Cancer discovery最新文献

{"title":"Mismatch Repair-Proficient Colorectal Cancer Can Evade Immune Surveillance through an Intrinsic Suppressive Program.","authors":"Chiara Maria Cattaneo, Sharon Scardellato, Gianluca Mauri, Vittoria Matafora, Veera K Ojala, Costanza Cannariato, Rosaria Chilà, Zulma Irene Magnani, Wouter Scheper, Luca Lazzari, Emile E Voest, Maria Chiara Bonini, Angela Bachi, Salvatore Siena, Silvia Marsoni, Giovanni Germano, Alberto Bardelli","doi":"10.1158/2159-8290.CD-26-0542","DOIUrl":"10.1158/2159-8290.CD-26-0542","url":null,"abstract":"<p><p>Although microsatellite-instable (MSI) colorectal cancers, reflecting mismatch repair (MMR) deficiency, often respond to immune checkpoint inhibitors, microsatellite-stable (MSS) tumors remain largely resistant. This disparity is typically attributed to differences in neoantigen load. However, whether antigen-independent mechanisms contribute to immune evasion in MSS colorectal cancer remains unclear. To address this, we engineered a model in which MSI and MSS colorectal cancer cells express identical levels of a defined antigen recognized by T-cell receptor-engineered T cells. Despite equivalent antigen presentation, MSS tumors exhibited impaired T-cell activation, reduced cytotoxicity, and resistance to killing. We linked this immune evasion to the MSS tumor secretome, which suppressed immune responses even in immunogenic MSI cells by impairing immune synapse formation. Surfaceome profiling by mass spectrometry identified glycosylation-dependent alterations that impair immune recognition. Our findings demonstrate that MSS colorectal cancer evades immune attack via intrinsic secretome-driven mechanisms, independent of antigenicity. Targeting glycosylation-linked suppressive pathways may restore T-cell responsiveness and improve immunotherapy efficacy in MSS colorectal cancer.</p><p><strong>Significance: </strong>This study reveals that MMR-proficient colorectal cancers resist T-cell attack not only due to low neoantigen load but also through glycosylation-dependent, secretome-mediated immunosuppression. These findings uncover a previously unrecognized immune evasion mechanism and identify actionable pathways to restore immunotherapy responsiveness in resistant colorectal tumors.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"1992-2007"},"PeriodicalIF":29.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13628094/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147926593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Senescent-Like Neutrophils Shape Angiogenic Immunosuppressive Niches in Colorectal Cancer Liver Metastasis.","authors":"Zhihang Chen, Xiaoxue Ren, Yifan Zhang, Youmei Kang, Ye Yang, Yihang Xu, Qian Zhou, Changyi Liao, Qianwen Zeng, Xin Liu, Renxuan Lin, Yu Yang, Feng Luo, Shunli Shen, Sui Peng, Xiaoxing Li, Jianting Long, Lixia Xu, Ming Kuang","doi":"10.1158/2159-8290.CD-25-0820","DOIUrl":"10.1158/2159-8290.CD-25-0820","url":null,"abstract":"<p><p>Neutrophils are major players in innate immunity. However, their landscape and functions in colorectal cancer liver metastasis (CRLM) remain poorly understood. In this study, using single-cell RNA sequencing and spatial-enhanced-resolution-omics sequencing, we provide a comprehensive transcriptional landscape of tumor-associated neutrophils (TAN) in CRLM. Our analysis reveals that a terminally differentiated protumor neutrophil subset (TAN1), characterized by a glycolysis signature and a senescent phenotype, is significantly enriched in liver metastasis and associated with poor prognosis. Mechanistically, TAN1 arises from other TAN subsets through the upregulation of BHLHE40, driven by glucose deprivation in the metastatic microenvironment. Functionally, TAN1 promotes angiogenesis via VEGFA and recruits immunosuppressive macrophages through potential CCL3L1-CCR1 signaling, thereby fostering an angiogenic immunosuppressive niche. As a result, neutrophil-specific knockout of Bhlhe40 in mice significantly promotes antitumor immunity and suppresses tumor growth. Our data uncover the critical role of BHLHE40+ senescent-like neutrophils in shaping the immunosuppressive microenvironment of CRLM.</p><p><strong>Significance: </strong>This study identifies a protumoral BHLHE40+ senescent-like neutrophil subset in CRLM that orchestrates vascular immunosuppressive niches to drive tumor progression, highlighting a potential target for neutrophil-specific therapeutic intervention. See related commentary by Droin and Garner, p. 1958.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"2130-2150"},"PeriodicalIF":29.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13628106/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147970523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Germline Differences Influence Tumor Evolutionary Trajectories.","authors":"","doi":"10.1158/2159-8290.CD-RW2026-080","DOIUrl":"10.1158/2159-8290.CD-RW2026-080","url":null,"abstract":"","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"OF1"},"PeriodicalIF":29.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148905082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular Glue Redirects p300/CBP to Rewire BCL6-Driven Lymphoma.","authors":"","doi":"10.1158/2159-8290.CD-RW2026-081","DOIUrl":"10.1158/2159-8290.CD-RW2026-081","url":null,"abstract":"","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"OF1"},"PeriodicalIF":29.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148918556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immunologic Consequences of Genomic Instabilities","authors":"Emily Alouani, Jean-David Fumet, Paul Johannet, Aurélien Marabelle, Benoit Rousseau","doi":"10.1158/2159-8290.cd-25-2063","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-2063","url":null,"abstract":"Genomic instability manifests in two distinct ways based on DNA alteration scale, differentially affecting the tumor−immune microenvironment. Mutational instability involves excessive accumulation of small-scale alterations, such as substitutions and indels, from defective DNA repair or aberrant mutagenic processes, generating neoantigens and increased immunogenicity. Chromosomal instability encompasses large-scale alterations in which cells gain, lose, or rearrange chromosomes, resulting in aneuploidy and immune evasion through chronic innate activation and myeloid remodeling. This review outlines differences between mutational and chromosomal instability and discuss how their interplay shapes tumor immunogenicity and response to immunotherapy. Understanding these opposing mechanisms could inform immunotherapeutic approaches in cancer. Significance: Mutational and chromosomal alterations exert opposing effects on antitumor immunity. Hypermutated tumors can generate abundant neoantigens that prime adaptive immunity and sensitize tumors to checkpoint blockade. In contrast, chromosomal instability triggers chronic innate immune signaling that is paradoxically immunosuppressive, in part through myeloid cell and T-cell dysfunction. Integrating both processes into a unified framework could help uncover mechanisms of immune evasion and guide personalized immunotherapeutic strategies.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"36 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149086343","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diet-Induced Phospholipid Remodeling Dictates Ferroptosis Sensitivity and Tumorigenesis in the Pancreas.","authors":"Christian Felipe Ruiz, Xiangyu Ge, Rylee McDonnell, Sherry S Agabiti, Daniel C McQuaid, Andy Tang, Meera Kharwa, Jennifer Goodell, Rocío Del M Saavedra-Peña, Allison Wing, Guangtao Li, Natasha Pinto Medici, Marie E Robert, Rohan R Varshney, Michael C Rudolph, Fred S Gorelick, John Wysolmerski, Daniel Canals, John D Haley, Matthew S Rodeheffer, Mandar Deepak Muzumdar","doi":"10.1158/2159-8290.CD-25-0734","DOIUrl":"10.1158/2159-8290.CD-25-0734","url":null,"abstract":"<p><p>High-fat diet (HFD) intake has been linked to an increased risk of pancreatic ductal adenocarcinoma (PDAC), a lethal and therapy-resistant cancer. However, whether and how specific dietary fats drive cancer development remains unresolved. Leveraging an oncogenic Kras-driven mouse model that closely mimics human PDAC progression, we screened a dozen isocaloric HFDs differing solely in fat source and representing the diversity of human fat consumption. Unexpectedly, diets rich in oleic acid-a monounsaturated fatty acid (MUFA) typically associated with good health-markedly enhanced tumorigenesis. Conversely, diets high in polyunsaturated fatty acids (PUFA) suppressed tumor progression. Relative dietary fatty acid saturation levels (PUFA/MUFA) governed pancreatic membrane phospholipid composition, lipid peroxidation, and ferroptosis sensitivity in mice, concordant with circulating PUFA/MUFA levels being linked to altered PDAC risk in humans. These findings directly implicate dietary unsaturated fatty acids in controlling ferroptosis susceptibility and tumorigenesis, supporting potential \"precision nutrition\" strategies for PDAC prevention.</p><p><strong>Significance: </strong>This study reveals that dietary unsaturated fatty acids divergently influence pancreatic cancer progression by incorporating into tissue phospholipids to modulate ferroptosis sensitivity. Dietary MUFAs promote tumorigenesis, whereas PUFAs confer protection. These findings suggest that alterations in dietary fat intake could affect cancer risk. See related commentary by Jeong and Lien, p. 1961.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"2108-2129"},"PeriodicalIF":29.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13227558/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147763316","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Spatial Atlas of Muscle-Invasive Bladder Cancer Reveals Lineage-Specific Vulnerabilities and Immune Architecture.","authors":"Kai Yu, Jianfeng Chen, Yu-Yi Chu, Sajith Nair, Emanuele Crupi, Elshad Hasanov, Ying Mei, Xueshuai Han, Yang Liu, Yunhe Liu, Guangsheng Pei, Fuduan Peng, Jianlong Liao, Enyu Dai, Tian Chu, Kyung Serk Cho, Jiahui Jiang, Xinmiao Yan, Yibo Dai, Jun Wang, Baifeng Zhang, Giannicola Genovese, Nagireddy Putluri, Livia Eberlin, Liuqing Yang, Chunru Lin, Lawrence N Kwong, Diana Shamsutdinova, Khalida M Wani, Bogdan A Czerniak, Wendong Yu, Jianping Zhao, Charles C Guo, Donna Hansel, Curtis Pettaway, Louis Pisters, Kelly Bree, Neema Navai, Byron H Lee, Ashish M Kamat, Padmanee Sharma, Paul Corn, Cindy Y Jiang, Amishi Y Shah, Omar Alhalabi, Pavlos Msaouel, Arlene O Siefker-Radtke, Christopher J Logothetis, Matthew T Campbell, Alexander J Lazar, Jianjun Gao, Linghua Wang","doi":"10.1158/2159-8290.CD-26-0099","DOIUrl":"10.1158/2159-8290.CD-26-0099","url":null,"abstract":"<p><p>Muscle-invasive bladder cancer (MIBC) is clinically heterogeneous, and current molecular subtyping does not capture the spatial organization of tumor states and microenvironmental context. In this study, we construct a spatial atlas of MIBC by integrating spatial transcriptomics from 22 tumors with matched bulk RNA and whole-exome sequencing data. We identify a continuous, spatially organized luminal-to-basal axis within individual tumors that is associated with greater chromosomal instability and transcriptional plasticity. Luminal tumor cores are enriched for FGFR3 and NECTIN4, whereas basal-like states localize toward invasive margins and are associated with elevated EGFR signaling, epithelial-mesenchymal transition, genomic instability, immune infiltration, and greater chemotherapy sensitivity. Spatial analyses further reveal lineage- and location-associated differences in tertiary lymphoid structure states. Pan-cohort analyses across more than 3,000 tumors confirm conserved FGFR3-EGFR lineage exclusivity and associated immune programs. Together, these findings define a spatial framework for understanding lineage states, immune architecture, and therapeutic vulnerabilities in MIBC.</p><p><strong>Significance: </strong>MIBC is clinically heterogeneous, yet current classification lacks spatial context for therapeutic guidance. This study establishes a spatial framework linking luminal and basal lineage states to distinct immune phenotypes and therapeutic vulnerabilities, providing a foundation for biomarker development and more precise, spatially informed, lineage-guided treatment strategies.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"2037-2059"},"PeriodicalIF":29.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13628100/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147926629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of CAR T Cells Targeting a Surface RNA-Binding Protein for the Treatment of Acute Leukemias.","authors":"Takeshi Fujino, Jennifer Lewis, Bingyi Chen, Tamar Y Feinberg, Maxim I Maron, Alexander M Lewis, Charlotte Wishnack, Quinlan Sievers, Satoshi Kaito, Winson Cai, Sarah Yoo, Serena C Mathew, Sydney Souness, Erin Burns, Jasmine Um, Elisa de Stanchina, Qing Chang, Besnik Qeriqi, Kevin Chen, Pu Zhang, Susan DeWolf, Joshua T Weinreb, Renata Mammone, Ileana C Miranda, Robert F Stanley, Maria Adriana Cuibus, Kenyon Weis, Brianna Gipson, Cynthia Castro, Nina Fox, Michael S Lee, Jaime Alvarez-Perez, Daoqi You, Filemon S Dela Cruz, Alyssa D Fronk, Martin Akerman, Andrew L Kung, Omar Abdel-Wahab, Anthony F Daniyan","doi":"10.1158/2159-8290.CD-25-0920","DOIUrl":"10.1158/2159-8290.CD-25-0920","url":null,"abstract":"<p><p>Developing chimeric antigen receptor (CAR) T cells for acute myeloid leukemia (AML) has been challenging due to a lack of known AML-associated antigens that spare normal hematopoietic precursor cells. In this study, we reasoned that donor autoantibodies from AML recipients cured following allogeneic transplant and responsible for the graft-versus-leukemia effect could be engineered to create effective CAR T cells. We generated CAR T cells against one such antigen-U5 snRNP200, an RNA helicase localized to the AML cell surface and absent from normal hematopoietic precursors. Anti-U5 snRNP200 CAR T cells were effective in human and syngeneic models of AML as well as B-cell acute lymphoblastic leukemia, a setting where surface U5 snRNP200 is also present. Armoring CAR T cells with IL-18 led to antigen gain on AML, durable remission, and protection from AML rechallenge. These data thereby identify a CAR T-cell platform that addresses prior limitations in tumor selectivity and safety for patients with acute leukemias.</p><p><strong>Significance: </strong>A major hurdle in developing cell therapies for patients with AML has been that there are few antigens that discriminate AML from vital normal hematopoiesis. In this study, we harnessed alloantibodies from patients with AML who were cured following allotransplant targeting a cell surface RNA-binding protein to create an effective cell therapy for acute leukemias.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"2085-2107"},"PeriodicalIF":29.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13271017/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147763266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genomic alterations and treatment define spatiotemporal patterns of glioblastoma recurrence","authors":"Sara Blaabjerg. Artzi, Dylan Scott Lykke. Harwood, Alessio Locallo, Atul Anand, Casper Carstens Lund, Marc Nihøj. Klausen, Matilde Righetti, Susanne Brun Madsen, Julie Jacobsen, Nadine Margaretha. Hammouda, Maya Jeje Schuang. Lü, Nikolaos Patikas, Jingyi Cao, Sven Nelander, Jonathan Frederik. Carlsen, Justin D. Lathia, Morten Frödin, Dorte Schou. Nørøxe, Ulrik Lassen, William L. Hwang, Jane Skjøth-Rasmussen, Martin Hemberg, Joachim Weischenfeldt, Bjarne W. Kristensen","doi":"10.1158/2159-8290.cd-25-2302","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-2302","url":null,"abstract":"The surgical margin is the primary site of glioblastoma recurrence, yet its molecular features remain poorly characterized. We performed histology-guided sampling and single-cell spatial transcriptomics of surgical margin and adjacent recurrent tumor regions, with matched primary tumors from 40 patients. The surgical margin constituted a distinct wound-healing microenvironment in the post-treatment setting. We also identified malignant states with pronounced mesenchymal transcriptomic and histological features that were enriched at the surgical margin and defined a \"stromal\" subtype. Patients who transitioned to this subtype at recurrence were characterized by early TP53 mutation, sustained proliferation during adjuvant temozolomide treatment, and shorter survival. Conversely, patients with TP53-wild-type tumors recurring during temozolomide treatment transitioned toward the mesenchymal subtype, with increased p53 pathway activity and reduced proliferation. Functional validation showed TP53 loss-of-function increased temozolomide resistance in a patient-derived glioblastoma model. Our findings identify distinct glioblastoma recurrence trajectories linked to genomic context, treatment exposure, and clinical outcomes.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"12 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149086388","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatial Immune Reorganization Characterizes Immunosuppressed Skin Tumors.","authors":"","doi":"10.1158/2159-8290.CD-RW2026-086","DOIUrl":"10.1158/2159-8290.CD-RW2026-086","url":null,"abstract":"","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"OF1"},"PeriodicalIF":29.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149023879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}