Cancer research最新文献

{"title":"Beyond Internalization: Target Binding as the Trigger","authors":"Cristina Simó, Patrícia M.R. Pereira","doi":"10.1158/0008-5472.can-26-4375","DOIUrl":"https://doi.org/10.1158/0008-5472.can-26-4375","url":null,"abstract":"Targeted drug conjugates often rely on receptor-mediated internalization and intracellular trafficking for payload release. This requirement limits the range of tumor-associated targets that can be effectively exploited and has motivated the development of strategies for extracellular drug release. Wen and colleagues introduce a binding-to-release (BTR) strategy in which target engagement itself serves as the trigger for payload release. The authors used ligand-directed chemistry to develop phosphorus(V)-phenol exchange (PhoPEx) chemistry that exploits proximity between an electrophilic linker and a nucleophilic tyrosine residue within the binding pocket of the target to initiate target-triggered payload release. Through optimization of the phenol-based scaffold, the authors evaluated 15 PhoPEx compounds to balance hydrolytic stability and reaction kinetics. The authors then used fibroblast activation protein, a poorly internalizing stromal target, to test the BTR strategy using a membrane-permeable payload, resulting in improved tumor drug exposure and antitumor activity in preclinical models. The BTR strategy was further extended to imaging applications and other targets, including programmed death-ligand 1. Although demonstrated primarily with small-molecule conjugates, BTR introduces an alternative approach for targeted drug delivery of poorly internalizing targets in which target binding could be exploited as a trigger, potentially expanding the landscape of tumor-associated targets accessible to targeted therapeutics.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"1 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149218777","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 Transcriptomics on a Diverse Pancreatic Cancer Cohort Reveals Race-Related Differences in Tumor Subtypes and Immune Microenvironments","authors":"Yuesong Wu, Daniel James. Sålas-Escabillas, Aoqi Xie, Ian M. Loveless, Yasmine Baca, Kailee Hartway, Rama Shankar, Samuel D. Zwernik, Logan Schneider, Ashley George, Madison George, Allison Wombwell, Julie M. Clark, David S. Kwon, Bin Chen, Benjamin H. Hinrichs, Ralph Francescone, Débora Barbosa Vendramini-Costa, Kerem Ozcan, Zhengfan Xu, Ling Huang, Brian K. Theisen, Yuehua Cui, Howard C. Crawford, Nina G. Steele","doi":"10.1158/0008-5472.can-25-2748","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-2748","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy 20% more likely to develop in Black African Americans (BAA) compared to Non-African Americans (NAA). Large-scale gene expression analysis of tumor subtypes and cellular microenvironments in a diverse PDAC cohort could help provide insights into cell and molecular differences in BAA cancer cells. Here, we conducted a multi-omics interrogation of BAA versus NAA PDAC using whole exome sequencing, spatial transcriptomics (ST), and spatial proteomics. Whole exome sequencing confirmed patient ancestry and showed no significant differences in driver mutations between race groups. BAA PDAC tumors had significantly fewer classical molecular subtype cells with no change in more aggressive basal-like cells. Instead, BAA patients showed a significant enrichment of the intermediate/hybrid subtype compared to NAA patients. BAA tumors also displayed increased B cell and reduced myeloid cell interactions compared to NAA tumors. Analysis of tertiary lymphoid structures in a validation cohort revealed that tumors in BAA patients displayed larger TLS size and number compared to NAA. In conclusion, these findings identify an increased intermediate molecular subtype signature in BAA tumors at the expense of cells with a classical subtype, accompanied by a distinct immune cell composition and spatial distribution. This study highlights that health disparities in patients of different ancestries may have a molecular basis that influences tumor aggressiveness and the immune response, which may inform therapeutic strategies.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"25 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149221381","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":"Mechanical Stress Induces Nuclear Envelope Rupture in Melanoma Cells to Reorganize Tumor–Stromal Interactions","authors":"HyunSeok Kim, Wooseok Kim, Minki Kim, Yongjun Koh, Xianglan Zhang, Semyeong Hong, Jun Young Kim, Hee So, Youngjo Kim, Hyung-Soon Park, Mi Ryung Roh, Jong-Eun Park, Joon Kim","doi":"10.1158/0008-5472.can-25-2084","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-2084","url":null,"abstract":"Growth-induced solid stress and fluid pressure contribute to tumor progression and drug resistance. Beyond tumor endogenous physical forces, cells in the tumor microenvironment may also experience external macroscopic mechanical stress, and some tumors preferentially develop in weight-bearing regions with higher focal pressure. Characterization of the impact of macroscopic mechanical stress on the tumor microenvironment could help uncover the mechanistic links between external mechanical forces and increased tumor incidence. Here, we showed that recurrent macroscopic mechanical stress disrupts nuclear envelope integrity, leading to spatial reorganization and fibroblast subtype changes at the tumor–stromal interface. In mouse models of plantar melanoma, exogenous mechanical stress induced nuclear envelope rupture in melanoma cells and increased LRRC15-positive myofibroblasts. Reduction of nuclear envelope integrity through inducible deletion of Lmna likewise increased LRRC15-positive myofibroblast generation. Co-culture with myofibroblasts promoted nuclear envelope rupture in melanoma cells in 3D culture, suggesting a positive feedback loop. In addition, mechanical stress-driven transcriptomic changes in tumor and stromal cells were observed alongside enhanced lymph node metastasis and immunotherapy resistance. Analysis of human melanoma samples revealed mechanical stress-associated stromal remodeling and a higher incidence of lymph node metastasis in tumors arising in mechanically stressed regions, although these features were not significantly associated with overall survival. Together, these findings suggest that macroscopic mechanical stress may influence cancer progression by inducing nuclear envelope damage and reshaping tumor–stromal interactions.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"56 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149221380","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":"Motherhood's Sentinels: Pregnancy Induces Tissue-Resident Memory T Cells to Curb Breast Cancer Growth.","authors":"Meenakshi Sudhakaran, Kelly Kersten","doi":"10.1158/0008-5472.CAN-26-3367","DOIUrl":"10.1158/0008-5472.CAN-26-3367","url":null,"abstract":"<p><p>Women who carry a pregnancy to term have long been known to have a reduced lifetime risk of breast cancer, yet the mechanisms underlying this protection remain poorly understood. Although parity-induced differentiation and hormonal remodeling of the mammary epithelium have been considered primary drivers of breast cancer protection, the contribution of immune adaptation has remained largely unexplored. In a recent issue of Nature Immunology, Hussain and colleagues identify pregnancy-induced tissue-resident memory-like (TRM-like) CD8+ T cells as key mediators of parity-associated breast cancer protection. The authors show that pregnancy establishes a nurturing niche in the mammary gland that supports the expansion of TRM-like cells through epithelial-derived IL15 and TGFβ and that depletion of these cells abolishes the cancer-protective effect of parity. Moreover, using therapeutic agents to enhance IL2Rβ signaling was sufficient to induce the expansion of breast cancer-protective TRM-like cells in nulliparous mice, raising the possibility that pregnancy's protective imprint could be pharmacologically induced. Given the established link between TRM cells and immune checkpoint blockade responsiveness in breast cancer, these findings also raise the possibility that pregnancy-induced TRM-like populations could be leveraged to improve immunotherapy outcomes. By linking physiologic developmental tissue remodeling to durable local immunosurveillance, this study expands current concepts of tissue-resident immunity and positions pregnancy as an immune-educating event with lasting consequences for breast cancer susceptibility.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"5020-5022"},"PeriodicalIF":22.6,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148705395","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":"Antiviral T cells doing double-duty to fight cancer.","authors":"Nicole H Hirsh, Joshua D Brody","doi":"10.1158/0008-5472.CAN-26-4373","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-26-4373","url":null,"abstract":"<p><p>The exquisite antigen specificity of T cells is one foundation of modern cancer immunotherapy. The therapeutic efficacy of checkpoint blockade, cancer vaccines, and engineered T-cell therapies, all appear to depend on T cells capable of recognizing specific antigens displayed by tumor cells. In a recent issue of Nature Immunology, Smith and colleagues challenge this paradigm by demonstrating that local activation of virus-specific memory T cells can eliminate tumors without direct tumor-cell recognition. Instead, activated T cells initiate a multicellular inflammatory response involving IFNγ, TNF, nitric oxide and recruited myeloid cells that collectively induce tumor-cell death. These findings separate the antigen specificity required for T-cell activation from that required for tumor killing and expand the role of T cells from direct cytotoxic effectors to organizers of a broader antitumor response. Together, these findings broaden the potential scope of T-cell-mediated antitumor immunity beyond the constraints of direct tumor-antigen recognition.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":""},"PeriodicalIF":22.6,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149191159","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":"MEKing Room: On the Quest for New Sources of Therapeutic Index in RAS/MAPK-Driven Cancers","authors":"Bijaya Gaire, Poulikos I. Poulikakos","doi":"10.1158/0008-5472.can-26-2050","DOIUrl":"https://doi.org/10.1158/0008-5472.can-26-2050","url":null,"abstract":"The RAS/MAPK pathway is among the most frequently dysregulated in human cancer, predominantly driven by activating mutations across RAS and BRAF in a broad spectrum of tumor types. The recent clinical validation of direct inhibitors of RAS, long considered undruggable, has reenergized the field and renewed focus on targeting the full RAS/MAPK axis. MEK, a central node in MAPK signaling, remains an attractive mutation-agnostic target, yet the efficacy of first-generation MEK inhibitors has been limited by pathway reactivation in tumors and by on-target, off-tissue toxicity. In this issue of Cancer Research, Kolitz and colleagues describe atebimetinib, a novel MEK inhibitor that also prevents feedback-induced MEK phosphorylation by RAF. The uniquely short plasma half-life of atebimetinib enables deep cyclic inhibition (DCI): transient but profound MEK/ERK output suppression with full recovery between doses. At each drug’s tolerability limit, atebimetinib outperformed the MEK inhibitor binimetinib across multiple RAS- and BRAF-mutant tumor models. Whether DCI or suppression of MEK phosphorylation is the primary driver of the improved therapeutic window and how atebimetinib compares with the clinical standard and other MEK-targeting agents remain important open questions, but the work makes a compelling case that novel pharmacology can unlock therapeutic spaces at targets long considered exhausted. See related article by Kolitz et al., p. 5223","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"53 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149172866","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":"ACKR3 Establishes a Squamous-Restricted Immune Checkpoint Axis in Lung Squamous Cell Carcinoma","authors":"Angeliki Karatza, Kaan Kumru, Jaylen M. Powell, Chengwei Peng, Yuan Hao, Metamia Ciampricotti, Dimitris Nasias, Hai Hu, Muhammad Elnaggar, Maayan Pour, Alison Chafitz, Yeuan Ting Lee, Priyanka Sahu, Yi Jer Tan, Yun Xue, Ruveyda Ayasun, Alfonso Lopez, Magdalena A. Ploszaj, Daniel Andrussier, Yun Zhang, Fiona Sherman, Cynthia A. Loomis, Peter Meyn, Jonathan So, Salman R. Punekar, Rajwanth Veluswamy, James A. Wells, Dafna Bar-Sagi, Kwok-Kin Wong","doi":"10.1158/0008-5472.can-25-5347","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-5347","url":null,"abstract":"Lung squamous cell carcinoma (LUSC) is an aggressive subtype of non–small cell lung cancer with limited targeted therapeutic options and incompletely defined immune-regulatory dependencies. Here, we identified atypical chemokine receptor 3 (ACKR3) as a squamous-enriched regulator that restrains malignant progression in LUSC. Integrative analyses of human LUSC datasets, autochthonous genetically engineered mouse models, and ex vivo organoid systems showed that ACKR3 loss accelerated tumor growth and remodeled the immune microenvironment, marked by reduced CD8⁺ T cell infiltration and increased T cell exhaustion. Mechanistically, ACKR3 limited activation of the MIF–CD74–PD-L1 axis, thereby constraining tumor-cell PD-L1 expression and preserving antitumor immune surveillance. In preclinical LUSC models, treatment with the ACKR3-directed PD-L1 degrader KineTAC, a bispecific molecule that co-engages ACKR3 and PD-L1 to promote lysosomal degradation of PD-L1, enhanced antitumor efficacy, particularly in combination with chemotherapy. Together, these findings define ACKR3 as a squamous-associated immune checkpoint regulator and nominate ACKR3-directed PD-L1 degradation as a tumor-selective therapeutic strategy for LUSC.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"5 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149172907","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":"ARID2 Loss Reprograms the Kynurenine-AhR Pathway to Restore Antitumor Immunity in CTNNB1-Mutant Hepatocellular Carcinoma","authors":"Qianyu Li, Yunfeng Yuan, Ning Liu, Linfeng Li, Yifei Qian, Fan Wang, Songling Li, Wenli Qin, Quankun Lin, Hongmin Lu, Yuliang Rao, Qiang Xia, Yanan Wang, Yanfeng Liu","doi":"10.1158/0008-5472.can-26-0860","DOIUrl":"https://doi.org/10.1158/0008-5472.can-26-0860","url":null,"abstract":"Hepatocellular carcinoma (HCC) driven by gain-of-function mutations in CTNNB1 (CTNNB1GOF) that stabilize β-catenin exhibits a profoundly immunosuppressive tumor microenvironment (TME), rendering it resistant to immune checkpoint blockade (ICB). Metabolic reprogramming is increasingly recognized as a crucial mediator of immune activity, highlighting the need to elucidate the specific metabolic mechanisms underlying immune exclusion in CTNNB1GOF HCC. Here, we identified a critical metabolic-immune network orchestrated by co-mutations of CTNNB1 and ARID2. Integrative analysis of HCC patient cohorts and a de novo MYC/CTNNB1GOF HCC mouse model revealed that tumors harboring concurrent CTNNB1 and ARID2 mutations exhibited a more immune-active TME and improved survival compared to tumors with CTNNB1 mutations alone. Mechanistically, β-catenin and ARID2 cooperatively enhanced the transcription of tryptophan 2,3-dioxygenase (TDO2), leading to accelerated kynurenine production and activation of the aryl hydrocarbon receptor (AhR) in myeloid-derived suppressor cells (MDSCs). This metabolic axis established an immunosuppressive milieu characterized by MDSC accumulation and impaired T cell function. Genetic ablation of Arid2 in CTNNB1GOF HCC attenuated TDO2-dependent kynurenine synthesis, reduced MDSC infiltration, and enhanced CD8⁺ T cell cytotoxicity, thereby sensitizing tumors to anti-PD-1 therapy. Clinically, co-mutations of CTNNB1 and ARID2 correlated with elevated immune infiltration and favorable ICB responses across multiple human cancers, including HCC. Importantly, pharmacological inhibition of AhR phenocopied the immunomodulatory effect of ARID2 loss and, when combined with anti-PD-1, robustly reversed the immune-cold phenotype of CTNNB1GOF HCC. These findings reveal TDO2-kynurenine-AhR signaling as a pivotal metabolic pathway enforcing immune evasion in CTNNB1-mutant HCC.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"10 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149172908","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":"A Germline-Encoded lncRNA-Mitochondrial Axis Rewires Oxidative Phosphorylation to Drive Progression in Clear Cell Renal Cell Carcinoma","authors":"Guowen Duan, Wenjie Xu, Wenjun Jiang, Linhui Zhang, Yi Lin, Cheng Lian, Qin Zhang, Zixian Wang, Zenglai Tan, Zixi Wang, Shengjie Zhai, Qi Liu, Aki Manninen, Ying Lu, Zhao Zhang, Yuanyuan Qu, Gong-Hong Wei","doi":"10.1158/0008-5472.can-25-5866","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-5866","url":null,"abstract":"Clear cell renal cell carcinoma (ccRCC) is characterized by profound metabolic reprogramming and substantial inherited susceptibility. The molecular mechanisms linking germline risk variation to tumor metabolic reprogramming could potentially be exploited for precision interventions. Here, we aimed to delineate the germline regulatory architecture underlying ccRCC susceptibility and to determine how inherited noncoding variation influences mitochondrial metabolism and tumor progression. Whole-genome sequencing and transcriptomic profiling of matched ccRCC tumor and adjacent normal kidney tissues were integrated with cross-ancestry genome-wide association, cis-expression quantitative trait locus, transcriptome-wide association, and fine-mapping analyses. LINC02068 was identified as a genetically regulated tumor suppressor associated with inherited ccRCC susceptibility, and cross-ancestry fine-mapping prioritized rs234043 as a candidate causal variant. The rs234043 risk allele preferentially recruited HOXC8 and repressed LINC02068 transcription. Reduced LINC02068 expression promoted malignant cellular phenotypes and was associated with adverse clinical outcomes. Mechanistically, LINC02068 localized to mitochondria, interacted with the co-chaperone DNAJA3, and promoted DNAJA3 destabilization, thereby attenuating mitochondrial oxidative phosphorylation. Allele-specific editing and genetic rescue experiments further supported a functional rs234043-HOXC8-LINC02068-DNAJA3 regulatory axis driving ccRCC progression. Pharmacologic impairment of mitochondrial complex I suppressed ccRCC cell migration and proliferation. These findings establish a mechanistic link between a germline noncoding variation and mitochondrial metabolic reprogramming in ccRCC and identify targeting oxidative phosphorylation as a potential avenue for precision therapy.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"98 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149172533","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":"A syngeneic murine glioma model recapitulates key molecular, immunologic, and functional features of human glioblastoma to enable therapeutic development","authors":"Katie B. Grausam, Marissa S. Pioso, Julio C. Sanchez, Marissa Li, David Rincon Fernandez Pacheco, Emily A. Hatanaka, Gilbert Herrera, Thomas J. Lai, Eddie Lu, Paul W. Linesch, Naomi Kobritz, Trinh L. Phan, Sophie Ashley, Ariel A. Andrade, Lauren Markus, Jingwen Yao, Xuemo Fan, Bohyeon Yu, Aaron A. Diaz, Linda M. Liau, Moise Danielpour, David A. Nathanson, Robert M. Prins, Joshua J. Breunig, Stephen L. Shiao","doi":"10.1158/0008-5472.can-25-5766","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-5766","url":null,"abstract":"Glioblastoma (GBM) is the most common and deadly primary brain tumor in adults, characterized by diffuse infiltrative lesions, distinct oncogenic alterations, and a suppressive tumor immune microenvironment (TIME). These traits, however, are not fully recapitulated in current syngeneic murine glioma models, thereby limiting the pre-clinical development of novel therapies. Here we developed murine GBM models with patient-specific mutations that shared striking resemblance with human disease. Mosaic analysis with dual-recombinase mediated cassette exchange (MADR) and CRISPR-Cas9 were leveraged to generate autochthonous tumor models with single-copy somatic transgenesis of murine epidermal growth factor receptor variant III (mEGFRvIII) and loss-of-function mutations commonly observed in GBM. Characterization of a model lacking Pten and Cdkn2a (mEGFRvIII-PC) via histopathologic analyses, functional assays, and single-cell RNA sequencing showed these tumors developed as diffuse, infiltrative lesions with ill-defined margins and a necrotic core. The TIME was primarily comprised of microglia with minimal lymphocyte infiltration, recapitulating patient tumors. Furthermore, these tumors displayed intrinsic resistance to immune checkpoint blockade, potentially due to poor myeloid cell antigen presentation and T cell priming. Additionally, mEGFRvIII-PC cells were the most resistant to antigen-specific T cell-induced cytotoxicity and simultaneously promoted T cell exhaustion, while murine interferon-γ (mIFN-γ) stimulation induced a greater response in vitro with enhanced upregulation of PD-L1 relative to MHC-I. In sum, these findings demonstrate the improved fidelity of the mEGFRvIII-PC model to patient tumors and support its use in developing and refining novel therapeutic paradigms for GBM.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"9 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149152550","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}