Cancer CellPub Date : 2025-08-21DOI: 10.1016/j.ccell.2025.07.023
Rebecca S. Hesterberg, Joshua T. Davis, Komal J. Handoo, Aya G. Elmarsafawi, Anthony C. Augello, Chia-Ho Cheng, Reginald Atkins, Dae Hyun Lee, Chunying Yang, Jiqiang Yao, Krishna R. Patel, Melanie Mediavilla-Varela, Javier Pinilla-Ibarz, Carolina Soto-Palma, Frederick L. Locke, Xiaofei Song, Xuefeng Wang, Anders E. Berglund, Paulo C. Rodriguez, Gero Knittel, Ruth Flümann, Hans Christian Reinhardt, Timothy I. Shaw, Xiaoqing Yu, Laura J. Niedernhofer, John L. Cleveland
{"title":"Lymphoma accelerates T cell and tissue aging","authors":"Rebecca S. Hesterberg, Joshua T. Davis, Komal J. Handoo, Aya G. Elmarsafawi, Anthony C. Augello, Chia-Ho Cheng, Reginald Atkins, Dae Hyun Lee, Chunying Yang, Jiqiang Yao, Krishna R. Patel, Melanie Mediavilla-Varela, Javier Pinilla-Ibarz, Carolina Soto-Palma, Frederick L. Locke, Xiaofei Song, Xuefeng Wang, Anders E. Berglund, Paulo C. Rodriguez, Gero Knittel, Ruth Flümann, Hans Christian Reinhardt, Timothy I. Shaw, Xiaoqing Yu, Laura J. Niedernhofer, John L. Cleveland","doi":"10.1016/j.ccell.2025.07.023","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.07.023","url":null,"abstract":"The combined effects of aging and cancer on immune cells were investigated in young versus aged mice harboring B cell lymphoma, and in T cells from young and aged B cell lymphoma patients. These analyses revealed that lymphoma alone is sufficient to trigger transcriptional, epigenetic, and phenotypic alterations in young T cells that manifest in aged T cells. In contrast, aged T cells are largely resistant to lymphoma-induced changes. Pathway analyses revealed open chromatin regions and genes controlling iron homeostasis are induced by both lymphoma and aging, and lymphoma-experienced and aged T cells have increased iron pools and are resistant to ferroptosis. Furthermore, both aged and lymphoma-experienced T cells have defects in proteostasis. B cell lymphoma also accelerates aging of other tissues, as evidenced by elevated expression of <ce:italic>Cdkn2a</ce:italic> and <ce:italic>Tnfa</ce:italic>. Finally, some lymphoma-induced aging phenotypes are reversible whereas others are fixed, indicating opportunities for improving some cancer-associated aging comorbidities.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"185 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144900565","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}
Cancer CellPub Date : 2025-08-14DOI: 10.1016/j.ccell.2025.07.014
Degao Chen, Zheng Jin, Han Chu, Yucui Wu, Yangping Bian, Ting Yuan, Hao Lv, Qiuyu Xia, Lei Wang, Qian Chu, Quanxing Liu, Dong Zhou, Wenfeng Fang, Xiaoming Cheng, Haoran Zha, Haixia Long, Li Zhang, Jigang Dai, Yisong Y. Wan, Qi-Jing Li, Bo Zhu
{"title":"DNASE1L3-expressing dendritic cells promote CD8+ T cell function and anti-PD-(L)1 therapy efficacy by degrading neutrophil extracellular traps","authors":"Degao Chen, Zheng Jin, Han Chu, Yucui Wu, Yangping Bian, Ting Yuan, Hao Lv, Qiuyu Xia, Lei Wang, Qian Chu, Quanxing Liu, Dong Zhou, Wenfeng Fang, Xiaoming Cheng, Haoran Zha, Haixia Long, Li Zhang, Jigang Dai, Yisong Y. Wan, Qi-Jing Li, Bo Zhu","doi":"10.1016/j.ccell.2025.07.014","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.07.014","url":null,"abstract":"CD8<sup>+</sup> T cell exclusion and dysfunction in the tumor microenvironment (TME) are among the most challenging obstacles for anti-PD-(L)1 therapy. Here, we report that tumor-infiltrating dendritic cell (DC)-specific expression of the deoxyribonuclease, DNASE1L3, is positively correlated with favorable outcomes of anti-PD-(L)1 treatment in cancer patients. DNASE1L3 conditional knockout in DCs leads to enhanced tumor growth and diminishes anti-PD-L1 therapeutic efficacy by impairing infiltration and effector functions of CD8<sup>+</sup> T cells. Conversely, injection with DNASE1L3 promotes CD8<sup>+</sup> T cell infiltration and reduces exhaustion in the TME, significantly retarding tumor growth and enhancing anti-PD-L1 response. DNASE1L3<sup>+</sup> DCs can degrade neutrophil extracellular traps that suppress the spatial distribution of CD8<sup>+</sup> T cells in tumors, enabling establishment of cytotoxic CD8<sup>+</sup> T cell hubs in human cancers. Our findings reveal a role of DC in regulating intratumoral CD8<sup>+</sup> T cells and identify DNASE1L3 as a promising target to improve anti-PD-(L)1 therapy.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"22 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144840304","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}
Cancer CellPub Date : 2025-08-14DOI: 10.1016/j.ccell.2025.07.013
Juan C. Osorio, David A. Knorr, Polina Weitzenfeld, Lucas Blanchard, Ning Yao, Maria Baez, Carlo Sevilla, Meghan DiLillo, Jahan Rahman, Ved P. Sharma, Jacqueline Bromberg, Michael A. Postow, Charlotte Ariyan, Mark E. Robson, Jeffrey V. Ravetch
{"title":"Fc-optimized CD40 agonistic antibody elicits tertiary lymphoid structure formation and systemic antitumor immunity in metastatic cancer","authors":"Juan C. Osorio, David A. Knorr, Polina Weitzenfeld, Lucas Blanchard, Ning Yao, Maria Baez, Carlo Sevilla, Meghan DiLillo, Jahan Rahman, Ved P. Sharma, Jacqueline Bromberg, Michael A. Postow, Charlotte Ariyan, Mark E. Robson, Jeffrey V. Ravetch","doi":"10.1016/j.ccell.2025.07.013","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.07.013","url":null,"abstract":"CD40 agonism enhances antitumor immunity but is limited by systemic toxicity and poor efficacy. Here, we present a phase 1 study (<span><span>NCT04059588</span><svg aria-label=\"Opens in new window\" focusable=\"false\" height=\"20\" viewbox=\"0 0 8 8\"><path d=\"M1.12949 2.1072V1H7V6.85795H5.89111V2.90281L0.784057 8L0 7.21635L5.11902 2.1072H1.12949Z\"></path></svg></span>) of intratumoral (i.t.) 2141-V11, an Fc-engineered anti-CD40 agonistic antibody with enhanced binding to the inhibitory receptor FcγRIIB. Among 12 metastatic cancer patients, 2141-V11 was well tolerated without dose-limiting toxicities. Six patients experienced tumor reduction, including two complete responses in melanoma and breast cancer. 2141-V11 induced regression in injected and non-injected lesions, correlating with systemic CD8<sup>+</sup> T cell activation and mature tertiary lymphoid structures (TLSs) in complete responders. In CD40/FcγRs humanized mice bearing orthotopic tumors, i.t. 2141-V11 promoted <em>de novo</em> TLS formation, facilitating i.t. CD8<sup>+</sup> T cell effector responses independent of lymph node priming. The resulting local immune responses by 2141-V11 mediated abscopal antitumor effects and sustained immune memory. These findings demonstrate that i.t. 2141-V11 is safe and promotes immune-privileged tumor microenvironments that promote systemic and durable antitumor immunity.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"9 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144840305","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}
Cancer CellPub Date : 2025-08-14DOI: 10.1016/j.ccell.2025.07.003
Eynav Klechevsky
{"title":"Dendritic cells function beyond antigen presentation","authors":"Eynav Klechevsky","doi":"10.1016/j.ccell.2025.07.003","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.07.003","url":null,"abstract":"In this issue of <em>Cancer Cell</em>, Chen et al. identify DNASE1L3-expressing dendritic cells (DCs) as enhancers of anti-tumor immunity. By degrading neutrophil extracellular traps, these DCs promote CD8⁺ T cell infiltration into tumors and enhance checkpoint blockade efficacy, extending DNASE1L3’s known immune regulatory role to physical remodeling of the tumor microenvironment.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"19 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144840306","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":"Long-range cholinergic input promotes glioblastoma progression.","authors":"Yang Yang, Chuanyan Yang, Xuezhu Chen, Yibin Jiang, Xuejiao Lei, Kang Ma, Yulian Quan, Tianran Li, Chenfu Guo, Yijing Meng, Lin Kang, Xinyu Zhang, Long Jin, Jiafeng Huang, Ning Mu, Zexuan Yan, Qinghua Ma, Shuai Wang, Yanxia Wang, Yong-Ning Shang, Cong Chen, Yu Shi, Shukun Hu, Likun Yang, Chuan Lan, Rong Hu, Ying Zhang, Xia Li, Yunqing Li, Chong Liu, Yu-Hai Wang, Fei Li, Hua Feng, Xiu-Wu Bian, Tunan Chen","doi":"10.1016/j.ccell.2025.07.024","DOIUrl":"10.1016/j.ccell.2025.07.024","url":null,"abstract":"<p><p>Glioblastoma (GBM), the most aggressive primary brain tumor, is shaped by its integration into neural networks. While glutamatergic input is linked to tumor progression, the broader architecture and function of neuron-glioma connectomes remain unclear. Using monosynaptic rabies tracing, we map brain-wide neural input to patient-derived xenografts and reveal a consistent organizational logic: local inputs are primarily glutamatergic, while long-range connections exhibit diverse neurotransmitter profiles, with basal forebrain cholinergic projections emerging as a conserved input across sites. Functionally, presynaptic acetylcholine release promotes GBM progression through muscarinic receptor CHRM3 in a circuit-specific manner. Mechanistically, glutamatergic and cholinergic signals converge to enhance glioma calcium transients but diverge in temporal transcriptional control, with their dual blockade producing additive anti-tumor effects. Therapeutically, the anticholinergic drug scopolamine attenuates glioma growth, whereas the acetylcholinesterase inhibitor donepezil exacerbates disease. These findings reveal the complexity of neuron-glioma connectivity, highlighting long-range neuromodulatory pathways as promising therapeutic targets in GBM.</p>","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":" ","pages":""},"PeriodicalIF":44.5,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144882291","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}
Cancer CellPub Date : 2025-08-07DOI: 10.1016/j.ccell.2025.07.016
Teresa Steffen, Dirk Baumjohann
{"title":"T’s to the rescue: Expanding the follicular T cell universe in follicular lymphoma","authors":"Teresa Steffen, Dirk Baumjohann","doi":"10.1016/j.ccell.2025.07.016","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.07.016","url":null,"abstract":"Follicular lymphoma is a neoplastic disease of B cell-rich follicular structures of lymphoid origin. In this issue of <em>Cancer Cell</em>, Abe et al. use multi-omics analyses to identify and characterize distinct follicular T cell subsets that can be used to stratify follicular lymphoma prognoses.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"34 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144792330","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}
Cancer CellPub Date : 2025-08-07DOI: 10.1016/j.ccell.2025.07.019
Brian M. Davis, Lisa A. McIlvried, Jami L. Saloman, Marci L. Nilsen, Nicole N. Scheff
{"title":"Rethinking relief: Targeting sensory neurons to combat cancer and pain","authors":"Brian M. Davis, Lisa A. McIlvried, Jami L. Saloman, Marci L. Nilsen, Nicole N. Scheff","doi":"10.1016/j.ccell.2025.07.019","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.07.019","url":null,"abstract":"Cancer pain is a complex problem that, when left unaddressed, can impact overall survival and decrease patients’ quality of life. Collaboration among medical oncologists, immunologists, and neurobiologists in the cancer neuroscience field has recently revealed a pivotal role for the sensory nervous system in cancer progression. We highlight recent scientific findings suggesting that selection of appropriate analgesics should consider not only their efficacy in reducing pain but also their potential to influence anti-tumor immunity and subsequent responses to immunotherapy.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"78 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144792329","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}
Cancer CellPub Date : 2025-08-07DOI: 10.1016/j.ccell.2025.07.010
Nicholas J. Salgia, Adil Khan, Wilhelm M. Aubrecht, Gavin C. Twoey, Jacky Chow, Kristopher Attwood, Han Yu, Jessie L. Chiello, Nathaniel Hansen, Brianna J. Wasik, Benjamin D. Mercier, Hedyeh Ebrahimi, Luis Meza, Orla Maguire, Michalis Mastri, Cassandra Whalen, Hans Minderman, Patrick Pirrotte, Sara Byron, Elizabeth A. Repasky, Jason B. Muhitch
{"title":"Comprehensive tumor-immune profiling reveals mediators of paradoxical immune sensitivity in sarcomatoid renal cell carcinoma","authors":"Nicholas J. Salgia, Adil Khan, Wilhelm M. Aubrecht, Gavin C. Twoey, Jacky Chow, Kristopher Attwood, Han Yu, Jessie L. Chiello, Nathaniel Hansen, Brianna J. Wasik, Benjamin D. Mercier, Hedyeh Ebrahimi, Luis Meza, Orla Maguire, Michalis Mastri, Cassandra Whalen, Hans Minderman, Patrick Pirrotte, Sara Byron, Elizabeth A. Repasky, Jason B. Muhitch","doi":"10.1016/j.ccell.2025.07.010","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.07.010","url":null,"abstract":"Renal cell carcinoma with sarcomatoid features (sRCC) is a highly aggressive tumor type yet preferentially responds to immune checkpoint blockade (ICB). To better understand microenvironmental mediators of this paradoxical immune sensitivity, we performed single-cell analyses of human sRCC tumors compared against clear cell RCC (ccRCC), with validation spatially and in bulk transcriptomic datasets totaling over 3,000 RCC tumors. We describe a robust immune network in sRCC using these orthogonal approaches: tumor-infiltrating T cells in sRCC are more activated, and subsequently exhausted, while being enriched for <em>CXCL13</em> expression. Congruently, tertiary lymphoid structures are pervasive in sRCC, paralleling functional enrichment of humoral immune activity. Tumor clone analysis revealed increased iron-associated programs in sRCC, presenting a potential vulnerability. We furthermore leveraged the paradoxical biology of sRCC to derive a genomic dedifferentiation signature (GDS) that, while negatively prognostic, identifies patients most likely to benefit from ICB across cohorts and tumor types.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"94 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144792374","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}
Cancer CellPub Date : 2025-08-07DOI: 10.1016/j.ccell.2025.07.012
Mingxu Xie, Kai Yuan, Yongxin Zhang, Yating Zhang, Ruyi Zhang, Jiuhe Gao, Wenchao Wei, Lanping Jiang, Tianhui Li, Yanqiang Ding, Luyao Wang, Yufeng Lin, Chi Chun Wong, Jun Yu
{"title":"Tumor-resident probiotic Clostridium butyricum improves aPD-1 efficacy in colorectal cancer models by inhibiting IL-6-mediated immunosuppression","authors":"Mingxu Xie, Kai Yuan, Yongxin Zhang, Yating Zhang, Ruyi Zhang, Jiuhe Gao, Wenchao Wei, Lanping Jiang, Tianhui Li, Yanqiang Ding, Luyao Wang, Yufeng Lin, Chi Chun Wong, Jun Yu","doi":"10.1016/j.ccell.2025.07.012","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.07.012","url":null,"abstract":"Most colorectal cancer (CRC) patients do not respond to immune checkpoint blockade (ICB) therapy. Here, we identify <em>Clostridium butyricum</em> as a probiotic that boosts anti-PD-1 efficacy in CRC. In orthotopic allografts of microsatellite instability-high (MSI-H) and microsatellite stable (MSS) CRC, <em>C. butyricum</em> potentiates tumor suppressive effect of anti-PD-1, which is verified in AOM/DSS-induced CRC and germ-free mice. Single-cell RNA-seq reveals that <em>C. butyricum</em> activates cytotoxic CD8<sup>+</sup> T lymphocytes (CTLs) and impairs tumor-associated macrophages (TAMs), especially in conjunction with anti-PD-1. Mechanistically, <em>C. butyricum</em> surface protein secD binds to CRC cell receptor glucose-regulated protein 78 (GRP78), which inactivates GRP78 and PI3K-AKT-NF-κB pathway, leading to reduced secretion of interleukin (IL)-6, an immunosuppressive cytokine that blunts CTLs and induces TAMs. Translational impact of <em>C. butyricum</em> in boosting anti-PD-1 efficacy is validated in huCD34<sup>+</sup> humanized mice and autologous patient-derived CRC organoids-CTLs co-culture system. To summarize, <em>C. butyricum</em> is a promising adjuvant to augment ICB therapy.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"1 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144792337","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 pan-KRAS inhibitor and its derived degrader elicit multifaceted anti-tumor efficacy in KRAS-driven cancers","authors":"Juanjuan Feng, Xuanzheng Xiao, Xinting Xia, Jian Min, Weiying Tang, Xinyi Shi, Ke Xu, Guizhen Zhou, Kangkang Li, Panpan Shen, Rujuan Bao, Shuyao Wu, Mengjia Lin, Kun Yuan, Zhengke Lian, Longmiao Hu, Na Li, Zhengzhen Wu, Xiaotong Zhai, Xiaogu Liu, Xiufeng Pang","doi":"10.1016/j.ccell.2025.07.006","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.07.006","url":null,"abstract":"KRAS remains a challenging therapeutic target with limited effective inhibitors currently available. Here, we report the discovery of MCB-294, a potent dual-state pan-KRAS inhibitor capable of binding both the active (GTP-bound) and inactive (GDP-bound) forms of KRAS. MCB-294 engages the switch-II pocket through a water-mediated hydrogen-bond network and selectively inhibits KRAS over NRAS and HRAS. It effectively suppresses oncogenic KRAS signaling, inhibits the growth of <em>KRAS</em>-dependent cancer cells and patient-derived organoids, and reduces tumor progression in multiple preclinical models. MCB-294 also demonstrates superior activity compared to the inactive-state selective pan-KRAS inhibitor Bl-2865 and the KRAS<sup>G12D</sup> inhibitor MRTX1133. Building upon MCB-294 as a pan-KRAS-targeting warhead, we further develop MCB-36, a von Hippel-Lindau (VHL)-recruiting pan-KRAS degrader that induces sustained KRAS degradation. Notably, both MCB-294 and MCB-36 effectively suppress KRAS<sup>G12C</sup> inhibitor-resistant cancer cells and remodel the tumor immune microenvironment. These findings highlight a promising therapeutic strategy for broadly targeting <em>KRAS</em>-driven tumors and overcoming drug resistance.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"733 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144792327","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}
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