N Nature Cell Biology · Dec 01, 2025 RASH3D19 mediates RAS activation through a positive feedback loop in KRAS-mutant cancer Therapeutic targeting of mutant KRAS pathways driving cancers is being actively investigated to identify feedback mechanisms responsible for the development of adaptive resistance to mutant KRAS inhibitors undergoing clinical trials. Here we report RASH3D19 as a mediator of RAS pathway activation through a positive feedback loop involving the KRAS–microRNA signalling axis. KRAS-induced miR-222 represses ETS1 expression and downstream transactivation of miR-301a leading to elevation of its target RASH3D19. RASH3D19 facilitates activation of RAS pathways by promoting dimerization and interaction of EGFR with the SOS2, GRB2, SHP2 and GAB1 complex. Genetic deletion of RASH3D19 in mutant KRAS-expressing cancer cells exhibits growth retardation in vitro, in vivo and sensitized pancreatic ductal adenocarcinoma and colorectal cancer cells, organoids and xenografts to mutant KRAS inhibitors, suppressing feedback reactivation of RAS pathways. Therapeutic targeting of RASH3D19 is expected to lead to tumour debulking and alleviating resistance to KRAS inhibitors in mutant KRAS-expressing cancers. Cancer therapeutic resistance Oncogenes Targeted therapies biology
N Nature Cell Biology · Nov 28, 2025 WDR4 drives tumour-associated macrophage reprogramming and tumour progression via selective translation and membrane cholesterol efflux Tumour-associated macrophages (TAMs) play a pivotal role in shaping the immune microenvironment of hepatocellular carcinoma (HCC), influencing tumour progression and immunotherapy response. WDR4, a tRNA-binding cofactor of theN7-methylguanosine (m7G) methyltransferase complex, remains poorly understood in its independent functions. Here we show that WDR4 is significantly upregulated in HCC-associated TAMs and correlates with poor prognosis. Loss of WDR4 in monocyte-derived macrophages, but not in resident Kupffer cells, reprogrammes TAMs towards an antitumoral phenotype and suppresses HCC progression. Mechanistically, cytoplasmic WDR4 acts independently of m7G modification by directly interacting with eIF4E2 to enhance eIF4E-mediated selective translation of ABCA1, thereby promoting membrane cholesterol efflux and maintaining pro-tumoral polarization. Targeted silencing of WDR4 in TAMs using a CpG-small interfering RNA delivery system enhances antitumour immunity, inhibits tumour progression and improves the efficacy of anti-PD-1 therapy. Our findings identify WDR4 as a key regulator of TAM polarization and a promising therapeutic target to enhance immunotherapeutic outcomes. Cancer metabolism Hepatocellular carcinoma Tumour immunology biology mouse experiments
N Nature Cell Biology · Nov 17, 2025 DNA fragmentation factor B suppresses interferon to enable cancer persister cell regrowth Oncogene-targeted cancer therapies can provide deep responses but frequently suffer from acquired resistance. Therapeutic approaches to treat tumours that have acquired drug resistance are complicated by continual tumour evolution and multiple co-occurring resistance mechanisms. Rather than treating resistance after it emerges, it may be possible to prevent it by inhibiting the adaptive processes that initiate resistance, but these are poorly understood. Here we report that residual cancer persister cells that survive oncogene-targeted therapy are growth arrested by drug stress-induced intrinsic type I interferon signalling. To escape growth arrest, persister cells leverage apoptotic machinery to transcriptionally suppress interferon-stimulated genes (ISGs). Mechanistically, persister cells sublethally engage apoptotic caspases to activate DNA endonuclease DNA fragmentation factor B (also known as caspase-activated DNase), which induces DNA damage, mutagenesis and stress response factor activating transcription factor 3 (ATF3). ATF3 limits activator protein 1-mediated ISG expression sufficiently to allow persister cell regrowth. Persister cells deficient in DNA fragmentation factor B or ATF3 exhibit high ISG expression and are consequently unable to regrow. Therefore, sublethal apoptotic stress paradoxically promotes the regrowth of residual cancer cells that survive drug treatment. Apoptosis Cancer biology
N Nature Cell Biology · Oct 21, 2025 Enhancer activation from transposable elements in extrachromosomal DNA Extrachromosomal DNA (ecDNA) drives oncogene amplification and intratumoural heterogeneity in aggressive cancers. While transposable element reactivation is common in cancer, its role on ecDNA remains unexplored. Here we map the 3D architecture ofMYC-amplified ecDNA in colorectal cancer cells and identify 68 ecDNA-interacting elements—genomic loci enriched for transposable elements that are frequently integrated onto ecDNA. We focus on an L1M4a1#LINE/L1 fragment co-amplified withMYC, which functions only in the ecDNA-amplified context. Using CRISPR-CATCH, CRISPR interference and reporter assays, we confirm its presence on ecDNA, enhancer activity and essentiality for cancer cell fitness. These findings reveal that repetitive elements can be reactivated and co-opted as functional rather than inactive sequences on ecDNA, potentially driving oncogene expression and tumour evolution. Our study uncovers a mechanism by which ecDNA harnesses repetitive elements to shape cancer phenotypes, with implications for diagnosis and therapy. Cancer Cell biology Gene regulation biology
N Nature Cell Biology · Oct 16, 2025 Epigenetic alterations facilitate transcriptional and translational programs in hypoxia Adaptation to cellular stresses entails an incompletely understood coordination of transcriptional and post-transcriptional gene expression programs. Here, by quantifying hypoxia-dependent transcriptomes, epigenomes and translatomes in T47D breast cancer cells and H9 human embryonic stem cells, we show pervasive changes in transcription start site (TSS) selection associated with nucleosome repositioning and alterations in H3K4me3 distribution. Notably, hypoxia-associated TSS switching was induced or reversed via pharmacological modulation of H3K4me3 in the absence of hypoxia, defining a role for H3K4me3 in TSS selection independent of HIF1-transcriptional programs. By remodelling 5′UTRs, TSS switching selectively alters protein synthesis, including enhanced translation of messenger RNAs encoding pyruvate dehydrogenase kinase 1, which is essential for metabolic adaptation to hypoxia. These results demonstrate a previously unappreciated mechanism of translational regulation during hypoxia driven by epigenetic reprogramming of the 5′UTRome. Cancer microenvironment Computer modelling Dynamic networks Gene regulatory networks biology
N Nature Cell Biology · Oct 13, 2025 CoCo-ST detects global and local biological structures in spatial transcriptomics datasets Spatial domain detection methods often focus on high-variance structures, such as tumour-adjacent regions with sharp gene expression changes, while missing low-variance structures with subtle gene expression shifts, like those between adjacent normal and early adenoma regions. Here, to address this, we introduce ‘compare and contrast spatial transcriptomics’ (CoCo-ST), a graph contrastive feature representation framework. By comparing a target sample with a background sample, CoCo-ST detects both high-variance, broadly shared structures and low-variance, tissue-specific features. It offers technical advantages, including multisample integration, batch-effect correction and scalability across technologies from spot-level Visium data to single-cell Xenium Prime 5K and subcellular Visium HD data. We benchmarked CoCo-ST against ten state-of-the-art spatial-domain-detection algorithms using mouse lung precancerous samples, demonstrating its superior ability to identify low-variance spatial structures overlooked by other methods. CoCo-ST also effectively distinguishes cell clusters and niche structures in Visium HD and Xenium Prime 5K data. CoCo-ST is accessible at GitHub ( https://github.com/WuLabMDA/CoCo-ST ). Wu, Zhang and colleagues introduce ‘compare and contrast spatial transcriptomics’ (CoCo-ST), a graph contrastive learning-based method for spatial transcriptomics analysis that detects low-variance structures. Bioinformatics Cancer models Computational biology and bioinformatics biology mouse experiments
N Nature Cell Biology · Sep 30, 2025 Defining heterogeneity in core regulatory circuitry reveals HOXB3 condensation as a potential target in glioblastoma Glioblastoma (GBM) exhibits marked heterogeneity, yet therapeutic strategies effectively targeting this variability remain inadequately developed. Here we employed single-cell CUT&Tag analysis to investigate H3K27ac modifications, uncovering pronounced heterogeneity within the core regulatory circuitry (CRC) of GBM. Notably, we observed heterogeneous condensation states of CRC factors, particularly HOXB3, which are shaped by its intrinsically disordered regions and interactions with RUNX1, driving the phenotypic manifestations. Leveraging these findings, we synthesized the peptide P621-R9, which effectively disrupted HOXB3 condensation, altered chromatin structure and reduced transcription at super-enhancer-associated oncogenic sites in GBM cells exhibiting HOXB3 condensation. Treatment with P621-R9 selectively diminished tumourigenic potential in GBM patient-derived xenograft models characterized by HOXB3 condensates, but showed no efficacy in the models lacking these condensates. These results highlight the critical role of CRC condensation in GBM heterogeneity and suggest that peptide-based targeting of distinct GBM subpopulations could represent an avenue for therapeutic exploration. Cancer epigenetics Cancer immunotherapy CNS cancer Cancer Single-cell Human Drug Development
N Nature Cell Biology · Sep 09, 2025 CD160 dictates anti-PD-1 immunotherapy resistance by regulating CD8+T cell exhaustion in colorectal cancer The colon exhibits higher propensity for tumour development than ileum. However, the role of immune microenvironment differences in driving this disparity remains unclear. Here, by comparing paired ileum and colon samples from patients with colorectal cancer (CRC) and healthy donors, we identified ileum-enriched CD160+CD8+T cells with previously unrecognized characteristics, including resistance to terminal exhaustion and strong clonal expansion. The transfer of CD160+CD8+T cells significantly inhibits tumour growth in microsatellite instability-high and inflammation-induced CRC models.Cd160knockout accelerates tumour growth, which is mitigated by transferring CD160+CD8+T cells. Notably, in microsatellite instability-high and anti-PD-1-resistant CRC models, CD160+CD8+T cells improve anti-PD-1 efficacy and overcome its resistance by increasing tumour-infiltrating progenitor-exhausted T cells, nearly eradicating tumours. Mechanistically, we uncover a CD160–PI3K (p85α) interaction that promotes FcεR1γ and 4-1BB expression via the AKT–NF-κB pathway, thereby enhancing CD8+T cell cytotoxicity. Our study reveals CD160 as a crucial regulator of CD8+T cell function and proposes an innovative immunotherapy strategy of transferring CD160+CD8+T cells to overcome anti-PD-1 resistance. Cancer immunotherapy Cancer therapeutic resistance Colorectal cancer T cells Immunology Cancer Mouse Drug Development Clinical
N Nature Cell Biology · Sep 05, 2025 MLKL PARylation in the endothelial niche triggers angiocrine necroptosis to evade cancer immunosurveillance and chemotherapy Chemoresistance is the leading cause of cancer-related death. How chemotherapy subjugates the cellular crosstalk in the tumour microenvironment to cause chemoresistance remains to be defined. Here we find chemotherapy enables immunosuppressive SDF1+endothelial niche to evade immunosurveillance in ovarian and breast cancers. We integrated human patient data and mouse models to show that chemotherapy selectively activates PARP1–SDF1 axis in tumour endothelial cells (ECs). This angiocrine SDF1 interferes with antitumour interplay between CXCL10+macrophages and CXCR3+CD8+T cells and promotes tumour progression in ovarian and breast cancers. Proteome-based screening revealed that endothelial PARP1 PARylates MLKL, a key necroptosis effector to upregulate angiocrine SDF1 in ECs. In sum, we identify PARylation-dependent necroptosis in tumour ECs as an important step in subverting the tumour microenvironment to evade immunosurveillance. Cancer microenvironment Chemotherapy Immunosurveillance Necroptosis Cancer Immunology Mouse Human Proteomics
N Nature Cell Biology · Aug 19, 2025 Systematic decoding of functional enhancer connectomes and risk variants in human glioma Genetic and epigenetic variations contribute to the progression of glioma, but the mechanisms underlying these effects, particularly for enhancer-associated genetic variations in non-coding regions, still remain unclear. Here we performed high-throughput CRISPR interference screening to identify pro-tumour enhancers in glioma cells. By integrating genome-wide H3K27ac HiChIP data, we identified the target genes of these pro-tumour enhancers and revealed the essential role of enhancer connectomes in promoting glioma progression. Through systematic analysis of enhancers carrying glioma risk-associated single-nucleotide polymorphisms (SNPs), we found that these SNPs can promote glioma progression through the enhancer connectome. Using CRISPR–Cas9-mediated enhancer interference and SNP editing, we demonstrated that glioma-specific enhancer carrying the risk SNPrs2297440regulatesSOX18expression by specifically recruiting transcription factor MEIS1 binding, thereby contributing to glioma progression. Our study sheds light on the molecular mechanisms underlying glioma susceptibility and provides potential therapeutic targets to treat glioma. Cancer epigenetics CNS cancer Epigenomics Cancer CRISPR Genomics Human
