antibody therapy is clinically significant. While the results reported so far come from serum assays and mouse models, and human clinical testing would be required before any regulatory deployment, the study demonstrates that the escape problem that has plagued antibody therapeutics throughout the pandemic is not an unsolvable one. By designing therapeutics that constrain viral escape rather than merely reacting to it, researchers are shifting the strategic balance in the long-running contest between antiviral drugs and the pathogens they target, offering a template for keeping pace with viruses that refuse to stand still.

Subject of Research: mRNA-encoded bispecific antibody therapies engineered to neutralize SARS-CoV-2 variants and constrain viral escape

Article Title: A new generation of mRNA antibody therapies may tackle ever-evolving SARS-CoV-2 variants

Article References: A new generation of mRNA antibody therapies may tackle ever-evolving SARS-CoV-2 variants. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: SARS-CoV-2, mRNA therapy, bispecific antibodies, Omicron variants, viral escape, antibody engineering, llama nanobodies, Science Translational Medicine, immunocompromised patients, XBB.1.5, JN.1, antiviral therapeutics

The centerpiece of current clinical success is the immune checkpoint inhibitor class, particularly antibodies that block the programmed cell death protein 1 (PD-1) receptor and its ligand PD-L1. Under normal conditions, the PD-1 pathway acts as a molecular brake on T cells, preventing autoimmune damage; tumors exploit this brake by expressing PD-L1 to disable attacking lymphocytes. Landmark trials such as KEYNOTE-048 demonstrated that pembrolizumab, alone or with chemotherapy, could outperform the cetuximab-based EXTREME regimen as first-line treatment for recurrent or metastatic head and neck squamous cell carcinoma, while nivolumab showed survival benefits in the platinum-refractory setting. For oral squamous cell carcinoma (OSCC), the most common malignancy of the oral cavity, these agents have translated into meaningful survival extensions, and the review highlights that anti-PD-1 therapy is now firmly embedded in standard practice for recurrent and metastatic disease.

Perhaps the most consequential shift described in the review is the migration of immunotherapy from the late-stage setting into the perioperative arena. In locally advanced disease, where surgery and radiation remain the backbone of care, neoadjuvant checkpoint blockade given before surgery has produced remarkable pathological responses. A phase 2 randomized trial by Schoenfeld and colleagues showed that nivolumab, alone or combined with ipilimumab, could be safely administered to untreated oral cavity squamous cell carcinoma patients before resection. More recently, the KEYNOTE-689 trial of perioperative pembrolizumab in locally advanced head and neck cancer and the GORTEC 2018-01 NIVOPOST-OP phase 3 trial, which tested postoperative nivolumab added to cisplatin chemoradiotherapy in high-risk patients, have begun to define how checkpoint inhibition can be woven into curative-intent treatment. A randomized phase 2 trial from China further showed that neoadjuvant immunotherapy with or without chemotherapy improved outcomes in locally advanced OSCC, suggesting that earlier immune intervention may prevent micrometastatic seeding and reduce relapse.

Yet the biology of the tumor microenvironment (TME) imposes hard limits on these gains. The review devotes substantial attention to the immunosuppressive ecosystem that OSCC builds around itself. Regulatory T cells, which express CD25 and the transcription factor FoxP3, accumulate in the blood and tumors of OSCC patients and actively suppress antitumor immunity. Myeloid-derived suppressor cells, identified by markers such as CD11b, contribute to malignant progression and correlate with poor prognosis. Tumor-associated macrophages, particularly the CD163-positive M2-like subset, are associated with lymphangiogenesis, lymph node metastasis, and cancer stem cell maintenance. Each of these cell populations represents both a mechanism of immune evasion and a potential therapeutic target.

Cancer-associated fibroblasts (CAFs) add another layer of resistance. These stromal cells remodel the extracellular matrix into a dense, often hypoxic scaffold that physically excludes cytotoxic T cells from tumor nests, a phenomenon the review describes as immune exclusion. Hypoxia, driven in part by hypoxia-inducible factors HIF-1α and HIF-2α, further promotes angiogenesis, metabolic reprogramming, and chemo-resistance, and meta-analyses have linked HIF-1α overexpression to worse survival in OSCC. Altered extracellular matrix composition has been shown to correlate with an immunosuppressive microenvironment and disease progression, particularly in younger patients. The practical consequence is that even when checkpoint inhibitors release the brakes on T cells, those cells may never reach their targets in sufficient numbers, explaining why response rates in unselected OSCC populations remain modest.

Beyond checkpoint blockade, the review catalogs a wave of emerging modalities now under active investigation. Near-infrared photoimmunotherapy (NIR-PIT) conjugates an antibody, typically against EGFR, to a photoabsorbing dye; when activated by near-infrared light, the conjugate induces rapid and selective necrosis of targeted tumor cells while sparing adjacent normal tissue. Phase 1 and 2 studies of RM-1929 photoimmunotherapy in recurrent head and neck squamous cell carcinoma have demonstrated encouraging local control. Bispecific antibodies (BsAbs), engineered molecules that simultaneously bind a tumor antigen and an immune cell receptor, are another fast-moving area. Petosemtamab, an IgG1 bispecific targeting EGFR and LGR5, has shown clinical activity in advanced head and neck cancer, and cadonilimab, a PD-1/CTLA-4 bispecific, is being tested with neoadjuvant chemotherapy in locally advanced disease. Oncolytic viruses, which infect and lyse tumor cells while releasing antigens that prime systemic immunity, have been combined with pembrolizumab in the MASTERKEY-232 study using talimogene laherparepvec.

Adoptive cell therapies represent the most technologically ambitious frontier. Tumor-infiltrating lymphocyte (TIL) therapy, which involves harvesting, expanding, and reinfusing a patient’s own tumor-reactive T cells, has already earned accelerated FDA approval for melanoma as lifileucel, and a 2025 report in the Journal for ImmunoTherapy of Cancer described efficacy and safety of one-time autologous TIL therapy in recurrent or metastatic head and neck squamous cell carcinoma. Chimeric antigen receptor (CAR) T and CAR-NK cells, genetically engineered to recognize surface antigens such as ErbB family receptors, MUC1, and CD276, have shown preclinical activity against oral tongue squamous cell carcinoma, and an intratumoral pan-ErbB targeted CAR-T study (T4 immunotherapy) has reported interim results in head and neck cancer. T cell receptor (TCR)-engineered T cells targeting viral antigens such as HPV-16 E6 and E7 have produced complete tumor regressions in metastatic HPV-associated epithelial cancers, while neoantigen-specific and cancer-testis antigen targets like MAGE-C2 are being explored for HPV-negative tumors, which dominate the oral cavity.

The obstacles, however, are formidable. The review identifies tumor heterogeneity, inadequate immune cell trafficking, antigen escape, and manufacturing complexity as the principal barriers to durable responses. Solid tumors like OSCC present a hostile terrain for engineered cells, and antigen loss following CAR-T therapy can render treated tumors invisible to the infused product. The lack of reliable predictive biomarkers remains perhaps the most clinically frustrating gap: PD-L1 expression, tumor-infiltrating lymphocyte density, and HPV status all provide hints, but none reliably forecasts which patient will benefit. Notably, HPV-positive tumors tend to harbor inflamed immune microenvironments and respond better to anti-PD-1 therapy, whereas most oral cavity cancers are HPV-negative and immunologically cold. Combination strategies, from checkpoint inhibitors paired with radiotherapy, which can release tumor antigens and inflame the microenvironment, to dual durvalumab and tremelimumab in the DUTRELASCO neoadjuvant study, are being pursued precisely to convert cold tumors into hot ones.

The authors conclude that future progress will depend on biomarker-guided patient selection, rational combination regimens, and engineered cellular therapies capable of overcoming microenvironment-mediated resistance. Cytokine-based approaches are also re-emerging: the IRX-2 natural cytokine biologic completed the INSPIRE trial as neoadjuvant therapy for resectable oral cavity carcinoma and is being combined with durvalumab in recurrent disease. As the field moves toward personalized, multimodal immunotherapy, the message of this comprehensive synthesis is clear: the immune system can be mobilized against oral cavity tumors, but doing so reliably will require dismantling the tumor’s protective ecosystem as systematically as the first generation of immunotherapy dismantled its molecular brakes. For patients with a disease whose five-year survival has barely budged in decades, that systematic dismantling may finally change the trajectory.

Subject of Research: Immunotherapy strategies and tumor microenvironment resistance mechanisms in oral squamous cell carcinoma

Article Title: Immunotherapy for oral cavity tumors: recent advances, key challenges, and future perspectives

Article References: Sharipova, G., Amonov, S., Kim, A., Kenjayev, S., Masharipova, N., Maxkamov, Z., Shaniyazov, S., & Alimova, Z. (2026). Immunotherapy for oral cavity tumors: recent advances, key challenges, and future perspectives. Molecular Biology Reports, 53(1), Article 1718. https://doi.org/10.1007/s11033-026-12906-4

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12906-4

Keywords: oral squamous cell carcinoma, immunotherapy, immune checkpoint inhibitors, PD-1, tumor microenvironment, CAR-T cells, tumor-infiltrating lymphocytes, bispecific antibodies, oncolytic viruses, neoadjuvant immunotherapy, cancer-associated fibroblasts, hypoxia

The rationale for these platforms stems from the many ways tumors evade immune surveillance. Cancer cells overexpress PD-L1 to suppress T cell activation, downregulate MHC class I to escape T cell receptor-mediated recognition, and display so-called don’t eat me signals such as CD47 and CD24 that bind SIRPα and Siglec-10 on macrophages and block phagocytosis. The tumor microenvironment compounds these defenses through hypoxia and dense extracellular matrix deposition that restrict immune infiltration. Immune checkpoint inhibitors such as ipilimumab and pembrolizumab have transformed treatment by blocking inhibitory signals, but they do not directly coordinate the membrane-level contact between immune cells and cancer cells that is required for lytic granule polarization and immune synapse formation. ICEs were conceived to fill precisely this gap.

At the mechanistic level, ICEs share a common structural principle: an immune cell-binding domain and a tumor-targeting domain integrated within a single construct. Yet physical proximity alone does not guarantee a productive synapse. In T cells, engager-mediated CD3 signaling must be coordinated with adhesion through LFA-1 and ICAM-1 interactions, TCR microcluster organization, F-actin remodeling, and polarization of the microtubule organizing center and lytic granules toward the target cell, culminating in polarized perforin and granzyme release. After target killing, synapse disassembly allows serial killing of subsequent targets. NK cells use similar downstream cytolytic machinery but regulate it through the balance of activating receptors, including CD16, NKp30, NKp44, NKp46, and NKG2D, against inhibitory receptors such as KIRs and NKG2A. Macrophage engagers instead drive an actin-rich phagocytic cup that engulfs and internalizes the tumor cell.

Engineered antibodies dominate the clinically established side of the field. Twelve CD3-engaging T cell engagers have now been approved by the FDA or European Medicines Agency, beginning with blinatumomab for CD19-positive B-cell acute lymphoblastic leukemia in 2014 and extending through CD20-directed agents for lymphoma, BCMA- and GPRC5D-directed agents for multiple myeloma, the TCR-based tebentafusp for uveal melanoma, tarlatamab for small cell lung cancer, and catumaxomab for EpCAM-positive malignant ascites. These approvals demonstrate that T cell redirection has moved from proof-of-concept hematologic applications into selected solid tumor settings, although antigen heterogeneity, limited T cell infiltration, and toxicity remain formidable obstacles.

Next-generation multispecific T cell engagers are addressing those limitations by adding functional modules to a single scaffold. MK-6070 targets DLL3, CD3, and serum albumin for half-life extension, while ISB 2001 and ramantamig co-target two myeloma antigens alongside CD3 to counter antigen escape, with early clinical results showing encouraging response rates and manageable toxicity. Tetraspecific formats push further: MP0533 recognizes a combinatorial antigen pattern of CD33, CD123, and CD70 in acute myeloid leukemia, and GNC-038 combines CD19 and PD-L1 targeting with CD3 engagement and 4-1BB costimulation. These designs illustrate that additional binding domains are being assigned defined jobs, from pharmacokinetic tuning to checkpoint neutralization, rather than merely increasing molecular complexity.

NK cell engagers are advancing rapidly behind them. CD16-targeting bispecific killer cell engagers have redirected NK cells against EpCAM-positive carcinomas, CD133-positive colorectal cancer, and CD33-positive AML, while the tetravalent CD30/CD16A TandAb, developed as AFM13, showed that avidity-enhanced formats retain tumor binding far better than monovalent counterparts. NKp30- and NKp46-directed engagers exploit natural cytotoxicity receptors, and NKG2D-based constructs recruit multiple cytotoxic lymphocyte populations at once because the receptor is shared by NK cells, CD8-positive T cells, γδ T cells, and NKT cells. Cytokine-armed TriKEs embed IL-15 directly into the engager to support NK cell expansion and persistence, and tetraspecific formats such as IPH6501 combine CD20 targeting, NKp46 and CD16A engagement, and an IL-2 variant in one molecule. Phagocytic cell engagers, meanwhile, pursue a distinct endpoint: macrophage-mediated engulfment, driven either by activating receptors such as CD89 or by tumor-localized blockade of the CD47-SIRPα checkpoint.

Beyond antibodies, aptamers offer a chemically programmable alternative. These short single-stranded DNA or RNA oligonucleotides, at 5 to 50 kilodaltons far smaller than antibodies, can be synthesized with high reproducibility and assembled into bispecific bridges classified by an m-plus-n valency scheme. A [1+1] aptamer targeting c-Met and CD16a redirected NK cells against tumor cells, with linker length proving critical: linkers of roughly 49 to 154 angstroms supported cytotoxicity while a 200-angstrom linker markedly reduced it. Circularized CD16/PD-L1 aptamers simultaneously recruit NK cells and block checkpoint suppression, [1+2] conjugates deliver 4-1BB costimulation selectively to PSMA-positive or stromal tumor sites without systemic toxicity, and newer aptamer-drug conjugates integrate immune recruitment with localized chemotherapy delivery.

Living cell engagers represent a striking biomaterial-based extension of the concept. Rather than injecting soluble molecules that largely fail to reach tumors, researchers install targeting ligands directly onto immune cell membranes ex vivo. Lipid-PEG conjugates bearing hyaluronic acid anchor into NK cell membranes through hydrophobic insertion and confer CD44-mediated recognition of pancreatic and breast cancer cells, and systematic optimization showed that DSPE anchors, intermediate PEG spacer lengths, and tuned ligand density each determine whether engineered contacts become signaling-competent synapses. Dual-ligand designs display both hyaluronic acid and phenylboronic acid to target heterogeneous tumors, antibody-capturing lipid anchors allow NK cells to be redirected with any chosen therapeutic antibody, and fusogenic liposomes can even remodel tumor cell glycans to make them more visible to NK cells. Metabolic glycoengineering with azide sugars and strain-promoted click chemistry provides covalent, more durable attachment of nanobodies and glycopolymers to NK and T cell surfaces.

Nanoparticle platforms add a third dimension by organizing multiple functions within a single nanoscale scaffold. Solid nanoparticles carrying anti-PD-L1 and anti-4-1BB antibodies have acted as immuno-switch particles that block checkpoint signaling while delivering costimulation, and trispecific nano-antibodies co-presenting anti-PD-L1, anti-4-1BB, and anti-NKG2A on albumin-polyester particles promoted infiltration of both NK and CD8-positive T cells and improved survival. Protein cage nanodrones bridge NK cells to HER2- or EGFR-positive tumors, PEG-PLGA nanoengagers combine NK cell bridging with encapsulated epirubicin, and macrophage-directed particles couple checkpoint blockade with STING agonist delivery. Liposomal engagers, including nanoBiTEs and TRAFsomes displaying defined copy numbers of anti-CD3 and tumor-targeting fragments, extend these principles with biomimetic membrane architecture and favorable circulation half-lives of roughly 50 to 60 hours.

Significant challenges remain before these platforms reach their full potential. Antibody-based engagers risk cytokine release syndrome, neurotoxicity, and antigen escape; aptamers face nuclease degradation and rapid clearance; living cell engagers must control ligand shedding and preserve cell phenotype; and nanoparticles contend with protein corona formation and clearance by the mononuclear phagocyte system. The review also highlights a translational gap: standardized criteria for defining a functionally productive immune synapse in potency testing have not yet been established, even though quantitative imaging of receptor clustering, F-actin accumulation, granule polarization, and serial killing is technically feasible. The authors argue that next-generation ICEs must move beyond simply increasing immune cell recruitment toward precise control over where, when, and to what extent immune activation occurs. If molecular engineering, immunology, and biomaterials science continue to converge, immune cell engagers could evolve from structurally diverse constructs into precisely controlled therapeutic systems that translate tumor recognition into effective, adaptable antitumor immunity.

Subject of Research: Engineering of immune cell engager platforms, including antibodies, aptamers, cell surface engineering, and nanoparticles, for cancer immunotherapy

Article Title: Engineering immune cell engagers: From molecular constructs to biomaterial platforms

Article References: Park, H. W., & Kim, S. (2026). Engineering immune cell engagers: From molecular constructs to biomaterial platforms. Materials Today Bio, 41, Article 103737. https://doi.org/10.1016/j.mtbio.2026.103737

Image Credits: AI Generated

DOI: 10.1016/j.mtbio.2026.103737

Keywords: immune cell engagers, bispecific antibodies, T cell engagers, NK cell engagers, macrophage engagers, aptamers, cell surface engineering, nanoparticles, cancer immunotherapy, immune synapse, checkpoint blockade, biomaterials

The structural logic of an antibody–drug conjugate explains why its immunological reach is broad. Each molecule combines a monoclonal antibody that recognises a tumour-associated antigen, a cleavable or non-cleavable linker and a cytotoxic payload, typically a tubulin-disrupting agent or a DNA-damaging topoisomerase I inhibitor. When the conjugate binds its target and is internalised, the payload is released inside the cancer cell. But the story does not end there. Many payloads, particularly those with membrane-permeable chemistry, diffuse out of the killed cell and kill neighbouring tumour cells regardless of antigen expression, a phenomenon known as bystander killing. That same permeability allows released drug to affect stromal and immune cells within the tumour, setting the stage for immune consequences that were largely unappreciated in the earliest clinical studies.

Central to the new paradigm is the concept of immunogenic cell death. Unlike silent apoptosis, immunogenic cell death releases damage-associated molecular patterns and tumour-associated antigens in a context that alerts the immune system. Preclinical work summarised in the review shows that maytansine-bearing conjugates induce hallmarks of immunogenic cell death selectively in antigen-positive cells, that brentuximab vedotin-driven microtubule disruption triggers endoplasmic reticulum stress leading to immunogenic cell death, and that trastuzumab deruxtecan activates the cGAS-STING pathway in gastric cancer models, upregulating HLA class I molecules and the chemokines CXCL9, CXCL10 and CXCL11. Datopotamab deruxtecan has likewise been shown to induce hallmarks of immunogenic cell death. The released antigens can then be taken up by dendritic cells, which mature and cross-present them to T cells, seeding a sustained adaptive antitumour response.

The antibody component contributes its own immunological layer. Fc-mediated functions such as antibody-dependent cell-mediated cytotoxicity and antibody-dependent cellular phagocytosis recruit natural killer cells and macrophages to destroy antibody-coated tumour cells. Tumour-associated macrophages can, in fact, contribute to antitumour activity through Fcγ receptor-mediated processing of antibody–drug conjugates, effectively acting as payload-delivery and antigen-release amplifiers. The choice of IgG subclass, glycosylation pattern and Fc engineering therefore has functional consequences: afucosylated antibodies augment CD16-mediated serial killing and interferon-γ secretion by natural killer cells, while Fc-silencing platforms can be used when effector engagement is undesirable. These design decisions determine whether a given conjugate behaves as a silent cytotoxic or as an active recruiter of innate immunity.

This biological foundation underpins the explosive clinical interest in combining antibody–drug conjugates with immune checkpoint inhibitors. The rationale is complementary: the conjugate converts an immunologically cold tumour into an inflamed one by releasing antigens and provoking dendritic cell activation, while checkpoint blockade removes the brakes on the T cells that are thereby primed. The most striking validation has come in urothelial cancer, where the combination of enfortumab vedotin with pembrolizumab produced practice-changing survival benefits in previously untreated metastatic disease, reshaping first-line standards of care. Perioperative studies of the same pairing have now reported positive results in bladder cancer, extending the strategy into earlier disease settings.

However, the review is careful to note that efficacy is not universal. In HER2-positive breast cancer, the phase 2 KATE2 trial of trastuzumab emtansine with atezolizumab did not meet its primary endpoint, and the phase 3 ASTEFANIA adjuvant trial of the same combination has not established the pairing in residual disease. By contrast, datopotamab deruxtecan plus durvalumab has shown encouraging activity in triple-negative breast cancer in the BEGONIA platform trial, including in first-line disease, and sacituzumab govitecan plus pembrolizumab outperformed chemotherapy plus pembrolizumab in PD-L1-positive metastatic triple-negative breast cancer in the randomised phase 3 ASCENT-04 study. Biomarker analyses from ASCENT-04 are now being used to understand which patients benefit, and the authors emphasise that biomarker-informed development will probably be required to avoid empiric, one-size-fits-all combination strategies.

Lung, gastric and other tumour types are also being tested. Trastuzumab deruxtecan has been combined with nivolumab and with pembrolizumab in phase 1b studies of HER2-expressing breast and urothelial cancers, and datopotamab deruxtecan plus pembrolizumab with or without platinum chemotherapy has been evaluated in first-line non-small cell lung cancer in the TROPION-Lung02 trial. In gastric and gastroesophageal cancers, DESTINY-Gastric03 is exploring trastuzumab deruxtecan-based doublets and triplets including pembrolizumab. Disitamab vedotin plus toripalimab has produced positive phase 3 results in HER2-expressing urothelial cancer, and tisotumab vedotin combinations are under study in cervical cancer. The breadth of these programmes reflects a shared hypothesis: that payload-driven immune priming can convert checkpoint-refractory or checkpoint-naive tumours into responsive ones.

The next generation of conjugate design is shifting explicitly towards immune-oriented engineering. Bispecific constructs that bind two antigens, such as the EGFR–HER3 bispecific antibody–drug conjugate BL-B01D1 and izalontamab brengitecan, have shown clinical activity and, in some settings, phase 3 superiority over chemotherapy. Dual-targeting designs can also improve lysosomal trafficking and payload delivery, as demonstrated by conjugates targeting HER2 together with CD63. Immune-stimulating antibody conjugates represent another frontier: molecules such as BDC-1001, which couples a HER2-directed antibody to TLR7/8 agonists, and XMT-2056, a STING-agonist conjugate, are designed to deliver innate immune activation directly to the tumour. Probody technology, in which the antibody is masked until cleaved by tumour proteases, aims to widen the therapeutic window, and high-avidity, low-affinity antibody engineering can auto-tune delivery across heterogeneous antigen expression.

Targeting the tumour microenvironment itself is emerging as a complementary strategy. Conjugates directed at fibroblast activation protein can deplete cancer-associated fibroblasts that maintain an immunosuppressive stroma, while agents targeting B7-H3, B7-H4 and even PD-L1 itself repurpose immune checkpoint molecules as delivery portals, potentially killing checkpoint-ligand-expressing cells and simultaneously relieving immunosuppression. Novel payload classes are also in play, including splicing modulators with intrinsic immune-stimulatory properties and immunosuppressive payloads that could theoretically be used to dampen harmful inflammation. The review also highlights TCR-mimic antibody–drug conjugates capable of targeting intracellular oncoproteins such as WT1 and MART-1 through peptide–MHC complexes, dramatically expanding the pool of druggable targets beyond surface antigens.

Safety considerations temper the enthusiasm. The same immune mechanisms that enhance efficacy can contribute to toxicity, and the interstitial pneumonitis associated with trastuzumab deruxtecan has been linked in preclinical work to perivascular niche–resident alveolar macrophages, suggesting an immune-mediated component. Fcγ receptor-dependent internalisation of conjugate aggregates can drive off-target cytotoxicity, and immune complex clearance mechanisms help explain some adverse events. A companion review in the same journal addresses the clinical toxicity of antibody–drug conjugates and their combinations with checkpoint inhibitors. The overall message from the Milan-based and Chapel Hill-based team is that antibody–drug conjugates should no longer be viewed merely as targeted cytotoxics but as modulators of tumour–immune interactions, a repositioning that will shape monotherapy use, combination regimens and drug design for years to come.

Subject of Research: Immunological mechanisms of action of antibody–drug conjugates and their combination with immune checkpoint inhibitors in cancer therapy

Article Title: Exploring the immunological effects of antibody–drug conjugates

Article References: Zagami, P., Trapani, D., Marra, A., Carey, L. A., & Curigliano, G. (2026). Exploring the immunological effects of antibody–drug conjugates. Nature Reviews Clinical Oncology. https://doi.org/10.1038/s41571-026-01209-z

Image Credits: AI Generated

DOI: 10.1038/s41571-026-01209-z

Keywords: antibody–drug conjugates, immunogenic cell death, immune checkpoint inhibitors, tumour microenvironment, dendritic cells, antibody-dependent cellular cytotoxicity, trastuzumab deruxtecan, enfortumab vedotin, bispecific antibodies, cGAS-STING pathway, breast cancer, urothelial cancer

The starting point for this transformation is a sober clinical reality. Although most patients with marginal zone lymphoma experience favorable outcomes, approximately twenty percent relapse or progress early, within twenty-four months of initial treatment. That minority represents the central unsolved problem in the field. For these patients, the disease often reveals a more aggressive biology than its indolent label suggests, and the therapeutic options available after frontline therapy have historically been limited. It is precisely this population that the new generation of targeted and immune-based therapies aims to serve, and the review places their needs at the center of its analysis.

What has made precision medicine possible in this disease is the accumulation of detailed molecular profiling. The authors describe recurrent alterations in three major signaling axes: the B-cell receptor pathway, the NF-κB pathway, and NOTCH signaling. These are not random findings. Chronic antigen drive through the B-cell receptor, constitutive activation of NF-κB-dependent survival programs, and dysregulated NOTCH signaling together form the wiring diagram of the malignant marginal zone B cell. Layered on top of these are epigenetic changes that alter gene expression without changing the underlying DNA sequence, as well as abnormalities in the immune microenvironment that surrounds and supports the tumor. Each of these layers offers a potential point of therapeutic intervention, and each has spawned a corresponding class of drugs now in clinical evaluation.

Among the targeted agents, the strongest clinical evidence belongs to Bruton tyrosine kinase inhibitors, known as BTK inhibitors. BTK is a signaling molecule essential to B-cell receptor function, and blocking it effectively starves the malignant cell of one of its principal survival signals. In relapsed or refractory marginal zone lymphoma, these agents have produced durable responses and have become a cornerstone of second-line and later therapy. The review emphasizes, however, that their use is not without complications. First-generation BTK inhibitors carry risks of atrial arrhythmias, bleeding, and hypertension, and resistance can emerge through mutations in BTK itself or in downstream signaling components. Newer, more selective inhibitors aim to retain efficacy while narrowing the toxicity profile, and the choice of agent increasingly depends on patient comorbidities and treatment goals.

Beyond BTK inhibition, the review surveys two additional classes of small-molecule targeted therapy. BCL-2 inhibitors exploit a different vulnerability: the overexpression of an anti-apoptotic protein that allows lymphoma cells to evade programmed cell death. By releasing the mitochondrial brake on apoptosis, these agents can trigger tumor cell death directly, and they have been evaluated across B-cell malignancies with growing interest in marginal zone lymphoma. PI3K inhibitors, meanwhile, target a lipid kinase downstream of the B-cell receptor that promotes cell survival, proliferation, and trafficking. Their clinical history in indolent lymphomas has been complicated by immune-mediated toxicities, including colitis and pneumonitis, which has prompted closer regulatory scrutiny and a more careful approach to patient selection. The review stresses that efficacy must always be weighed against these safety considerations, particularly in an indolent disease where patients may live with treatment consequences for decades.

Monoclonal antibodies remain a foundational element of the therapeutic arsenal, and the review highlights how this class continues to evolve. Antibodies directed against CD20 have long formed the backbone of frontline treatment, and novel antibodies with enhanced immune-recruiting properties are extending this approach. Antibody-drug conjugates represent a further refinement, coupling the targeting specificity of an antibody to a potent cytotoxic payload that is released only after the drug reaches the tumor cell. This design concentrates chemotherapy’s killing power where it is needed while limiting collateral damage to healthy tissue. The result is a class of agents that blurs the traditional line between targeted therapy and cytotoxic treatment, offering a middle path with distinct pharmacological logic.

Perhaps the most striking advances described in the review lie in the realm of immune-based therapeutics. Bispecific antibodies are engineered molecules capable of binding two targets simultaneously: one arm attaches to a marker on the malignant B cell, while the other engages CD3 on T cells, physically bridging the two and forcing the immune system to attack the tumor. These off-the-shelf agents have demonstrated impressive activity in other indolent lymphomas and are being evaluated in marginal zone lymphoma across treatment settings. Chimeric antigen receptor T-cell therapy, or CAR-T, takes a different route to the same goal. A patient’s own T cells are harvested, genetically engineered to recognize a B-cell antigen such as CD19, expanded in the laboratory, and reinfused. The engineered cells then hunt down and destroy lymphoma cells throughout the body. For patients whose disease has failed multiple prior lines of therapy, these cellular and bispecific approaches have opened doors that simply did not exist a decade ago.

The review is careful to frame these advances within their limitations. Clinical evidence for several of the newer modalities in marginal zone lymphoma specifically remains less mature than in other B-cell malignancies, and the heterogeneity of the disease itself complicates interpretation. Marginal zone lymphoma encompasses distinct subtypes arising in different anatomical sites, from the stomach to the spleen to the lymph nodes, each with its own biology and treatment considerations. Extrapolating results from one subtype or from related lymphomas carries genuine uncertainty. The authors also emphasize the importance of biomarkers: molecular alterations identified at diagnosis or relapse may eventually guide which patients benefit from which agents, but validated predictive markers remain an aspiration rather than a routine clinical reality for many of these drugs.

Questions of treatment sequencing loom large over the entire field. With BTK inhibitors, BCL-2 inhibitors, PI3K inhibitors, antibody-based approaches, bispecifics, and CAR-T all now available or in development, clinicians face an increasingly complex decision tree. Should a novel targeted agent be deployed at first relapse, or should conventional therapy be exhausted first? Can immune-based approaches such as bispecific antibodies or CAR-T be moved earlier in the disease course, where patients may be fitter and more likely to tolerate them? How should resistance to one class of agent influence the choice of the next? The review addresses these questions directly, arguing that rational sequencing, informed by molecular profiling and by the toxicity profiles of successive therapies, will be essential to maximizing the benefit each approach can deliver over a patient’s lifetime.

What emerges from this comprehensive synthesis is a portrait of a disease in transition. Marginal zone lymphoma, once treated with a relatively blunt toolkit, is becoming a testing ground for the full breadth of modern cancer therapeutics, from kinase inhibitors that rewire intracellular signaling to engineered immune cells that patrol the body seeking malignant targets. The molecular alterations that drive the disease, in B-cell receptor, NF-κB, and NOTCH pathways, in the epigenome, and in the tumor microenvironment, are no longer merely descriptive findings; they are the blueprint for drug development. For the majority of patients who do well with current therapy, these advances promise more tailored and less toxic options when treatment is needed. For the twenty percent who relapse early, they represent something more consequential: a genuine expansion of hope, grounded in a deeper understanding of what keeps their cancer alive and how to take it apart.

Subject of Research: Targeted and immunotherapeutic strategies for marginal zone lymphoma

Article Title: Emerging frontiers in targeted and immunotherapeutic strategies for marginal zone lymphoma

Article References: Wang, X., Xiong, Q., Zhou, Y., Yu, M., & Li, F. (2026). Emerging frontiers in targeted and immunotherapeutic strategies for marginal zone lymphoma. Annals of Hematology. https://doi.org/10.1007/s00277-026-07288-3

Image Credits: AI Generated

DOI: 10.1007/s00277-026-07288-3

Keywords: marginal zone lymphoma, BTK inhibitors, BCL-2 inhibitors, PI3K inhibitors, bispecific antibodies, CAR-T therapy, immunotherapy, targeted therapy, NF-κB signaling, NOTCH signaling, B-cell lymphoma, antibody-drug conjugates