Acylation is a diverse class of post-translational modification in which metabolites act as chemical donors that alter proteins. Beyond the canonical form of acetylation, emerging acylation marks are dynamically controlled by the availability of acyl donors and by “writer,” “eraser” and “reader” systems. The authors describe these systems as regulatory networks that can reshape chromatin, metabolism, protein stability and localization, cytoskeletal dynamics and immune responses.

The review integrates the chemistry and enzymatic control of major protein acylations with their roles across metabolic, epigenetic, signaling and tumor-immune networks. In this framework, acylation is not presented as one isolated pathway. Instead, it connects changing metabolic states with protein function and signaling, providing a possible basis for the adaptability and plasticity seen in cancer cells under stress.

The scope is a synthesis of existing evidence rather than a report of a new clinical trial or a demonstration of a precision treatment. Translational applications remain an important part of the review, but they are not presented as established clinical outcomes. The authors examine whether acylation patterns could support biomarkers or patient stratification and discuss pharmacological targeting and mechanism-guided combination strategies.

Major obstacles include the specificity of protein modifications and the need for clinical validation.

Subject of Research: Protein acylation in cancer metabolism, tumor plasticity and therapeutic response

Article Title: Protein acylation in cancer: from regulatory networks to precision therapeutics

Article References: Wei, Z., Ma, C., Gao, J., Zhang, X., Xu, Y., Ma, D., Liu, W., & Xing, X. (2026). Protein acylation in cancer: from regulatory networks to precision therapeutics. Journal of Experimental & Clinical Cancer Research. https://doi.org/10.1186/s13046-026-03857-6

Image Credits: AI Generated

DOI: 10.1186/s13046-026-03857-6

Keywords: protein acylation, cancer metabolism, post-translational modification, tumor plasticity, therapeutic resistance, biomarkers, precision oncology, epigenetic regulation, tumor immunity, drug targeting, Protein, acylation

Autophagy maintains metabolic and proteostatic homeostasis under physiological and stressful conditions, but its relationship with cancer is highly context-dependent. According to the editorial, its effects can vary with tumor type, genetic background, disease stage and therapeutic pressure. Autophagy may restrain early tumorigenesis, yet promote survival, adaptation, progression and resistance once a tumor is established.

The collection therefore emphasizes patient selection, treatment timing, biomarker development and a more precise definition of the relevant autophagic process. The pathway is closely integrated with several networks that control growth, metabolism, cell death and stress responses. The editorial highlights interactions with PI3K/AKT/mTOR and AMPK signaling, apoptosis and mitochondrial quality control.

Such connections can help malignant cells adapt to hypoxia, nutrient deprivation, chemotherapy, targeted therapy and other forms of stress. This biological integration helps explain the difficulty of therapeutic targeting, but it also identifies potential combination strategies. The collection considers pairing autophagy-directed interventions with targeted drugs, chemotherapy, stress-inducing agents, apoptosis-related interventions or approaches directed at mitochondrial function.

These are investigational concepts, not clinical approaches established by the collection alone. A review by Tiwari and colleagues examines chaperone-mediated autophagy, or CMA, a selective process that recognizes soluble proteins bearing KFERQ-like motifs and delivers them to lysosomes for degradation. The review places CMA within a wider set of cancer-related functions, including sustained proliferative signaling, resistance to cell death, metabolic reprogramming, invasion, metastasis, immune evasion, genome instability and tumor-promoting inflammation.

It also links the process to cellular plasticity and cancer stem-cell maintenance, both associated in the review with tumor progression and therapeutic resistance. The authors interpret these findings as evidence that targeted degradation of key regulatory proteins can affect tumor biology, while cautioning that the context-dependent functions of CMA require appropriate biomarkers and therapeutic windows before clinical translation. Autophagy also appears to change function as thyroid cancer advances, according to a review by Fang and colleagues covering papillary, follicular, medullary and anaplastic thyroid carcinomas.

The authors propose that a transition from tumor-suppressive to tumor-supporting autophagy may accompany disease progression and may represent a largely directional shift toward an adaptive state rather than a simple reversible equilibrium. Major thyroid-cancer drivers, including BRAF V600E, RAS and RET, regulate autophagy through different mechanisms, indicating that genotype may influence a tumor’s dependence on the pathway. The review presents autophagy primarily as an adaptive resistance mechanism rather than a principal oncogenic driver, consistent with the absence of established autophagy-gene mutations as major thyroid-cancer drivers.

It supports biomarker-enriched, hypothesis-driven trials of autophagy inhibitors combined with treatments that impose metabolic or cellular stress, including investigation of hydroxychloroquine with tyrosine kinase inhibitors, particularly in anaplastic thyroid carcinoma. A mini-review by Yan and colleagues focuses on mitophagy, the selective elimination of damaged mitochondria, and its relationship to treatment resistance in solid tumors. Mitochondria regulate energy production, metabolism, redox balance and apoptosis, so their quality control becomes important when malignant cells encounter therapeutic stress.

By removing damaged mitochondria, mitophagy can preserve mitochondrial fitness and support survival in unfavorable conditions. The review summarizes evidence linking this process with tumor survival, proliferation and resistance to anticancer treatments. Its therapeutic implication depends on identifying the mechanisms that make mitophagy critical in a particular cancer and treatment context.

The article does not establish a universal target or demonstrate clinical benefit, but it frames mitochondrial quality control as a possible source of exploitable dependence. The relationship between autophagy and apoptosis is particularly prominent in non-small cell lung cancer in a review by Qin and colleagues. Autophagy and apoptosis are distinct but interconnected processes, and their balance can influence whether a stressed tumor cell survives or undergoes cell death.

The authors review the molecular mechanisms and major points of crosstalk between the two pathways, then examine natural products investigated for effects on both. Four representative agents receive more detailed attention because of their range of biological activities and their capacity to influence multiple molecular targets. The review identifies an avenue for further investigation, not an established clinical substitute for existing lung-cancer treatment.

Glioblastoma supplies a specific example of adaptive resistance to pathway-targeted therapy. A review by Xia and colleagues examines autophagy-mediated resistance to PI3K/AKT/mTOR inhibition in this aggressive, highly treatment-resistant tumor, where the signaling axis is frequently activated. Pharmacological inhibition of the pathway can activate autophagy as a cytoprotective response, potentially contributing both to treatment effects and to the later survival of residual tumor cells.

The authors assess the rationale for combining autophagy inhibitors with PI3K/AKT/mTOR inhibitors to counter that response. The strategy specifically targets a survival mechanism that may be induced by treatment, but its value depends on demonstrating that autophagy is a critical dependency in the relevant glioblastoma context. It remains a therapeutic hypothesis requiring rigorous testing.

p>The collection’s only original study links virus-associated changes in autophagy-related gene expression with clinical outcomes in nasopharyngeal carcinoma. Alanazi and colleagues assessed messenger RNA expression of nine autophagy-related genes by quantitative PCR in 35 nasopharyngeal carcinoma specimens and five non-cancerous nasopharyngeal mucosa controls, while immunohistochemistry was used to evaluate protein expression. ATG3, ATG4D, ATG4C, ATG4A, ATG2B and ATG5 showed higher expression in Epstein–Barr virus-positive tumors, suggesting that viral infection may be associated with altered regulation of the autophagy machinery.

ATG3 and ATG4C protein expression was also more frequent in virus-positive tumors. Elevated ATG4B and ATG4D expression was associated with reduced distant metastasis, whereas reduced ATG4D messenger RNA levels were associated with increased metastatic rates and shorter distant metastasis-free survival. The small sample and need for validation in larger cohorts limit the conclusions, but the findings identify candidate molecules for further study as potential indicators of disease stratification and outcomes.

Taken together, the studies portray autophagy as a network of selective processes with distinct mechanisms and consequences rather than as a single switch that should always be activated or inhibited. The reviewed evidence spans protein quality control, mitochondrial maintenance, metabolism, inflammation, immune regulation, cellular plasticity, tumor progression and resistance to several treatment classes. The collection’s most consistent conclusion is methodological: researchers should identify the form and location of autophagy, the cells in which it operates, the disease stage and the treatment pressure under examination.

Combination approaches may reveal hidden tumor dependencies, but the editorial does not establish clinical efficacy for any of them. Rigorous biomarker development, validation in larger cohorts and carefully designed clinical trials will be needed to determine which patients and treatment settings could benefit from strategies directed at autophagy.

Subject of Research: Context-dependent roles of autophagy in solid tumors, inflammation and therapeutic resistance

Article Title: Editorial: Autophagy in solid tumors and inflammation: mechanisms and therapies

Article References: An, Z., Larafa, S., & Vega Rubin de Celis, S. (2026). Editorial: Autophagy in solid tumors and inflammation: mechanisms and therapies. Frontiers in Oncology, 16, Article 2016779. https://doi.org/10.3389/fonc.2026.2016779

Image Credits: AI Generated

DOI: 10.3389/fonc.2026.2016779

Keywords: autophagy, solid tumors, cancer, therapeutic resistance, chaperone-mediated autophagy, mitophagy, inflammation, thyroid cancer, glioblastoma, nasopharyngeal carcinoma, Editorial, solid

The story of MOTS-c began with the recognition that the mitochondrial genome, long assumed to encode only 13 proteins of the oxidative phosphorylation machinery plus tRNAs and rRNAs, harbors short open reading frames that yield functional peptides. MOTS-c, whose name derives from “mitochondrial open reading frame of the 12S rRNA type-c,” emerged as a representative member of this expanding family of mitochondrial-derived peptides, which also includes humanin and the small humanin-like peptides SHLP1 through 6. Structurally, MOTS-c is unusual: it is rich in methionine and basic residues, and it can translocate to the nucleus, where it acts directly on chromatin, a property that distinguishes it from most circulating peptide hormones and gives it a uniquely intimate connection to gene regulation.

At the mechanistic level, the review lays out a coherent signaling framework. In the cytosol, MOTS-c can activate the AMP-activated protein kinase, or AMPK, a master energy sensor, partly through accumulation of AICAR, an intermediate of the purine synthesis pathway that MOTS-c helps generate from folate cycle metabolites. AMPK activation in turn suppresses the mechanistic target of rapamycin complex 1, mTORC1, shifting cells from an anabolic, growth-oriented state toward a catabolic, stress-adaptive one. In the nucleus, MOTS-c interacts with transcription factors and chromatin-modifying machinery, including the transcription factor ATF4-dependent integrated stress response and, in some settings, the antioxidant transcription factor Nrf2, driving the expression of genes bearing antioxidant response elements. These pathways converge on redox control, promoting the activity of enzymes such as superoxide dismutase, catalase, heme oxygenase-1, and NAD(P)H quinone dehydrogenase 1, thereby buffering reactive oxygen species and stabilizing cellular homeostasis under metabolic stress.

The physiological repertoire attributed to MOTS-c is remarkably broad. The review catalogs reported roles in exercise adaptation, where MOTS-c levels rise with physical activity and the peptide appears to contribute to muscle metabolic remodeling and thermogenesis through pathways involving PGC-1α and uncoupling proteins. It details protective effects in models of diet-induced obesity and insulin resistance, where MOTS-c administration improves glucose tolerance and lipid profiles. It also covers endothelial protection, suppression of inflammatory signaling through the NF-κB and NLRP3 inflammasome axes, regulation of apoptosis via the Bcl-2 and Bax balance, and benefits in preclinical models of chronic kidney disease, osteoporosis, and cardiopulmonary bypass injury. In each of these contexts, the peptide behaves as a homeostatic buffer, helping cells and tissues adapt to metabolic and oxidative stress rather than succumbing to it.

Yet the clinical evidence is strikingly heterogeneous, and the authors devote considerable attention to why. Measurements of circulating MOTS-c abundance in human cohorts have produced inconsistent results, with some studies reporting lower levels in type 2 diabetes, obesity, or coronary artery disease, and others finding elevated or unchanged concentrations. The review identifies plausible biological and methodological culprits: assay variability between enzyme-linked immunosorbent assay kits and mass spectrometry, the short half-life and rapid clearance of the peptide, the influence of age, sex, body mass index, and circadian rhythms, and the fact that circulating MOTS-c may not reflect intracellular or intramitochondrial pools that could be the functionally decisive fraction. Without standardized detection methods and agreed-upon reference compartments, the authors argue, the true relationship between MOTS-c abundance and human disease remains an open question.

The most provocative section of the review concerns cancer, where the context-dependence of MOTS-c becomes starkest. In some tumor models, MOTS-c acts as a suppressor: it can promote apoptosis of cancer cells, sensitize them to chemotherapy, and restrain epithelial-mesenchymal transition through modulation of pathways involving YAP, STAT3, and TGF-β. The peptide has also been implicated in promoting ferroptosis, the iron-dependent form of cell death, by influencing glutathione metabolism, the cystine transporter SLC7A11, and the GPX4 axis, offering a potential route to undermine the redox resilience that tumors depend upon.

In other contexts, however, the same peptide appears to work in the tumor’s favor. The review describes evidence that MOTS-c can contribute to metabolic reprogramming that supports tumor cell survival, help cancer cells adapt to oxidative stress, remodel the tumor microenvironment through effects on cancer-associated fibroblasts and extracellular matrix deposition, and modulate immune cell populations, including regulatory T cells and dendritic cells, in ways that may blunt antitumor immunity. There are also indications that MOTS-c signaling may contribute to therapeutic resistance, potentially through mechanisms involving multidrug resistance transporters, enhanced stress granule formation, and activation of survival kinases such as AKT and ERK. The authors are careful to frame this evidence as emerging and still limited, but the conceptual implication is clear: a signal that protects normal cells from stress can, under the altered selection pressures of malignancy, protect tumor cells from the very therapies designed to kill them.

This duality is not a contradiction but a lesson in biological context. The review emphasizes that MOTS-c’s action is shaped by subcellular localization, since nuclear MOTS-c reprograms gene expression while cytosolic and mitochondrial pools may act locally; by cell type, since stromal and immune cells in the tumor microenvironment may respond differently from epithelial cancer cells; by the metabolic state of the tissue, since AMPK and mTOR signaling are interpreted differently in nutrient-replete versus nutrient-deprived conditions; and by the inflammatory milieu, since the same redox-buffering activity that quells damaging inflammation in chronic disease may also shield tumor cells from oxidative attack by immune cells. Any therapeutic strategy that delivers MOTS-c systemically, or blocks it indiscriminately, would therefore need to account for which compartment and which cell population is being targeted.

The authors close with a research agenda that reads like a checklist for the field’s maturation. Priority tasks include establishing standardized, quantitative detection methods for MOTS-c in plasma, tissues, and subcellular fractions; mapping the trafficking routes that carry the peptide from mitochondria to nucleus and into the circulation; identifying the full set of molecular targets and binding partners in a cell-specific manner; and dissecting the effects of MOTS-c separately in tumor cells and in the stromal and immune compartments of the microenvironment. Only with that granularity, they argue, can the field determine in which disease contexts boosting MOTS-c signaling would be therapeutically beneficial and in which it could be detrimental.

For a 16-amino-acid peptide discovered barely a decade ago, MOTS-c has traveled an extraordinary conceptual distance, from metabolic curiosity to a candidate mediator of exercise, aging, inflammation, and cancer biology. The review’s central message is a caution against hype in either direction: MOTS-c is neither a universal elixir of metabolic health nor a straightforward oncogene. It is a stress signal, and like all stress signals, its meaning depends entirely on who is listening, under what conditions, and to what end. As mitochondria continue to shed their reputation as mere power plants, MOTS-c stands as a vivid example of how much biology remains encoded in the small, overlooked corners of the human genome, and how carefully that biology must be read before it is exploited in the clinic.

Subject of Research: The mitochondria-derived peptide MOTS-c as a context-dependent stress signal in metabolic homeostasis and cancer

Article Title: MOTS-c: a context-dependent mitochondrial stress signal in homeostasis and tumor

Article References: Kong, W., Yin, Y., Zhao, S., Ma, B., Chen, Z., Xi, J., & Yang, H. (2026). MOTS-c: a context-dependent mitochondrial stress signal in homeostasis and tumor. Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-09029-6

Image Credits: AI Generated

DOI: 10.1186/s12967-026-09029-6

Keywords: MOTS-c, mitochondrial-derived peptide, mitochondrial signaling, AMPK, oxidative stress, inflammation, tumor microenvironment, ferroptosis, metabolic homeostasis, cancer biology, therapeutic resistance, mitochondrial genome

The review, led by Tao Huang and Qiaoying Li of Southwest Medical University in Sichuan, China, together with colleagues, takes an unusually rigorous approach to a field notorious for loose claims. Rather than accepting every published association between fibroblasts and drug failure, the authors graded the evidence according to strict criteria: whether a defined drug was actually being administered, whether treatment-related outcomes were measured, and—critically—whether blocking the fibroblast pathway functionally restored drug sensitivity in experiments. Only mechanisms passing these tests earn the label of true resistance mechanisms. The distinction matters, because fibroblasts drive tumor progression in many ways, and progression is not the same thing as resistance to therapy.

Cancer-associated fibroblasts arise largely from hepatic stellate cells, the liver’s resident vitamin A-storing cells that normally lie dormant until injury wakes them. In chronic liver disease they become the workhorses of fibrosis, laying down scar tissue. When a tumor takes root in this scarred landscape, the activated fibroblasts multiply and diversify into subtypes with very different personalities: inflammatory fibroblasts that pump out signaling molecules, myofibroblastic fibroblasts that build dense extracellular matrix, and even antigen-presenting fibroblasts that can interact directly with immune cells. Single-cell and spatial transcriptomic studies have mapped these populations in hepatocellular carcinoma in increasing detail, and the picture that emerges is of a tumor wrapped in a living, communicating stroma.

The most convincing resistance story in the review concerns a fibroblast-secreted protein called SPP1, also known as osteopontin. When patients receive sorafenib or lenvatinib, fibroblasts respond by secreting SPP1, which binds integrins on the surface of tumor cells and activates a bypass signaling route through protein kinase C alpha. In effect, the drug blocks the main growth pathway while the fibroblasts quietly open a side door. Experiments in which SPP1 was knocked down genetically or blocked pharmacologically restored the tumor cells’ sensitivity to the kinase inhibitors, satisfying the review’s strictest evidentiary standard. This is no longer a correlation; it is a mechanism with a demonstrated rescue experiment behind it.

A second well-supported pathway involves the chemokine CXCL12. Fibroblast-derived CXCL12 signals through its receptor CXCR4 on hepatocellular carcinoma cells, triggering upregulation of a molecule called FOLR1, the folate receptor 1. The result is a reduction in the apoptosis—the programmed cell death—that sorafenib is supposed to induce. Independent work using quantitative proteomics had already implicated FOLR1 in sorafenib resistance through activation of autophagy, the cellular recycling program that helps stressed cancer cells survive. When researchers interfered with the CXCL12–CXCR4 axis, including with the CXCR4 antagonist plerixafor, sorafenib’s killing power returned.

The third mechanistically resolved pathway is perhaps the most elegant. Fibroblasts deposit fibronectin bearing an extra domain A, an embryonic splice variant of the matrix protein that is largely absent from healthy adult liver but abundant in tumors and fibrotic tissue. This oncofetal form of fibronectin, long recognized as a molecular marker of hepatocellular carcinoma, appears to signal through the innate immune receptor Toll-like receptor 4 on tumor cells, activating the transcription factor NF-κB and the metabolic enzyme SHMT1. The consequence is a shift in redox metabolism: the cancer cells adapt to the oxidative stress that sorafenib generates and simply keep going. Blocking this axis restores drug sensitivity, completing the causal chain from fibroblast product to receptor to transcription factor to metabolic enzyme to survival.

When the review turns to immunotherapy, the evidence becomes more circumstantial, and the authors are careful to say so. Periostin-positive fibroblasts, a stromal subset identified in patient tumors, are associated with recruitment of macrophages through the interleukin-6 signaling pathway, elevated SPP1 expression within those macrophages, physical exclusion of immune cells from the tumor, and reduced responsiveness to immune checkpoint inhibitors. The proposed chain of events is coherent: fibroblasts build a stromal-immune barrier that keeps cytotoxic T cells at arm’s length, so the checkpoint drug has no targets to reactivate. But unlike the tyrosine kinase inhibitor stories, no experiment has yet shown that selectively reversing this specific periostin-positive fibroblast program restores immunotherapy responses in hepatocellular carcinoma. The association is strong; the causal proof is pending.

That gap reflects a broader and sobering lesson from the fibroblast field. In pancreatic cancer, the classic cautionary tale, researchers depleted carcinoma-associated fibroblasts in mouse models and expected tumors to shrink. Instead, the tumors became more aggressive and the animals died faster, revealing that some fibroblasts restrain cancer rather than feed it. The review emphasizes that fibroblast heterogeneity makes blanket depletion strategies dangerous: eliminating the wrong subtype could dismantle the stromal barriers that contain the tumor while sparing the very cells that drive resistance. The field’s central question has accordingly shifted from whether to target fibroblasts to which ones, when, and how.

Translational efforts are already adapting to this nuance. Nanoparticle systems have been engineered to deliver small interfering RNA directly to fibroblasts, silencing stromal targets such as microfibril-associated protein 5 in antistromal therapy for hepatocellular carcinoma. Other platforms exploit fibroblast biology for drug delivery: lipid nanoparticles that transform in size in response to fibroblast activation protein activity, releasing their payload deep within fibrotic tumor tissue, and dual-targeting nanoparticles that simultaneously remodel the stroma and reprogram immune cells. CXCR4 antagonist-loaded nanoparticles have been shown to reprogram the tumor microenvironment and enhance immunotherapy in preclinical models. Even diagnostic imaging is joining in, with fibroblast activation protein-targeted PET tracers now being tested to monitor liver fibrosis and tumor burden, potentially allowing clinicians to stratify patients by the stromal character of their tumors before choosing a therapy.

The review’s authors, funded by the National Natural Science Foundation of China, frame their conclusions as a call for discipline in a rapidly growing literature. The fibroblast field has generated an abundance of associations—extracellular vesicles carrying resistance-promoting microRNAs, exosomal signals that decrease sorafenib sensitivity, fibroblast-derived growth factors that sustain tumor cells through metabolic crosstalk—but only a handful of mechanisms in hepatocellular carcinoma have been validated with the combination of defined drug exposure, treatment outcomes, and functional rescue. SPP1, CXCL12–FOLR1, and fibronectin extra domain A now stand on the firmest ground, each with a plausible route to clinical intervention. For patients whose liver cancers stop responding to the current arsenal, the hope is that the next generation of treatments will not merely attack the tumor harder, but will disarm the cellular accomplices that have been quietly protecting it all along.

Subject of Research: Cancer-associated fibroblast mechanisms of therapeutic resistance in hepatocellular carcinoma

Article Title: Cancer-associated fibroblasts in therapeutic resistance of hepatocellular carcinoma: evidence, mechanisms, and translational implications

Article References: Huang, T., Li, Q., Yu, Z., Wu, Z., Cheng, H., Zhang, X., Yang, L., & Wang, S. (2026). Cancer-associated fibroblasts in therapeutic resistance of hepatocellular carcinoma: evidence, mechanisms, and translational implications. Medical Oncology, 43(11), Article 314. https://doi.org/10.1007/s12032-026-03435-y

Image Credits: AI Generated

DOI: 10.1007/s12032-026-03435-y

Keywords: hepatocellular carcinoma, cancer-associated fibroblasts, therapeutic resistance, tyrosine kinase inhibitors, immune checkpoint inhibitors, sorafenib, lenvatinib, SPP1, CXCL12, fibronectin extra domain A, tumor microenvironment, spatial transcriptomics

The central premise of the review is that HPV-mediated checkpoint disruption is only the first act. Once the p53 and RB brakes are released, the malignant cell must still stabilize a proliferative, treatment-tolerant state, and the authors propose that this stabilization depends on epigenetic permissiveness and the spatial organization of the genome. Chromatin is not a passive spool of DNA. It is folded into topologically associating domains, or TADs, insulated neighborhoods in which enhancers preferentially contact the promoters they regulate. Structural maintenance of chromosomes complexes, chiefly cohesin, extrude DNA loops that bring distant regulatory elements together, while the insulator protein CTCF anchors domain boundaries. The WAPL cohesin release factor limits how far loops extend, tuning the overall folding landscape. When any of these components are altered, enhancers can be rewired onto inappropriate promoters, a mechanism long implicated in oncogene activation across many cancers.

HPV integration into the host genome is where viral biology and chromatin architecture collide. Integration is not a random insertion event; it frequently disrupts host regulatory regions and places viral and host sequences into new cis-regulatory relationships. Recent work cited in the review shows that the cis-regulatory effect of HPV integration is constrained by pre-existing host chromatin architecture, meaning the local folding context determines which genes a viral integration event can actually activate. Long-read sequencing of cervical cancer cell lines has revealed the structural complexity of these integration junctions, and genome-wide analyses have documented allele-specific impacts of viral-human rearrangements on cancer genome regulation. In effect, the virus hijacks the host’s own enhancer-promoter wiring, and the resulting rewiring can amplify MYC and E2F-centered transcriptional programs that drive uncontrolled proliferation.

The review gives particular attention to MYC, the transcription factor whose amplification has been detected even in preinvasive cervical lesions. MYC operates as a transcriptional amplifier, and tumors with rewired enhancer landscapes can become addicted to this sustained transcriptional output, a concept known as transcriptional addiction. That dependency creates a therapeutic opening. Bromodomain-containing protein 4, a BET family protein that recruits transcriptional machinery to active enhancers, has emerged as a druggable node: experimental studies show that BRD4 inhibition suppresses HPV16 E6 expression and enhances chemotherapy response, and separate work demonstrates that BRD4 inhibition sensitizes cervical cancer cells to radiotherapy by attenuating DNA repair. Early-phase clinical trials of MYC-targeting approaches in solid tumors, such as the peptide-based OMO-103, suggest that the long-undruggable MYC axis is finally becoming addressable.

Cohesin dynamics add another layer of vulnerability. The authors highlight their own prior finding that WAPL, the cohesin release factor, can induce cervical intraepithelial neoplasia in experimental models even without HPV E6 and E7, when modulated by estrogen signaling. This is a striking result because it implies that perturbing the genome’s folding machinery alone can push cervical epithelium toward premalignant states. Conversely, it suggests that cervical cancers may develop dependencies on specific cohesin regulators to maintain their malignant chromatin configuration. Recent single-molecule imaging of loop extrusion in living cells and studies showing extensive mutual influence among SMC complexes are refining how researchers understand these folding dynamics, and the review argues that such dependencies should be systematically screened in cervical cancer models using CRISPR perturbation and dependency mapping resources such as DepMap.

Chromatin remodeling complexes themselves are also implicated. Loss of ARID1A, the AT-rich interaction domain 1A subunit of the SWI/SNF complex, has been linked to tumor progression and adverse prognosis in cervical cancer, and emerging clinical data suggest that ARID1A and B2M mutations, together with antigen presentation pathway status, may predict response to definitive chemoradiotherapy. Histone modification enzymes, including the polycomb methyltransferase EZH2 and the demethylase KDM6A, are altered in HPV E6/E7-expressing keratinocytes, indicating that viral oncoproteins reprogram the epigenome from the earliest stages of infection. Three-dimensional chromatin analyses have additionally identified the transcription factor Sp1 as a mediator that programs and reprograms HPV-host epigenetic architecture in cervical cancer, providing a concrete molecular handle on how viral and host regulatory systems become intertwined.

Non-genetic plasticity is a recurring theme in the review’s account of therapeutic resistance. Cancer cells can evade drugs by reprogramming their transcriptional states without any new mutation, and rare pre-existing cell variants can seed drug-induced reprogramming within heterogeneous populations. Epigenetic plasticity is increasingly recognized as a hallmark that fuels tumor evolution while simultaneously exposing weaknesses. In cervical cancer specifically, single-nucleus and single-cell RNA sequencing studies have revealed heterogeneous microenvironments and distinct drug responses between squamous cell carcinoma and adenocarcinoma, while spatial transcriptomics is mapping how cancer-associated fibroblasts and immune cells shape the transcriptional landscape. Context-dependent signaling through PI3K-AKT, RAS-ERK, NOTCH1, and the Hippo pathway effectors YAP and TAZ, whose roles vary by HPV type, cooperates with chromatin state to determine whether a cell tolerates treatment or dies.

The tumor microenvironment completes the resistance circuit. CXCL8, a chemokine produced within the inflammatory milieu, has been shown to be essential for acquired radioresistance in cervical cancer cells and is proposed as a therapeutic target. HPV-mediated immune evasion mechanisms, the composition of the immune microenvironment, and the cancer-immune set point all influence how patients respond to the checkpoint inhibitor pembrolizumab, which in the phase 3 KEYNOTE-A18 trial improved outcomes when added to chemoradiotherapy for high-risk locally advanced disease. The review argues that chromatin-informed biomarkers, such as enhancer landscapes and chromatin accessibility profiles measured by ATAC-seq, ChIP-seq, and CUT&Tag, should be integrated with microenvironmental data to stratify patients more accurately than viral status alone allows.

Methodologically, the authors lay out an experimentally testable framework that leans on public datasets from The Cancer Genome Atlas and the Gene Expression Omnibus, perturbation-guided prioritization using CRISPR activation and interference screens, and computational tools including compositional perturbation autoencoders and in silico perturbation methods that predict cellular responses to genetic and pharmacological interventions. Multimodal artificial intelligence approaches that combine imaging, genomic, and clinical data are highlighted as a route to precision management, and network pharmacology offers a way to target causal resistance mechanisms rather than symptoms. Crucially, the framework depends on experimentally faithful models: authenticated cervical cancer cell lines, patient-derived organoids that recapitulate cervical tissue dynamics and viral oncogenesis, and patient-derived xenograft-style cultures that can predict sensitivity to chemotherapy and radiation.

The significance of this review lies in its reframing of HPV-driven cervical cancer as a disease of coupled viral and host genome regulation. Rather than treating E6 and E7 expression as the whole story, it positions chromatin architecture, enhancer rewiring, cohesin dynamics, and epigenetic plasticity as the machinery that converts viral checkpoint disruption into stable, adaptable, treatment-resistant malignancy. If the proposed framework holds up under experimental scrutiny, chromatin-informed stratification could identify which patients need intensified or combination therapy, while vulnerabilities in BET proteins, MYC signaling, cohesin regulators, and microenvironmental cytokines could yield rational combination strategies. For a cancer that remains a major global cause of mortality despite vaccination and screening, shifting the therapeutic lens from the viral oncogenes alone to the three-dimensional regulatory genome they exploit may prove a consequential conceptual advance.

Subject of Research: Host chromatin architecture and 3D genome rewiring in HPV-driven cervical cancer and therapeutic resistance

Article Title: Host chromatin architecture in HPV-driven cervical cancer: molecular mechanisms and therapeutic resistance

Article References: Kumagai, K., Suzuki, Y., Kitahara, K., Chiba, A., & Yajima, H. (2026). Host chromatin architecture in HPV-driven cervical cancer: molecular mechanisms and therapeutic resistance. Medical Oncology, 43(11), Article 324. https://doi.org/10.1007/s12032-026-03445-w

Image Credits: AI Generated

DOI: 10.1007/s12032-026-03445-w

Keywords: HPV, cervical cancer, chromatin architecture, 3D genome, enhancer rewiring, cohesin, WAPL, MYC, BRD4, therapeutic resistance, epigenetic plasticity, tumor microenvironment

Fibroblasts are, in healthy tissue, the quiet maintenance workers of the body. They secrete structural proteins, maintain the extracellular matrix, and coordinate wound healing. In the tumor microenvironment, however, they become reprogrammed. Signals from malignant epithelial cells, immune cells, and inflammatory mediators push resident fibroblasts into an activated state reminiscent of the myofibroblasts that close a healing wound, but in cancer this activation never switches off. The result is a chronic, tumor-supportive state in which fibroblasts proliferate, deposit matrix, secrete growth factors, and communicate with nearly every other cell type in the tumor. The review’s authors emphasize that CAFs are instrumental in tumor progression precisely because of these multifaceted interactions with tumor cells, other stromal components, and the extracellular matrix.

One of the most important conceptual shifts in recent years is the recognition that CAFs are not a uniform population. The review details how single-cell transcriptomics and lineage-tracing studies have revealed a bewildering heterogeneity of fibroblast states within colorectal tumors. Myofibroblastic CAFs, characterized by alpha-smooth muscle actin expression and contractile properties, tend to sit adjacent to invasive fronts and deposit dense matrix. Inflammatory CAFs secrete cytokines such as interleukin-6 and interleukin-8 that fuel pro-tumor signaling and immune evasion. Antigen-presenting CAFs express major histocompatibility complex molecules and can modulate immune surveillance, while other subtypes with lipogenic or developmental programs have been described in various contexts. Markers such as FAP, fibroblast activation protein; PDGFR-alpha and PDGFR-beta; FSP1; and TAGLN are used to distinguish these populations, though no single marker cleanly defines a functional state, a limitation the authors highlight as a persistent obstacle to both research and therapy.

Where these CAFs come from matters as much as what they become. The review surveys evidence that colorectal CAFs can arise from resident tissue fibroblasts, from stellate-like cells, from mesenchymal stem cells recruited to the tumor, from epithelial cells undergoing epithelial-to-mesenchymal transition, and even from endothelial cells transitioning through endothelial-to-mesenchymal processes. Each origin may imprint distinct behaviors and sensitivities on the resulting fibroblast, which helps explain why CAFs in different patients, or even in different regions of the same tumor, can behave so differently. This plasticity also means that therapies aimed at eliminating CAFs must contend with the possibility that new CAFs will be recruited or converted from untapped precursor pools, a phenomenon that has undermined several otherwise promising stromal-targeting strategies in other cancers.

A central theme of the review is extracellular matrix remodeling. CAFs in colorectal cancer secrete collagen I, fibronectin, laminins, and tenascin C, and they cross-link and stiffen this matrix through enzymes such as lysyl oxidase and matrix metalloproteinases. The consequences are twofold. Mechanically, a stiffened, dense matrix raises interstitial fluid pressure and compresses blood vessels, creating a physical barrier that prevents chemotherapeutic drugs from penetrating the tumor at adequate concentrations. Biologically, matrix stiffness itself is a signaling input: integrin-mediated mechanotransduction in both cancer cells and fibroblasts activates pro-survival pathways, promotes invasion, and reinforces the activated state of the CAFs themselves. In colorectal cancer, this stromal barricade has been repeatedly linked to poor prognosis and to the desmoplastic phenotype that pathologists recognize as abundant pale stroma surrounding malignant glands.

The mechanistic core of the review concerns how CAFs drive therapeutic resistance through defined signaling pathways. The TGF-beta pathway stands out as a master regulator: CAFs both produce and respond to TGF-beta, which maintains their activated state, promotes epithelial-to-mesenchymal transition in neighboring cancer cells, and suppresses anti-tumor immune activity. The Wnt and beta-catenin axis, so central to colorectal carcinogenesis through APC loss, is further amplified by stromal Wnt ligands secreted by CAFs, sustaining stem-like properties in cancer cells that are associated with recurrence after treatment. The Hedgehog pathway, Notch signaling, the PI3K-AKT-mTOR cascade, and JAK-STAT signaling downstream of interleukin-6 all feature in the resistance mechanisms catalogued by the authors. Through these circuits, CAFs can shield cancer cells from apoptosis induced by 5-fluorouracil, oxaliplatin, and irinotecan, the backbone drugs of colorectal cancer chemotherapy, and can blunt the effectiveness of radiotherapy by buffering oxidative stress and enhancing DNA damage repair in adjacent tumor cells.

Resistance is not only biochemical but also metabolic and immunological. The review describes how CAFs rewire their metabolism toward aerobic glycolysis, exporting lactate and other metabolites that cancer cells can take up and use, a metabolic symbiosis that sustains tumor growth under the nutrient- and oxygen-poor conditions created by the abnormal stromal vasculature. At the same time, CAFs sculpt the immune landscape by secreting chemokines that recruit immunosuppressive myeloid cells and regulatory T cells, by expressing checkpoint ligands such as PD-L1 and PD-L2, and by physically excluding cytotoxic T lymphocytes from tumor nests through their dense matrix. This has direct implications for immunotherapy: colorectal cancers with high stromal content, particularly the microsatellite-stable majority of cases, respond poorly to immune checkpoint inhibitors, and CAF-mediated immune exclusion is increasingly viewed as a key contributor to that failure.

What can be done about it? The review surveys preclinical agents and clinical trials aimed at disrupting the CAF compartment in colorectal cancer. Strategies fall into several broad categories: depleting or inhibiting CAFs directly, for example with FAP-targeted approaches including antibodies, CAR-T cells, and radioligands; blocking CAF-activating signals such as TGF-beta, with small-molecule kinase inhibitors and ligand traps, some of which have reached clinical testing in gastrointestinal cancers; disrupting matrix deposition and cross-linking, notably with lysyl oxidase inhibitors; and reprogramming CAFs from a tumor-promoting to a quiescent or even tumor-inhibiting state, an approach that avoids the toxicity of wholesale depletion. Vitamin D receptor agonists and retinoids have shown stromal-reprogramming effects in preclinical models of pancreatic and colorectal cancer, and the authors discuss how such agents might restore the differentiated, matrix-suppressive phenotype of quiescent fibroblasts.

The authors are careful to note the hard lessons from the field. In pancreatic cancer, the depletion of alpha-smooth muscle actin-positive myofibroblasts in mouse models once accelerated tumor progression, a result that shocked the community and underscored that some CAF subsets may restrain, rather than promote, tumor growth. The emerging consensus, reflected throughout this review, is that the goal should not be to eliminate all fibroblasts but to selectively target the pro-tumor subsets while preserving or enhancing protective ones. This demands better markers, a deeper understanding of CAF ontogeny, and combination strategies that pair stromal targeting with chemotherapy, radiotherapy, or immunotherapy so that dismantling the stromal shield sensitizes tumors to existing treatments rather than being used alone.

For patients with colorectal cancer, particularly the substantial fraction who develop resistance to standard chemotherapy and radiotherapy, the stakes of this research are high. Colorectal cancer remains one of the most common and lethal malignancies worldwide, and the review’s authors argue that the advances they summarize, from CAF subtype characterization to stromal-targeted therapeutics, could contribute to improving survival in tumors that currently defy classic therapies. The tumor microenvironment has moved from the margins of cancer biology to its center, and the fibroblast, once dismissed as passive scaffolding, is now understood as an active engineer of malignancy. Learning to outmaneuver these cellular architects, the review concludes, may be one of the decisive steps toward finally breaking through the wall of therapeutic resistance in colorectal cancer.

Subject of Research: The role of cancer-associated fibroblasts in therapeutic resistance and tumor progression in colorectal cancer

Article Title: Cancer-associated fibroblasts as key mediators of therapeutic resistance and tumor progression in colorectal cancer

Article References: de Lima Coelho, B. M., Murad, L. B., Costa, R. M. B., Castillo-Medina, Y. K., Lopes-Rios, L. L., & Morgado-Diaz, J. A. (2026). Cancer-associated fibroblasts as key mediators of therapeutic resistance and tumor progression in colorectal cancer. Cancer Cell International. https://doi.org/10.1186/s12935-026-04474-1

Image Credits: AI Generated

DOI: 10.1186/s12935-026-04474-1

Keywords: cancer-associated fibroblasts, colorectal cancer, tumor microenvironment, therapeutic resistance, extracellular matrix, TGF-beta, epithelial-mesenchymal transition, chemotherapy, radiotherapy, immunotherapy, CAF subtypes, tumor stroma

The central concept emerging from the review is metabolic plasticity. Unlike many differentiated cancer cells that become locked into a single metabolic strategy, BCSCs can dynamically shift among glycolysis, the rapid but inefficient fermentation of glucose; oxidative phosphorylation, the mitochondrial process that extracts far more energy per glucose molecule; lipid metabolism, which supplies both fuel and membrane components; and amino acid metabolism, which feeds protein synthesis and redox balancing. This flexibility allows BCSCs to maintain their stem-like properties, including self-renewal and the capacity to regenerate an entire tumor, even as oxygen levels, nutrient availability, and signaling conditions fluctuate dramatically within a growing tumor.

Historically, cancer metabolism research was dominated by the Warburg effect, the observation that many tumors prefer glycolysis even in the presence of oxygen. The BCSC literature complicates that picture considerably. Studies cited in the review indicate that stem-like breast cancer cells often rely heavily on mitochondrial oxidative phosphorylation, particularly in populations enriched for markers such as ALDH activity, while more proliferative, non-stem tumor cells tend toward glycolysis. Other work has shown that under hypoxia, hypoxia-inducible factors drive glycolytic enzymes and stemness factors simultaneously, linking a low-oxygen niche directly to the maintenance of the stem-like state. The lesson is that no single metabolic fingerprint defines a BCSC; rather, the fingerprint changes with cellular state and environmental context, and that adaptability is itself a therapeutic problem.

Lipid metabolism has emerged as a particularly important pillar of BCSC biology. Fatty acid oxidation provides abundant ATP and NADPH, helping these cells resist oxidative stress, while de novo lipid synthesis supports membrane expansion during division and the generation of signaling lipids. Enzymes such as acetyl-CoA carboxylase and fatty acid synthase, along with uptake of exogenous fatty acids through CD36, have been implicated in stemness and metastatic potential in breast cancer models. The review emphasizes that lipid handling is not merely a fuel issue: lipid species can influence membrane fluidity, signaling cascades, and even the epigenetic marks that keep stemness programs active, tying metabolism directly to gene regulation.

Amino acid metabolism completes the picture. Glutamine, the most abundant circulating amino acid, feeds the tricarboxylic acid cycle through glutaminolysis, supplies nitrogen for nucleotide synthesis, and supports glutathione production for antioxidant defense. BCSCs, which must endure reactive oxygen species generated by chemotherapy and by their own metabolic activity, appear particularly dependent on such redox-buffering pathways. Serine, glycine, and branched-chain amino acid metabolism have also been linked to tumor initiation and progression in breast cancer, underscoring how the manipulation of nutrient streams beyond glucose shapes the fitness of the most dangerous cells in a tumor.

What elevates the review beyond a catalog of pathways is its insistence that BCSC metabolism cannot be understood in isolation. The tumor microenvironment is a metabolic ecosystem in which adipocytes, cancer-associated fibroblasts, endothelial cells, and immune cells all exchange nutrients and emit paracrine signals that reshape how cancer cells process fuel. In the breast, adipocytes are abundant and can release fatty acids and adipokines that tumor cells readily exploit. Fibroblasts can secrete lactate and alanine that neighboring cancer cells take up as carbon sources, a phenomenon sometimes described as metabolic symbiosis. Endothelial cells lining tumor vasculature influence oxygen and nutrient delivery, while immune cells both compete for nutrients and respond to metabolic signals that can dampen antitumor activity.

The relationship runs in both directions. The review highlights that BCSCs actively remodel their niche to favor tumor initiation, immune evasion, and metastatic colonization. By consuming key nutrients, secreting lactate and other metabolites, and altering extracellular matrix composition, BCSCs can condition their surroundings to suppress cytotoxic T cell function and recruit immunosuppressive cell types. Metabolites themselves act as signaling molecules: lactate, for example, is now recognized as an immunosuppressive oncometabolite, while lipid accumulation in the tumor microenvironment has been associated with dysfunction in antitumor immune cells. This metabolic crosstalk means that targeting BCSC metabolism may simultaneously disarm the protective niche those cells construct around themselves.

Metastasis represents perhaps the most dramatic test of metabolic plasticity. A cancer cell leaving a primary tumor must survive in circulation, endure shear stress and detachment-induced stress, and then colonize tissues with entirely different nutrient and oxygen landscapes, whether bone, lung, liver, or brain. The review discusses how BCSCs and cells with stem-like properties appear pre-adapted for this journey, in part because their flexible metabolism allows them to switch fuel sources as they encounter new microenvironments. At metastatic sites, interactions with resident stromal cells, including osteoclasts in bone or astrocytes in brain, can supply additional metabolic support, illustrating how niche-derived signals continue to govern BCSC behavior long after cells have left the primary tumor.

These insights are now informing therapeutic strategies. The review surveys approaches aimed at metabolic vulnerabilities, including inhibitors of mitochondrial complexes, fatty acid oxidation and synthesis blockers, glutaminase inhibitors, and agents targeting key regulators such as AMPK, mTOR, and hypoxia-inducible factors. Combination strategies that pair metabolic drugs with chemotherapy, endocrine therapy, or immunotherapy are of particular interest, since metabolic rewiring is one route by which BCSCs survive conventional treatment. The authors also acknowledge the challenges: metabolic redundancy means that blocking one pathway often pushes cells onto another, systemic toxicity is a real concern because normal stem cells and immune cells share many of these pathways, and the plasticity that makes BCSCs dangerous also makes them capable of adapting to single-agent metabolic therapies.

The broader message of the Lee and Kang review is that breast cancer should be viewed not just as a genetic disease but as a metabolic and ecological one, in which the fittest cells thrive by continuously renegotiating their relationship with available fuel and with their neighbors. Understanding the interconnected metabolic networks and niche-derived signals that govern BCSC behavior, the authors argue, may enable the development of more effective therapies designed to reduce breast cancer progression and recurrence. As open-access work, the review offers researchers and clinicians alike a comprehensive map of a field that is moving rapidly, and it makes a compelling case that the next generation of breast cancer treatments will need to target not only what cancer cells are, but what they eat, how they breathe, and the company they keep.

Subject of Research: Metabolic plasticity and microenvironmental regulation of breast cancer stem cells

Article Title: Breast cancer stem cell metabolism: metabolic plasticity and microenvironmental regulation

Article References: Lee, E., & Kang, Y. (2026). Breast cancer stem cell metabolism: metabolic plasticity and microenvironmental regulation. Cellular and Molecular Life Sciences. https://doi.org/10.1007/s00018-026-06435-3

Image Credits: AI Generated

DOI: 10.1007/s00018-026-06435-3

Keywords: breast cancer stem cells, metabolic plasticity, tumor microenvironment, glycolysis, oxidative phosphorylation, lipid metabolism, amino acid metabolism, metastasis, therapeutic resistance, immune evasion, cancer metabolism, tumor niche

The stakes could hardly be higher. Diffuse midline glioma, including diffuse intrinsic pontine glioma, accounts for roughly 10 to 20 percent of pediatric central nervous system tumors and is the leading cause of cancer-related death in children. Median overall survival is a mere 11 months, and fewer than 10 percent of patients survive beyond two years. For decades, radiotherapy has been the only standard-of-care option, offering transient benefit at best. In August 2025, the US Food and Drug Administration granted accelerated approval to dordaviprone, also known as ONC201, for previously treated patients aged one year and older with H3K27M-mutant disease, and preclinical work supporting combination with the PI3K/mTOR inhibitor paxalisib provided the rationale for the adaptive Phase II PNOC022 trial. Yet responses remain variable and often fleeting, raising the question that sits at the heart of the review: which molecular programs allow these tumors to adapt, evolve and resist?

The answer begins with the tumor’s origin. Diffuse midline glioma is defined by alterations in histone H3 lysine 27, most commonly the H3K27M mutation, or by overexpression of EZHIP. Both events converge on disruption of polycomb repressive complex 2, the cellular machinery that maintains repressive chromatin marks, producing a global collapse in H3K27 trimethylation and a profoundly dysregulated epigenetic landscape. The consequence is aberrant reactivation of developmental programs that should have been silenced after cells committed to a lineage. Single-cell studies show the tumor arises within a developmentally restricted glial progenitor context and recapitulates an oligodendroglial differentiation hierarchy, dominated by proliferative oligodendrocyte precursor cell-like states. This extensive heterogeneity and plasticity means therapy can select for, or actively induce, resistant cellular states that remain poorly characterized.

To bring order to this complexity, the authors organize tumor adaptation into four axes: compositional shifts in cellular populations, functional state remodeling, malignant cell plasticity, and intercellular communication networks. Each axis represents a different way a tumor can respond to treatment, and each demands its own computational approach. The framework matters because resistance is not a single phenomenon. A tumor may expand a pre-existing resistant population, reprogram its transcriptional programs without changing cellular identity, transition cells between differentiation states, or rewire the signaling conversations between malignant cells and their microenvironment. Disentangling these possibilities from high-dimensional single-cell and spatial transcriptomic data requires sophisticated mathematics and machine learning.

On the first axis, the review highlights methods that model differential abundance while accounting for the compositional and technical pitfalls that plague single-cell data. Because cell populations are measured as relative proportions, depletion of one group can masquerade as enrichment of another, and conventional clustering can force cells into discrete groups even when states exist along a continuum. Tools such as Milo represent cellular states as neighborhoods within a k-nearest neighbors graph, enabling detection of responsive intermediate states, while newer machine learning approaches like Cellograph use graph neural networks to identify treatment-responsive and resistant states across conditions. Spatially informed methods such as NicheCompass extend this to tissue architecture, relevant because in diffuse midline glioma, proliferating OPC-like and OC-like cells cluster within mitotic niches, while mesenchymal-like cells colocalize with vascular cells and SPP1-positive, GPNMB-positive myeloid cells in an immunosuppressive niche.

Functional state remodeling captures a subtler phenomenon: a cell population may persist after treatment while undergoing profound reprogramming. The H3K27M mutation drives extensive metabolic rewiring, creating both vulnerabilities and escape routes. Inhibiting oxidative phosphorylation with phenformin extends survival in preclinical models, but tumors adapt by activating alternative pathways including cholesterol synthesis. Similarly, these tumors depend heavily on purine metabolism, and after radiotherapy they upregulate the purine salvage pathway; targeting hypoxanthine-guanine phosphoribosyltransferase alongside radiation produces durable responses in mouse models. Computational tools such as RECODR can detect shifts in pathway activity and identify the transcription factors driving adaptation, while TransMarker and CancerTrace reconstruct dynamic regulatory networks. Spatial methods including C-SIDE and SPATA2 then correlate these programs with anatomical position, from tumor core to infiltrative margin.

Plasticity, the third axis, may be the defining feature of this disease. H3K27 alterations elevate α-ketoglutarate, a cofactor for histone demethylases, reinforcing the hypomethylated state. Dordaviprone disrupts mitochondrial homeostasis and alters α-ketoglutarate availability, partially restoring H3K27 methylation, proof that epigenetic states are therapeutically modifiable. To track how cells move between states, the review describes trajectory inference methods such as Monocle and Slingshot, which have revealed multiple OPC-like states in diffuse midline glioma and a resistance-associated trajectory in DIPG models, with resilient mesenchymal-like and mitotic populations emerging after triple therapy. Because pseudotime from static snapshots cannot establish directionality, RNA velocity approaches and deep generative models such as PRESCIENT, GRNvelo and CytoTRACE2 add temporal and potency information. Optimal transport methods including STIFT, Moscot and STORIES reconstruct cellular trajectories while preserving spatial context, potentially revealing whether resistant states pre-exist or are induced by therapy.

The fourth axis acknowledges that tumor cells do not adapt in isolation. The microenvironment of diffuse midline glioma is dominated by tumor-associated myeloid cells with sparse lymphocyte infiltration, and neuron-glioma connectivity is increasingly implicated in tumor genesis. Ligand-receptor inference tools such as CellChat and CellPhoneDB have exposed extensive tumor-myeloid communication, including the IGSF11-VISTA immune checkpoint axis. Newer frameworks push further: scComm uses supervised contrastive learning to reconstruct communication at single-cell resolution, CELLetter integrates large language models to predict novel ligand-receptor pairs, Tensor-cell2cell models interactions across multiple conditions simultaneously, and COMMOT and CellNEST exploit spatial proximity and graph attention to map signaling between neighboring cells. DualCellChat even infers directionality, identifying senders and receivers. These networks highlight actionable pathways that could be disrupted to restore antitumor immunity or enhance treatment efficacy.

Translating these models into the clinic remains formidable. True longitudinal sampling is largely unfeasible in patients, with matched specimens typically limited to diagnostic biopsies and post-mortem autopsies, confounded by cumulative therapy effects. Deep learning demands patient-level replication, careful separation of training and test data, and robust generalization across institutions. The authors point to preclinical models, organoids, patient-derived xenografts and liquid biopsies of blood or cerebrospinal fluid as bridges toward prospective modeling, and note that biomarkers such as TP53 mutation status, linked to radioresistance and reduced dordaviprone response, could stratify patients in adaptive trials. Foundation models like NicheFormer, pretrained on large single-cell atlases, have yet to be applied to resistance trajectories but represent a promising direction. If the field succeeds, the authors conclude, artificial intelligence integrated with scientific and ethical rigor could make diffuse midline glioma care predictive, personalized and proactive, a future in which resistance is anticipated before it emerges rather than discovered after treatment fails.

Subject of Research: Machine learning and computational modeling of therapeutic response and resistance in diffuse midline glioma using single-cell and spatial transcriptomics

Article Title: Machine learning and computational approaches to model therapeutic response and resistance in diffuse midline glioma

Article References: Dubois, O. A., Loughnan, O. E. L., Jiang, Y., Petraello, B., Douglas, A. M., McLachlan, T., Findlay, I. J., Vo, T., Savary, C., & Dun, M. D. (2026). Machine learning and computational approaches to model therapeutic response and resistance in diffuse midline glioma. Journal of Neuro-Oncology, 179(3), Article 104. https://doi.org/10.1007/s11060-026-05817-8

Image Credits: AI Generated

DOI: 10.1007/s11060-026-05817-8

Keywords: diffuse midline glioma, DIPG, machine learning, single-cell RNA sequencing, spatial transcriptomics, therapeutic resistance, H3K27M, tumor plasticity, tumor microenvironment, dordaviprone, computational biology, pediatric oncology

The review, led by researchers at West China Hospital of Sichuan University, is notable for its insistence on rigor. The authors point out that while aberrant condensate behavior is increasingly implicated in cancer, many intracellular assemblies that have been attributed to LLPS have not been validated using strict experimental criteria. This matters because the cell contains many different ways of organizing matter: stable enzymatic complexes, scaffold-driven assemblies, polymer networks, and gel-like aggregates can all look like droplets under a microscope without being true liquid phases. A true LLPS droplet typically forms through weak, multivalent interactions among intrinsically disordered regions of proteins, fuses and relaxes like a liquid, exchanges components dynamically with the surrounding dilute phase, and dissolves predictably when conditions such as salt concentration, temperature, or protein concentration change. The review lays out an evidence-oriented framework for applying these criteria before labeling a structure a phase-separated condensate, a discipline the authors say the cancer field urgently needs.

At the biophysical level, condensate formation depends on a set of molecular determinants that the review examines in detail. Intrinsically disordered regions, or IDRs, are stretches of protein sequence that do not fold into a single rigid structure but instead sample many conformations. These regions carry distributed motifs—charged blocks, aromatic residues, proline-rich motifs, and arginine-glycine rich elements—that engage in multiple weak, transient interactions with one another. When the combined valence and strength of these interactions cross a threshold, the molecules demix into a dense phase enriched in those components and a dilute phase depleted of them. RNA, multivalent scaffolding proteins, and post-translational modifications such as phosphorylation, methylation, SUMOylation, and O-GlcNAcylation all tune where that threshold sits. The result is that a cell can, in principle, switch entire condensates on or off, reshape their composition, alter their viscosity, or harden them into less dynamic states without synthesizing new proteins—a degree of regulatory control that conventional signaling pathways cannot match.

Cancer exploits this control system in several ways, and the review systematically catalogues them. Mutations can add, remove, or charge-flip residues within disordered regions, shifting the phase boundary so that droplets form at concentrations where healthy cells never condense. Chromosomal translocations generate fusion proteins that stitch together a DNA-binding domain with a prion-like disordered domain, a combination notorious for driving condensate formation at oncogenic loci. Altered post-translational modification patterns, changes in RNA abundance, shifts in metabolic state, and the crowded, hypoxic, acidic environment of a tumor can all push condensates past their saturation point. The unifying theme, according to the authors, is that tumor cells do not need to invent new molecular machines; they can repurpose an existing physical mechanism of cellular organization and tilt it toward growth, survival, and spread.

The functional consequences are evaluated across five major domains of cancer biology. The first is signaling and transcription. Phase separation offers a mechanistic explanation for how transcription factors, co-activators, and the RNA polymerase machinery concentrate at specific genomic loci to form transcriptional hubs, and how signaling receptors cluster at membranes to amplify weak extracellular signals. If a tumor amplifies or mutates the multivalent components of these hubs, the hubs can become hyper-condensed, locking oncogenic programs into a permanently active state. The second domain is genome maintenance, where condensates are implicated in the response to double-strand breaks, in heterochromatin organization, and in the sequestration of repair factors. Condensate dysregulation here can either blunt DNA repair, promoting mutation accumulation, or paradoxically protect tumor cells from genotoxic therapies by concentrating repair machinery at damage sites.

The third and fourth domains—metastasis with cellular plasticity and tumor immunity—illustrate how condensate physics reaches beyond the nucleus. The review discusses how phase-separated assemblies participate in the epithelial–mesenchymal transition, cytoskeletal remodeling, and extracellular vesicle biology that enable tumor cells to detach, survive in circulation, and colonize distant tissues. On the immunity side, condensates shape the antigen presentation machinery, the formation of immune synapses in T cells, the behavior of stress granules during interferon signaling, and the cGAS–cGAMP–STING-type innate sensing pathways that determine whether a tumor looks like a threat to the immune system. A condensate that sequesters double-stranded RNA or dampens interferon-stimulated gene expression can effectively switch off the molecular alarm bells that would otherwise recruit cytotoxic T cells and natural killer cells to the tumor.

The fifth domain, therapeutic resistance, ties these mechanisms to the clinic. The review evaluates evidence that condensate formation contributes to resistance against tyrosine kinase inhibitors, PARP inhibitors, and androgen receptor pathway inhibition, among other therapies. The proposed mechanisms include the physical sequestration of drugs within dense phases, the concentration of drug targets into compartments where inhibitor penetration is poor, the buffering of inhibited pathways by condensate-stored reserves of signaling molecules, and stress granule–mediated survival programs that keep cells alive long enough to evolve durable resistance. Because these are physical, population-level phenomena rather than single gene mutations, they may explain forms of resistance that genomic sequencing alone cannot predict—adding a spatial and material dimension to the pharmacology of cancer treatment.

Perhaps the most forward-looking portion of the review concerns condensate-directed therapeutic strategies, which the authors assess explicitly according to the strength of their experimental and clinical evidence. Several classes of approach are now in play. Small molecules that partition into specific condensates can disrupt or remodel them; some such molecules have already demonstrated that selective condensate modulation is chemically achievable. Proteolysis-targeting chimeras, or PROTACs, can be designed to degrade the scaffold proteins or IDRs around which oncogenic condensates assemble. Oligonucleotide therapeutics can target the RNAs that nucleate pathological droplets. Nanoparticle platforms, including engineered particles designed to home in on and perturb specific condensates, represent a delivery-oriented strategy. The authors’ verdict, however, is deliberately cautious: the overwhelming majority of this work remains preclinical. Demonstrating that a compound dissolves a droplet in a test tube, or even in a cell line, is a long way from showing that it shrinks tumors in patients without dissolving the healthy condensates that normal cells depend on.

That caveat reflects the central challenge the review identifies for the field: specificity and validation. Cells are full of condensates that perform essential functions in nucleolar assembly, ribosome biogenesis, RNA processing, and stress adaptation, so a broadly acting condensate disruptor risks toxicity through collateral damage. Experimental validation remains difficult because phase separation in living cells is hard to prove unambiguously; methods such as live-cell imaging of fusion events, fluorescence recovery measurements, optogenetic control of multivalency, and proximity labeling are powerful but each carries its own artifacts. The authors also flag the conceptual danger of overextension, noting that the umbrella term biomolecular condensation covers a broader range of mechanisms and material states than LLPS proper, and that blurring the distinction has led the literature into claims that later scrutiny could not support. Their framework asks researchers to state which process they are actually observing and to apply matching criteria.

What emerges from the review is both a warning and a promise. The warning is that the condensate-cancer literature contains a mixture of rigorously validated LLPS mechanisms and incompletely characterized assemblies, and that therapeutic enthusiasm should be calibrated accordingly. The promise is that a genuine physical principle underlies a strikingly wide range of malignant behaviors—from oncogenic transcription to immune evasion to drug resistance—and that principle, unlike a mutation, is in principle reversible by changing the chemical environment of the cell. If the field can agree on how to prove that a droplet is a droplet, and if chemistry can deliver molecules that reshape only the condensates that matter, the energy stored in a decade of condensate biology may yet translate into the next generation of cancer therapeutics. For now, as the authors conclude, the potential remains predominantly preclinical, and the framework they propose is intended to make sure that the path from droplet to drug is followed with the same rigor that the physics itself demands.

Subject of Research: The role of liquid–liquid phase separation and biomolecular condensates in cancer mechanisms and therapy

Article Title: Liquid–liquid phase separation in cancer: mechanisms, biological functions, and therapeutic perspectives

Article References: Tang, P., Li, Y., Huang, C., Xiong, Y., Li, Y., Zhang, T., & Zhang, C. (2026). Liquid–liquid phase separation in cancer: mechanisms, biological functions, and therapeutic perspectives. Molecular Cancer. https://doi.org/10.1186/s12943-026-02798-0

Image Credits: AI Generated

DOI: 10.1186/s12943-026-02798-0

Keywords: liquid–liquid phase separation, biomolecular condensates, cancer biology, intrinsically disordered regions, therapeutic resistance, transcriptional condensates, tumor immunity, metastasis, PROTACs, drug discovery, Molecular Cancer, condensate dysregulation

Extrachromosomal DNA first attracted attention decades ago when researchers noticed strange, ring-shaped DNA fragments floating outside the chromosomes of tumor cells. Unlike chromosomal DNA, ecDNA is structurally independent, frequently circular and acentromeric, meaning it lacks the centromere structures that normally ensure chromosomes are distributed evenly during cell division. This absence has profound consequences. During mitosis, ecDNA molecules are inherited through noncanonical behaviors that allow unequal segregation between daughter cells, meaning one daughter cell can receive a windfall of oncogene copies while the other receives few or none. The review emphasizes that this non-Mendelian inheritance pattern also permits coordinated co-inheritance, in which multiple ecDNA species carrying different oncogenes and regulatory elements travel together through cell generations, allowing advantageous combinations of genes and regulatory states to persist and propagate within a tumor population.

The classical view of ecDNA centered on copy-number biology: more copies of an oncogene such as MYC or EGFR meant more messenger RNA and more oncogenic protein, fueling aggressive growth. The new synthesis argues that this framing misses the most consequential part of the story. ecDNA molecules carry not just genes but enhancers, the short DNA sequences that act as volume controls for gene expression. Because ecDNA is circular, enhancers that were once distant from their target genes on linear chromosomes can be brought into immediate physical proximity, rewiring enhancer-oncogene communication in ways that linear DNA cannot easily achieve. The review describes how ecDNA can hijack pre-existing enhancers, activate noncanonical regulatory elements that would normally remain silent, and thereby transform a raw genome rearrangement event into genuine epigenetic innovation.

At the physical level, ecDNA does not float passively in the nucleus. Advanced imaging and genomic mapping studies summarized in the review show that ecDNA molecules cluster together into transcriptionally active nuclear hubs, dense assemblies where multiple circular molecules and their target genes on chromosomes converge. These hubs behave like condensate-associated structures, membrane-less compartments that concentrate transcription machinery, transcription factors and co-activators at extraordinarily high local concentrations. The result is a hyperactive transcriptional factory that can drive oncogene expression to levels unattainable through ordinary chromosomal regulation. In this sense, ecDNA-positive tumor cells are not merely carrying extra genetic cargo; they are constructing an entirely new layer of nuclear architecture dedicated to amplifying and fine-tuning oncogenic signaling.

This architectural rewiring has direct consequences for chromatin itself. The review details how ecDNA reshapes chromatin accessibility, the degree to which DNA is physically open and available to transcription factors. ecDNA tends to maintain an unusually open chromatin state, rich in active histone marks, which keeps its passenger enhancers and promoters in a perpetually transcription-ready configuration. Because ecDNA hubs can also contact chromosomal targets, this openness can extend to the ordinary genome, altering which chromosomal genes are switched on or off. Through these mechanisms, ecDNA generates transcriptional plasticity, the capacity of a tumor cell to shift its gene-expression program rapidly in response to changing conditions, whether that condition is a drug, an immune attack or a change in nutrient supply.

That plasticity feeds directly into some of the most clinically feared phenomena in oncology. The review positions ecDNA as a key driver of intratumoral heterogeneity, the coexistence of genetically and epigenetically distinct cell populations within a single tumor. Because ecDNA segregates unequally during mitosis, daughter cells diverge quickly in oncogene dosage and regulatory state, generating a diverse portfolio of cellular phenotypes from a single founding lineage. This diversity provides abundant raw material for clonal evolution: when chemotherapy eliminates cells with one regulatory configuration, subpopulations with different ecDNA compositions and enhancer landscapes survive and repopulate the tumor. The same logic applies to metastatic adaptation, where disseminated cells must reprogram their transcriptional identity to colonize new tissues, and to therapeutic resistance, where ecDNA-mediated enhancer rewiring can rapidly upregulate drug targets or bypass inhibited pathways.

Yet the very features that make ecDNA so powerful for the tumor may also constitute its Achilles’ heel. The review highlights that the high transcriptional burden carried by ecDNA creates a form of genomic stress known as transcription-replication conflict. When the transcription machinery and the DNA replication machinery collide on the same stretch of DNA, the resulting collisions can stall replication forks and generate DNA damage. ecDNA-positive cells, with their extraordinarily high transcriptional output, may live permanently near the threshold of tolerable transcription-replication interference. This dependence suggests selective vulnerabilities that could be exploited therapeutically: drugs that further stress transcription or replication, or that disrupt the specialized regulatory architecture of ecDNA hubs, might preferentially harm ecDNA-rich tumors while sparing normal cells.

The authors also point to the dependence of ecDNA-positive tumors on the integrity of their nuclear hubs and condensates as a second class of vulnerability. If transcriptional output in these tumors relies on the physical coalescence of ecDNA molecules and their associated regulatory factors, then interventions that dissolve or destabilize those assemblies, for example by targeting condensate-forming proteins or the chromatin regulators that maintain open chromatin on ecDNA, could collapse the tumor’s oncogenic transcription program. Similarly, because ecDNA inheritance depends on noncanonical mitotic behaviors rather than centromeres, the machinery that distributes ecDNA during cell division represents another potential point of attack. None of these strategies has yet produced approved therapies, but the review frames them as a conceptual frontier for precision oncology, in which treatment decisions could one day be guided by mapping a tumor’s ecDNA complement and its regulatory architecture.

Perhaps the most significant contribution of the review is conceptual. By shifting the focus from copy-number biology to regulatory biology, the authors reframe ecDNA not as a passive amplifier of oncogenes but as an active platform for epigenetic reprogramming, a mobile, self-perpetuating module that converts structural genome chaos into functional transcriptional diversity. This reframing has implications for how scientists model tumor evolution, how pathologists assess tumor aggressiveness and how drug developers search for targets in the least stable, most adaptable corners of the cancer genome. As long-read sequencing, spatial genomics and chromatin mapping technologies mature, the ability to read a tumor’s ecDNA landscape may become as routine as today’s copy-number profiling, opening a window onto the epigenetic strategies that cancers use to survive everything medicine throws at them.

The review, published open access in Molecular Cancer, was supported by the Shandong Provincial Traditional Chinese Medicine Science and Technology Project and the Health Commission of Jiangxi Province. Its authors span institutions across China, including Nanchang University, Hunan University, Naval Medical University and Shandong First Medical University, reflecting the rapidly growing international effort to understand the nonchromosomal genome of cancer. What emerges from their synthesis is a picture of tumors that are not just collections of mutated genes but ecosystems of mobile regulatory elements, and of ecDNA as the engine that keeps those ecosystems adaptable, heterogeneous and, for now, one step ahead of treatment.

Subject of Research: The role of extrachromosomal DNA as a regulatory platform for epigenetic reprogramming in cancer

Article Title: Extrachromosomal DNA as a platform for epigenetic reprogramming in cancer

Article References: Liu, B.-X., Zhou, L., Lai, S., Han, X., Dai, X.-J., Liu, R., Wang, Y., Chen, D., Wei, J., Hu, H., Zu, W., Jiang, L., Chang, J., & Zha, L. (2026). Extrachromosomal DNA as a platform for epigenetic reprogramming in cancer. Molecular Cancer. https://doi.org/10.1186/s12943-026-02789-1

Image Credits: AI Generated

DOI: 10.1186/s12943-026-02789-1

Keywords: extrachromosomal DNA, ecDNA, epigenetic reprogramming, chromatin accessibility, enhancer rewiring, transcriptional plasticity, tumor evolution, intratumoral heterogeneity, therapeutic resistance, nuclear hubs, precision oncology, Molecular Cancer