The review, led by Kexun Li, Zilong Qian and Jie Mao with senior authors Yongtao Han and Xuefeng Leng, synthesises evidence across the major gastrointestinal malignancies: gastric and esophageal cancers, colorectal cancer, pancreatic ductal adenocarcinoma, hepatocellular carcinoma and biliary tract cancers. Its central claim is that the tumour secretome, the full complement of proteins released by tumour cells, stromal cells and immune cells into the extracellular space, functions as a dynamic signalling layer that determines whether immune cells are recruited to the tumour, whether they penetrate it, whether they function once they arrive, and whether they exhaust themselves in the struggle. When checkpoint blockade releases the brakes on T cells, the success of that manoeuvre depends on the state of the road ahead, and the secretome largely builds that road.

The authors catalogue an imposing roster of recurrent suppressive circuits. Transforming growth factor beta, long implicated in immune exclusion and fibroblast activation, appears across nearly every gastrointestinal tumour type as a driver of stromal barriers that physically wall off cytotoxic lymphocytes. Vascular endothelial growth factor, best known for promoting the chaotic, leaky vasculature of tumours, also actively repels T-cell infiltration and fosters immunosuppressive myeloid cells. The chemokine CXCL12, acting through its receptor CXCR4, excludes T cells from tumour nests in pancreatic and colorectal cancers, while CXCL8, also known as interleukin-8, signalling through CXCR1 and CXCR2, attracts neutrophils and suppresses T-cell function. The CCL2-CCR2 axis recruits inflammatory monocytes that can differentiate into tumour-promoting macrophages, and the CSF1-CSF1R pathway sustains those macrophages in a suppressive, pro-tumour state.

Beyond these canonical axes, the review highlights a second tier of secreted mediators whose roles have crystallised more recently. Interleukin-6 family cytokines drive chronic inflammatory programmes that blunt antitumour immunity and correlate with poor outcomes. SPP1, the gene encoding osteopontin, marks a distinctive population of tumour-associated macrophages and fibroblasts that sculpt an immunosuppressive niche. Periostin, secreted largely by cancer-associated fibroblasts, reinforces extracellular matrix barriers and promotes metastatic colonisation. Galectins, a family of beta-galactoside-binding lectins, can directly induce T-cell apoptosis and dysfunction. DKK1, a Wnt pathway antagonist, contributes to immune exclusion and stemness. Macrophage migration inhibitory factor, or MIF, sustains inflammatory suppression, while components of the complement cascade, traditionally viewed as blood-borne effectors of innate immunity, have been co-opted by tumours to remodel the microenvironment in their favour. Finally, soluble forms of PD-L1 and PD-L1 carried on extracellular vesicles circulate through the bloodstream, potentially mopping up therapeutic antibodies and dampening T-cell activity far from the tumour itself.

Against this suppressive chorus, the review sets out the secretome signatures of immune-permissive tumours. The chemokines CXCL9, CXCL10 and CXCL11, signalling through the receptor CXCR3, recruit effector T cells expressing that receptor, and their abundance consistently correlates with T-cell infiltration and responsiveness to checkpoint blockade. Even more striking is CXCL13, the chemokine that draws B cells and organises tertiary lymphoid structures, ectopic lymph-node-like aggregates that form within tumour tissue. Tumours rich in tertiary lymphoid structures, particularly in colorectal and gastric cancer, respond to immunotherapy at markedly higher rates, and CXCL13-associated signalling appears to be a key driver of their formation. The secretome, in other words, is not uniformly hostile; it can be reprogrammed toward a state that amplifies the effect of checkpoint inhibitors once stromal and myeloid barriers are relieved.

To bring analytical order to this complexity, the authors organise the suppressive and permissive circuits into four overlapping functional modules. The myeloid-enriched module encompasses the chemokines and colony-stimulating factors that flood tumours with suppressive macrophages, monocytes and granulocytes. The fibroblast-driven exclusion module centres on TGF-beta, periostin and matrix-remodelling signals that build physical and biochemical barriers to immune infiltration. The angiogenic-immunosuppressive module couples VEGF-driven vascular dysfunction to myeloid suppression and hypoxia. The immune-permissive module, by contrast, comprises the CXCR3 ligand axis and CXCL13-driven tertiary lymphoid structure programmes that characterise tumours primed for immunotherapy response. This modular framework allows clinicians and researchers to describe a tumour’s secretome state not as an undifferentiated list of molecules but as a pattern of dominant biological programmes with distinct therapeutic implications.

Perhaps the review’s most consequential methodological contribution is its insistence on a four-level evidence hierarchy that separates clinical validation from mechanistic inference. Many secreted proteins have been convincingly shown in cell culture and animal models to suppress or promote antitumour immunity, yet only a subset has been validated as predictive or prognostic biomarkers in large clinical cohorts, and fewer still have been targeted successfully in combination trials. TGF-beta, for example, has mechanistic support at every level, and signatures of TGF-beta-driven fibroblast activity have been shown to predict poor checkpoint response in multiple cancer types, yet TGF-beta inhibitors have delivered mixed results in the clinic, suggesting that timing, context and combination partners matter enormously. The hierarchy is designed to prevent over-interpretation of preclinical enthusiasm and to guide rational prioritisation of which secretome targets should advance toward biomarker-guided trials.

Equally important is the review’s argument that protein abundance alone is biologically meaningless without context. The same chemokine can recruit antitumour T cells or immunosuppressive myeloid cells depending on which receptor-bearing cells are present. The same cytokine can promote or restrain immunity depending on its spatial distribution within the tumour, whether it is produced by malignant epithelium, fibroblasts or infiltrating immune cells, and whether it is measured before treatment, during therapy or at the moment of acquired resistance. Metastatic sites differ from primary tumours in their secretome programmes, and host physiology, including liver function, microbiome composition and systemic inflammation, modulates the interpretation of circulating protein signals. A clinically useful secretome biomarker must therefore integrate cellular source, spatial localisation, receptor context, temporal dynamics and linkage to actionable immune-state transitions, a demand that far exceeds what a single blood test or immunohistochemical stain can deliver.

This contextual complexity helps explain why genomic biomarkers such as microsatellite instability and tumour mutational burden, while genuinely predictive in defined settings, leave most gastrointestinal cancer patients without a reliable answer. A colorectal tumour with high mutational burden may nonetheless be saturated with CXCL12-expressing fibroblasts and CSF1-dependent macrophages that render even reinvigorated T cells ineffective. A pancreatic cancer with modest genomic immunogenicity may be so thoroughly walled off by TGF-beta-driven stroma that no quantity of checkpoint blockade can achieve meaningful infiltration. Conversely, a gastric tumour with abundant tertiary lymphoid structures and a CXCL9-rich chemokine milieu may respond even with intermediate genomic predictors. The secretome is the layer at which these competing influences are integrated and expressed.

The therapeutic implications are substantial. Combination strategies already in clinical testing, including TGF-beta inhibition, CSF1R blockade, CXCR4 antagonism, VEGF pathway targeting and IL-6 pathway suppression, can be understood as attempts to dismantle specific suppressive modules and convert tumours from an excluded or suppressive secretome state into a permissive one. The review suggests that the rational design of such combinations should be guided by modular secretome profiling of individual tumours, with the goal of matching each patient to the barrier-removing strategy most likely to unmask checkpoint activity. Biomarker development, the authors argue, should focus on identifying actionable immune-state transitions, moments at which a tumour’s secretome programme is poised to flip from suppression to permissiveness, and on capturing that transition with spatially resolved, temporally informed measurements. As single-cell and spatial transcriptomic technologies mature and become clinically deployable, the prospect of reading a tumour’s secreted protein circuitry and intervening accordingly moves from aspiration toward practice. For the majority of gastrointestinal cancer patients who today derive little benefit from immunotherapy, that shift may ultimately determine whether the immunotherapy revolution reaches them at all.

Subject of Research: Secreted protein signalling circuits in the gastrointestinal tumour microenvironment that determine immunotherapy response and resistance

Article Title: Secreted protein circuits in the gastrointestinal tumour microenvironment: determinants of immunotherapy response and resistance

Article References: Li, K., Qian, Z., Mao, J., Han, Y., & Leng, X. (2026). Secreted protein circuits in the gastrointestinal tumour microenvironment: determinants of immunotherapy response and resistance. Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-08945-x

Image Credits: AI Generated

DOI: 10.1186/s12967-026-08945-x

Keywords: gastrointestinal cancer, tumour microenvironment, secretome, immune checkpoint blockade, TGF-beta, VEGF, chemokines, tertiary lymphoid structures, cancer-associated fibroblasts, tumour-associated macrophages, immunotherapy resistance, biomarkers

The challenge the researchers set out to address is well known to immunotherapy researchers. Checkpoint-blocking drugs have transformed outcomes for some patients with melanoma, lung cancer and other malignancies, but many solid tumours remain resistant because their surroundings actively suppress immune activity. Tumour-associated macrophages, or TAMs, are abundant white blood cells found inside tumours that, in their tumour-associated state, help the cancer evade destruction. Professor Zhao explained the central problem succinctly: the immune system may be fully capable of attacking a tumour, but the tumour environment can stop those immune cells from doing their job. Her team’s answer was to change that environment from within, delivering treatment precisely to the cells that maintain the immunosuppressive order and persuading them to switch sides.

The delivery vehicle at the heart of the study is the lipid nanoparticle, the same class of fatty droplet that carries mRNA in COVID-19 vaccines. But these particles were given a targeting upgrade: their surface is coated with an antibody that recognises TREM2, a protein expressed at high levels on tumour-associated macrophages. This molecular address label guides the nanoparticles to the very cells responsible for tumour immune suppression. Once inside the macrophages, the particles release two payloads with complementary functions. The first is an mRNA molecule carrying instructions for the macrophage to produce CXCL9, a chemical signalling protein. The second is Resiquimod, a small-molecule compound that pushes macrophages away from their immune-suppressing behaviour and toward a more inflammatory, immune-supportive state.

The two payloads work in concert in a way that illustrates the elegance of the design. CXCL9 acts as a chemical beacon, drawing cytotoxic CD8+ T cells, the immune system’s primary tumour-killing soldiers, into the tumour mass, where they are often excluded or rendered inactive. Meanwhile, Resiquimod shifts the local macrophage population away from suppression, easing the hostile conditions that would normally exhaust or repel those T cells. Rather than depleting the macrophages outright, an approach that can carry inflammatory side effects, the researchers effectively re-educated them, converting a tumour-protective population into an accomplice of the anti-cancer immune response.

In experiments with mouse models, the approach produced measurable shifts in the tumour immune landscape. Treatment reduced the proportion of immune-suppressing macrophages by more than 60 percent, a substantial remodelling of the tumour’s defensive cellular makeup. Levels of CXCL9 within the tumours rose fourfold, confirming that the delivered mRNA was being translated into functional chemical beacon by the targeted cells. The researchers also documented greater numbers and heightened activity of cancer-fighting T cells inside the treated tumours, along with a moderate reduction in tumour growth. While the growth slowdown alone was not dramatic, the immunological changes suggest a tumour environment becoming markedly more permeable and hospitable to immune attack.

The team then tested whether their nanoparticle therapy could amplify the effects of existing immunotherapies. When combined with immune checkpoint-blocking antibodies targeting PD-L1 and CTLA-4, two of the most widely used targets in clinical oncology, the treatment produced further increases in cytotoxic T cells and, notably, the generation of central memory T cells. These long-lived memory cells could give the immune system the ability to recognise and respond to cancer if it returns, a property highly valued in cancer therapy because it hints at durable protection rather than transient tumour shrinkage. Interestingly, however, the combination did not yield additional tumour-growth inhibition in this particular mouse model, a nuance the researchers report candidly and one that will guide future experimental design.

Professor Zhao framed the findings as an important proof of concept that mRNA and nanoparticle technology can reprogramme the immune environment of a tumour. She emphasised that significant work remains before the approach could be considered for patients, but described the results as an encouraging foundation for developing more targeted cancer immunotherapies. That caution reflects the well-known gap between promising mouse studies and clinical reality: nanoparticle manufacturing, dosing, safety profiling and the variability of human tumour environments all present substantial hurdles. Still, the strategy addresses a specific failure mode of current immunotherapy, immune exclusion, and does so with a precision that conventional drugs have struggled to achieve.

The broader significance of the work lies in the expanding repertoire of mRNA medicine. The pandemic demonstrated that lipid nanoparticles can deliver genetic instructions safely and at scale; researchers worldwide are now exploring whether the same platform can carry therapeutic instructions for enzymes, antibodies, cytokines and tumour antigens. This study adds a subtle new use case: not delivering a drug or an antigen, but delivering the blueprint for a signalling molecule that changes the behaviour of the cells receiving it. By targeting TREM2-positive macrophages, the Adelaide team also taps into a growing body of research on macrophage reprogramming, an area increasingly seen as fertile ground for solid tumour therapy where T-cell-focused approaches alone often fall short.

The research was led by Adelaide University scientists in collaboration with SA Pathology and the Royal Adelaide Hospital, and is published under the title ‘Targeting tumor-associated macrophages using mRNA lipid nanoparticles for cytotoxic T lymphocyte–mediated cancer immunotherapy’. For patients whose tumours shut out immunotherapy, the study offers a vision of treatment that does not fight the tumour’s fortress head-on but instead quietly converts its guards, arming them with the instructions to raise a signal flare that guides the immune system’s most lethal cells inside. If subsequent studies can translate those beacon-lit results into durable clinical benefit, mRNA nanoparticles may find a second act in oncology as architects of the tumour microenvironment rather than mere couriers of vaccines.

The biology underlying the study helps explain why macrophages have become such a sought-after target. Macrophages are not inherently tumour-friendly; in healthy tissue they patrol, clear debris and coordinate inflammatory responses. Tumours, however, gradually reshape the macrophages they recruit, coaxing them into a state that suppresses cytotoxic T cells, promotes new blood vessel growth and remodels the fibrous matrix surrounding the cancer. High densities of these suppressive macrophages have been associated in many cancer types with poorer responses to checkpoint inhibitors, which is why strategies that convert rather than eliminate them have attracted growing interest.

The choice of TREM2 as a targeting marker reflects recent advances in understanding macrophage identity within tumours. TREM2 is a receptor expressed on a subset of macrophages that accumulates in tumours and is linked to immunosuppressive function, and blocking or depleting TREM2-positive cells has emerged as an active area of preclinical investigation. Using an antibody against TREM2 as a homing device, rather than as a therapeutic agent itself, is a distinctive feature of the Adelaide approach: the antibody serves as an address label that concentrates the therapeutic payload where it is most needed, potentially limiting off-target effects in healthy tissue.

The signalling components of the formulation also draw on established immunology. Resiquimod is a synthetic agonist of toll-like receptors, pathways that act as alarm bells for the innate immune system and have previously been explored as topical treatments and vaccine adjuvants. Encapsulating it alongside mRNA allows the two stimuli to act within the same cell, pairing a behavioural switch with a genetic instruction. CXCL9, meanwhile, belongs to a family of chemokines long known for their role in recruiting CD8+ T cells to sites of inflammation, and low CXCL9 expression has been linked to immune-excluded tumours in human studies, making it a rational choice for restoring T-cell infiltration.

The appearance of central memory T cells in the combination experiments deserves particular attention. Memory T cells persist long after an initial immune response subsides and can mount faster, stronger reactions upon re-encounter with their target. In cancer, inducing such cells is a goal of therapeutic approaches such as cancer vaccines and intratumoural therapies, because tumour recurrence remains a leading cause of treatment failure even when initial therapy is successful. The fact that this memory phenotype emerged despite the absence of added tumour shrinkage suggests that immunological benefit and immediate tumour control may follow different timelines, a distinction that longer animal studies would need to resolve.

The candid reporting of the combination result also illustrates a broader principle in immunotherapy research: immune activation and tumour regression are not always tightly coupled in early experiments. Factors such as the mouse model used, the timing of treatment relative to tumour establishment, and the dose and schedule of each component can all influence whether enhanced T-cell activity translates into measurable growth control. The authors’ decision to publish these nuances alongside the positive findings provides a transparent baseline for other laboratories seeking to refine the formulation, test it across additional tumour types, and determine which patient populations might ultimately benefit most from a macrophage-reprogramming strategy.

Subject of Research: mRNA lipid nanoparticle reprogramming of tumour-associated macrophages for cancer immunotherapy.

Article Title: New ‘smart’ nanoparticles help the immune system better attack tumours

Article References: New ‘smart’ nanoparticles help the immune system better attack tumours. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: lipid nanoparticles, mRNA, tumour-associated macrophages, cancer immunotherapy, CXCL9, TREM2, CD8+ T cells, immune checkpoint inhibitors, tumour microenvironment, Resiquimod, Science Advances, Adelaide University

Chemotherapy remains a cornerstone of cancer treatment, yet its efficacy is frequently undermined by tumours’ ability to resist and evade therapeutic attack. Central to this resistance is the presence of tumour-associated macrophages (TAMs), a subset of immune cells that infiltrate tumour microenvironments, particularly clustering around tumour vasculature. These macrophages serve as immunological gatekeepers, creating a fortress-like barrier that prevents beneficial immune cells from penetrating tumours and supporting chemotherapy’s effectiveness.

The team from King’s College London has identified a critical protein produced by these macrophages—heme oxygenase-1 (HO-1)—which plays a pivotal role in this immune evasion strategy. HO-1 catalyzes the degradation of heme into biliverdin, iron ions, and carbon monoxide, exerting potent anti-inflammatory and cytoprotective effects within the tumour milieu. By leveraging this enzymatic function, the macrophages effectively shield cancer cells from immune-mediated destruction as well as the cytotoxic effects of chemotherapeutic agents.

To disrupt this protective shield, researchers engineered a small molecule inhibitor named KCL-HO-1i, designed specifically to inhibit HO-1 activity. The targeted inhibition of HO-1 undermines the macrophages’ ability to protect tumour cells, thereby restoring immune surveillance and enhancing chemotherapy efficacy. This strategic targeting represents an innovative angle in tumour immunotherapy, focusing on the tumour microenvironment rather than directly attacking cancer cells.

Professor James Arnold, leading the Tumour Immunology Group at King’s College London, emphasizes the significance of this approach: “Our discovery reveals that HO-1 expression in tumour-associated macrophages is a key factor limiting chemotherapy effectiveness. KCL-HO-1i enables us to modify the tumour microenvironment, facilitating the infiltration of immune effector cells and enhancing drug delivery, which collectively translate into improved tumour suppression, even in previously resistant cases.”

Remarkably, KCL-HO-1i presents a patient-friendly mode of administration. Unlike many cancer therapeutics that necessitate frequent hospital visits and invasive delivery methods, this drug is formulated as an oral tablet. Patients can conveniently take KCL-HO-1i at home during periods between chemotherapy sessions, greatly easing treatment burdens and improving adherence without compromising therapeutic outcomes.

The preclinical data supporting KCL-HO-1i’s potential are compelling. Utilizing robust mouse models of breast cancer, funded by Cancer Research UK and the Medical Research Council, the researchers demonstrated that combining KCL-HO-1i with standard chemotherapies significantly enhanced tumour regression across diverse chemotherapy regimens. These findings strongly suggest the drug’s utility may extend beyond breast cancer to a broad spectrum of solid tumours, magnifying its clinical impact.

Professor James Spicer, an authority in Experimental Cancer Medicine at King’s College London, remarks, “This drug represents a vital adjunct to current chemotherapy protocols. Our research unmasked one of the tumour’s stealth mechanisms and offered a tangible strategy to overcome it. We are eager to advance KCL-HO-1i into clinical trials to validate its safety and efficacy in patients, potentially transforming cancer care paradigms.”

Supporting this translational endeavor, Professor Miraz Rahman, Professor of Medicinal Chemistry, highlights the interdisciplinary collaboration underpinning this success. “Bridging immunology, chemistry, and clinical oncology enabled us to swiftly move from molecular target identification to drug development. Should clinical trials confirm preclinical promise, KCL-HO-1i could become an indispensable co-therapy, augmenting the effectiveness of existing cancer treatments and potentially reducing reliance on more aggressive therapeutic approaches,” he explains.

Experts beyond King’s College London echo excitement about this novel strategy. Tanya Hollands, Research Information Manager at Cancer Research UK, underscores the importance of optimizing existing treatments through rational combinations. “By pairing new agents like KCL-HO-1i with established chemotherapies, we may accelerate delivery of improved care, leveraging previous clinical experience while mitigating risk. This drug exemplifies the potential of precision medicine to refine and enhance conventional cancer therapy.”

Critical to the drug’s mechanism is reprogramming the tumour microenvironment from an immunosuppressive state to one conducive to immune activation and drug penetration. This reprogramming involves not only inhibiting HO-1 but also diminishing the production of immunosuppressive metabolites and signaling molecules. Subsequent immune infiltration and enhanced chemotherapy-induced cytotoxicity create a synergistic effect, profoundly influencing tumour control.

Looking ahead, the King’s College team anticipates that with appropriate funding, human clinical trials for KCL-HO-1i could commence within the next two years. These trials will probe not only safety and tolerability but also the drug’s capacity to overcome chemoresistance in diverse patient cohorts. Success in these studies would mark a pivotal advancement, becoming a new weapon in the oncologist’s arsenal against refractory cancers.

This discovery exemplifies the power of multidisciplinary research and innovative thinking in oncology. By targeting the cellular interplay within the tumour microenvironment rather than focusing solely on cancer cells, KCL-HO-1i represents a paradigm shift in therapeutic development. As the oncology community awaits clinical validation, this approach heralds a promising new chapter in the fight against resilient cancers, offering hope for improved survival and quality of life for patients worldwide.

Subject of Research: Development of a novel inhibitor targeting heme oxygenase-1 (HO-1) in tumour-associated macrophages to enhance chemotherapy efficacy.

Article Title: Not provided.

News Publication Date: Not provided.

Web References:

• Aethox Therapeutics

References:

• Full scientific article published in Science Translational Medicine (specific link not provided).

Image Credits:
Credit: King’s College London

Keywords:
Cancer, Cancer immunotherapy, Chemotherapy, Cancer medication, Medical treatments, Clinical medicine, Health and medicine, Life sciences, Pharmacology, Pharmaceuticals