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}
Cancer CellPub Date : 2025-08-07DOI: 10.1016/j.ccell.2025.07.007
Tao Shi, Wei Liu, Yuting Luo, Kaijie Liang, Shiji Ren, Xueru Song, Fangcen Liu, Chun Lu, Daniel Hirschhorn, Hanbing Wang, Yipeng Zhang, Yiran Cai, Yue Wang, Yunfeng Pan, Wenqi Liu, Yang Nie, Ziliang Zhang, Lixia Yu, Shuai Ding, Baorui Liu, Jia Wei
{"title":"CHI3L3+ immature neutrophils inhibit anti-tumor immunity and impede immune checkpoint blockade therapy in bone metastases","authors":"Tao Shi, Wei Liu, Yuting Luo, Kaijie Liang, Shiji Ren, Xueru Song, Fangcen Liu, Chun Lu, Daniel Hirschhorn, Hanbing Wang, Yipeng Zhang, Yiran Cai, Yue Wang, Yunfeng Pan, Wenqi Liu, Yang Nie, Ziliang Zhang, Lixia Yu, Shuai Ding, Baorui Liu, Jia Wei","doi":"10.1016/j.ccell.2025.07.007","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.07.007","url":null,"abstract":"Bone metastases remain incurable and respond poorly to immune checkpoint blockade (ICB) therapy. The impact of neutrophil maturation in cancer, particularly in refractory tumors including bone metastases, is not well understood. Here, we observed the predominance of immature neutrophils in the bone metastasis microenvironment of both mouse models and cancer patients. Dickkopf1 (DKK1) induces an immature-like functional state in neutrophils, which exhibit robust immunosuppressive capabilities to inhibit anti-tumor response of CD8<sup>+</sup> T cells. Mechanistically, the DKK1-CKAP4-STAT6 signaling pathway drives CHI3L3 expression, which is necessary for the immune suppression mediated by immature neutrophils in bone metastases. Moreover, blocking DKK1 promotes neutrophil maturation to improve the immune microenvironment, induces tumor shrinkage, and enhances ICB therapy response in multiple bone metastasis mouse models. These findings uncover a critical role for immature neutrophils in bone metastases and suggest a potential strategy for modulating neutrophils to improve cancer immunotherapy.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"27 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144792331","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.2025.07.022
Sonia A. Melo, Hikaru Sugimoto, Joyce T. O’Connell, Noritoshi Kato, Alberto Villanueva, August Vidal, Le Qiu, Edward Vitkin, Lev T. Perelman, Carlos A. Melo, Anthony Lucci, Cristina Ivan, George A. Calin, Raghu Kalluri
{"title":"Cancer Exosomes Perform Cell-Independent MicroRNA Biogenesis and Promote Tumorigenesis","authors":"Sonia A. Melo, Hikaru Sugimoto, Joyce T. O’Connell, Noritoshi Kato, Alberto Villanueva, August Vidal, Le Qiu, Edward Vitkin, Lev T. Perelman, Carlos A. Melo, Anthony Lucci, Cristina Ivan, George A. Calin, Raghu Kalluri","doi":"10.1016/j.ccell.2025.07.022","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.07.022","url":null,"abstract":"(Cancer Cell <em>26</em>, 707–721; November 10, 2014)","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"86 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145009328","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 : 2025-07-31DOI: 10.1016/j.ccell.2025.07.011
Shankha Satpathy, Natalie M. Clark, Yi-Ju Chen, Noshad Hosseini, Ya-Hsuan Chang, Yi Hsiao, Jonathan T. Lei, Francesca Petralia, Jin-Shing Chen, Yifat Geffen, David I. Heiman, Indranil Paul, Hanbyul Cho, Michelle Hollenberg, Giacomo B. Marino, Kuen-Tyng Lin, Rahul Mannan, C. Jackson White, Joe Allen, Shayan C. Avanessian, Zoran Andric
{"title":"Integrative analysis of lung adenocarcinoma across diverse ethnicities and exposures","authors":"Shankha Satpathy, Natalie M. Clark, Yi-Ju Chen, Noshad Hosseini, Ya-Hsuan Chang, Yi Hsiao, Jonathan T. Lei, Francesca Petralia, Jin-Shing Chen, Yifat Geffen, David I. Heiman, Indranil Paul, Hanbyul Cho, Michelle Hollenberg, Giacomo B. Marino, Kuen-Tyng Lin, Rahul Mannan, C. Jackson White, Joe Allen, Shayan C. Avanessian, Zoran Andric","doi":"10.1016/j.ccell.2025.07.011","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.07.011","url":null,"abstract":"Lung adenocarcinomas (LUAD) are a pressing global health problem with enduring lethality and rapidly shifting epidemiology. Proteogenomic studies integrating proteomics and post-translational modifications with genomics can identify clinical strata and oncogenic mechanisms, but have been underpowered to examine effects of ethnicity, smoking and environmental exposures, or sex on this heterogeneous disease. This comprehensive proteogenomic analysis of LUAD tumors and matched normal adjacent tissues from 406 patients across diverse geographic and demographic backgrounds explores the impact of understudied driver mutations, prognostic role of chromosomal instability, patterns of immune signaling, differential and sex-specific effects of endogenous mutagens and environmental carcinogens, and pathobiology of early-stage tumors with “late-like” characteristics. Candidate protein biomarkers are proposed for unstable tumors with highly fragmented genomes and for carcinogen exposures, and a LUAD subtype-specific atlas of therapeutic vulnerabilities is presented. These observations and the associated data resource advance the objective of precision management strategies for this devastating disease.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"131 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144748120","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 : 2025-07-31DOI: 10.1016/j.ccell.2025.05.001
Analisa DiFeo
{"title":"Immune memory shapes ovarian cancer recurrence","authors":"Analisa DiFeo","doi":"10.1016/j.ccell.2025.05.001","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.05.001","url":null,"abstract":"Despite current progress, many patients with ovarian cancer (OC) often relapse after therapy. In this issue of <em>Cancer Cell</em>, Ghisoni et al. integrate multiomic and functional analyses to provide a roadmap for biomarker-driven therapy in OC and suggest that immune phenotyping could be incorporated into clinical stratification.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"44 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144747835","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 : 2025-07-31DOI: 10.1016/j.ccell.2025.07.008
Charles S. Dai, Avanish Mishra, Jon Edd, Mehmet Toner, Shyamala Maheswaran, Daniel A. Haber
{"title":"Circulating tumor cells: Blood-based detection, molecular biology, and clinical applications","authors":"Charles S. Dai, Avanish Mishra, Jon Edd, Mehmet Toner, Shyamala Maheswaran, Daniel A. Haber","doi":"10.1016/j.ccell.2025.07.008","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.07.008","url":null,"abstract":"Circulating tumor cells (CTCs) are cancer cells, shed from primary tumors or metastases into the bloodstream. The first non-invasive “liquid biopsy” for cancer monitoring, CTCs have been largely surpassed by circulating tumor DNA (ctDNA) for clinical applications, given the ease of DNA sequencing without specialized cell isolation methods. However, emerging rare cell capture technologies that can process larger blood volumes and enable advanced single-cell analyses may enhance the range and potential of CTC-based biomarkers. CTCs are increasingly valuable for assessing tumor heterogeneity, guiding protein biomarker-driven cancer immune therapies, and assessing heterogeneous drug resistance, as well as for detecting minimal disease. CTCs, thus, remain central to understanding cancer dissemination and are poised to offer complementary diagnostic roles in the application of minimally invasive liquid biopsies for cancer. Here, we review recent advances in the study of these rare circulating cancer cells and discuss current limitations and future directions.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"15 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144748118","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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