Cancer CellPub Date : 2025-03-13DOI: 10.1016/j.ccell.2025.02.026
Housaiyin Li, Dan P. Zandberg, Aditi Kulkarni, Simion I. Chiosea, Patricia M. Santos, Brian R. Isett, Marion Joy, Gabriel L. Sica, Kevin J. Contrera, Curtis M. Tatsuoka, Matthias Brand, Umamaheswar Duvvuri, Seungwon Kim, Mark Kubik, Shaum Sridharan, Fei Tu, Jie Chen, Tullia C. Bruno, Dario A.A. Vignali, Anthony R. Cillo, Robert L. Ferris
{"title":"Distinct CD8+ T cell dynamics associate with response to neoadjuvant cancer immunotherapies","authors":"Housaiyin Li, Dan P. Zandberg, Aditi Kulkarni, Simion I. Chiosea, Patricia M. Santos, Brian R. Isett, Marion Joy, Gabriel L. Sica, Kevin J. Contrera, Curtis M. Tatsuoka, Matthias Brand, Umamaheswar Duvvuri, Seungwon Kim, Mark Kubik, Shaum Sridharan, Fei Tu, Jie Chen, Tullia C. Bruno, Dario A.A. Vignali, Anthony R. Cillo, Robert L. Ferris","doi":"10.1016/j.ccell.2025.02.026","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.02.026","url":null,"abstract":"We leverage a clinical trial (<span><span>NCT04080804</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>) that compared neoadjuvant anti-PD-1, anti-PD-1+CTLA-4, and anti-PD-1+LAG-3 therapies in head and neck squamous cell carcinoma patients. Combination therapies promote higher pathologic response rates versus monotherapy, and major pathologic response is associated with better survival. To address whether successful immune checkpoint inhibitor (ICI) regimens act through similar or distinct pathways, we robustly and longitudinally characterize transcriptional and proteomic dynamics of CD8<sup>+</sup> tumor-infiltrating lymphocytes (TILs) in a clonal manner. Anti-PD-1+LAG-3 reprograms CD8<sup>+</sup> TIL with type-I interferon response and exhaustion gene programs into effector memory and resident memory (T<sub>EM</sub>/T<sub>RM</sub>). In contrast, anti-PD-1+CTLA-4 activates and expands pre-existing T<sub>EM</sub>/T<sub>RM</sub> CD8<sup>+</sup> TIL, but does not rejuvenate exhausted phenotypes into T effector cells. Anti-PD-1+LAG-3, but not anti-PD-1+CTLA-4, induces widespread TCR sharing among the different transcriptional states, as well as increased TCR diversity in responding patients. Our data suggest doublet regimen-specific transcriptional and clonal dynamics of tumor-reactive CD8<sup>+</sup> T cells.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"31 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143608697","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 : 2025-03-10DOI: 10.1016/j.ccell.2025.02.006
Cynthia L. Palmer, Britton Boras, Bernadette Pascual, Na Li, Danan Li, Scott Garza, Nanni Huser, Jing Tang Yuan, Julie A. Cianfrogna, Tae Sung, Elizabeth McMillan, Na Wei, Jason Carmody, Aubrey Nayeon Kang, Seth Darensburg, Taran Dodd, James V. Oakley, James Solowiej, Lisa Nguyen, Suvi T.M. Orr, Lars Anders
{"title":"CDK4 selective inhibition improves preclinical anti-tumor efficacy and safety","authors":"Cynthia L. Palmer, Britton Boras, Bernadette Pascual, Na Li, Danan Li, Scott Garza, Nanni Huser, Jing Tang Yuan, Julie A. Cianfrogna, Tae Sung, Elizabeth McMillan, Na Wei, Jason Carmody, Aubrey Nayeon Kang, Seth Darensburg, Taran Dodd, James V. Oakley, James Solowiej, Lisa Nguyen, Suvi T.M. Orr, Lars Anders","doi":"10.1016/j.ccell.2025.02.006","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.02.006","url":null,"abstract":"CDK4/6 inhibitors have revolutionized treatment of hormone receptor positive (HR+), HER2 non-amplified (HER2−) breast cancer. Yet, all “dual” CDK4/6 inhibitors show common dose-limiting hematologic toxicities, foremost neutropenia. This poses challenges to provide these agents at concentrations necessary to extinguish cell cycling in tumors. HR+ breast cancer cells are highly dependent on CDK4 but not CDK6. By contrast, CDK4 is dispensable for human bone marrow derived cells, due to the primary and compensatory role of CDK6 in hematopoiesis. This prompted us to develop atirmociclib (PF-07220060), a next-generation CDK4 selective inhibitor. Atirmociclib’s impact on circulating neutrophils was reduced, in proportion with its increase in CDK4 versus CDK6 selectivity. Realized dose intensification led to greater CDK4 inhibition and deeper anti-tumor responses, pointing to CDK4 target coverage as a limiting factor of CDK4/6 inhibitor efficacy. We also highlight combinatorial agents that may counter acquired resistance to CDK4 selective inhibition and widen its clinical application.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"87 6 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143582535","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 : 2025-03-10DOI: 10.1016/j.ccell.2025.02.013
Fabio Conforti, Laura Pala, Diletta Di Mitri, Chiara Catania, Emilia Cocorocchio, Daniele Laszlo, Giovanni Ceresoli, Marzia Locatelli, Flaminia Facella, Tommaso De Pas, Benedetta Rambaldi, Alessandro Rambaldi, Giuseppe Viale, Vincenzo Bagnardi, Giuseppe Giaccone, Alberto Mantovani
{"title":"Sex hormones, the anticancer immune response, and therapeutic opportunities","authors":"Fabio Conforti, Laura Pala, Diletta Di Mitri, Chiara Catania, Emilia Cocorocchio, Daniele Laszlo, Giovanni Ceresoli, Marzia Locatelli, Flaminia Facella, Tommaso De Pas, Benedetta Rambaldi, Alessandro Rambaldi, Giuseppe Viale, Vincenzo Bagnardi, Giuseppe Giaccone, Alberto Mantovani","doi":"10.1016/j.ccell.2025.02.013","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.02.013","url":null,"abstract":"Sex-based differences have been observed in the incidence and prognosis of various cancers, as well as in the response to immune check point inhibitors (ICIs). These disparities are partially attributed to sex-based differences in the molecular characteristics of the anticancer immune response, which are largely influenced by sex hormones. Here, we provide a comprehensive overview on how sex hormones affect innate and adaptive immunity and contribute to shaping the features of tumor immune microenvironment and response to anticancer immunotherapy. We also discuss the promising potential and challenges of combining sex hormone manipulation with anticancer immunotherapy as new therapeutic strategy. We surmise that a sex-based perspective should be part of precision medicine approaches, and sex hormones manipulation provides opportunities for innovative immune therapeutic approaches.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"15 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143582531","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 : 2025-03-10DOI: 10.1016/j.ccell.2025.02.014
Huan Song, Lin Chen, Xuanxuan Pan, Yuru Shen, Maolin Ye, Guohong Wang, Can Cui, Qi Zhou, Yujen Tseng, Zheng Gong, Bin Zhong, Haoshu Cui, Shaocong Mo, Jiayue Zheng, Bryan Jin, Wanwei Zheng, Feifei Luo, Jie Liu
{"title":"Targeting tumor monocyte-intrinsic PD-L1 by rewiring STING signaling and enhancing STING agonist therapy","authors":"Huan Song, Lin Chen, Xuanxuan Pan, Yuru Shen, Maolin Ye, Guohong Wang, Can Cui, Qi Zhou, Yujen Tseng, Zheng Gong, Bin Zhong, Haoshu Cui, Shaocong Mo, Jiayue Zheng, Bryan Jin, Wanwei Zheng, Feifei Luo, Jie Liu","doi":"10.1016/j.ccell.2025.02.014","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.02.014","url":null,"abstract":"STING is an important DNA sensing machinery in initiating immune response, yet therapies targeting STING have shown poor outcomes in clinical trials. Here, we reveal that STING signaling induces PD-L1<sup>hi</sup> tumor monocytes (Tu.Mons) that dominate the resistance against STING agonist therapy. Cell-intrinsic PD-L1, induced by the STING-IRF3-IFN-I axis, is identified as the driving factor for protumoral PD-L1<sup>hi</sup> Tu.Mons. Notably, TLR2-activated Tu.Mons resist STING-induced upregulation of cell-intrinsic PD-L1 and the associated protumoral functions. Mechanistically, TLR2 stimulation remodels STING signaling by facilitating STING and TRAF6 interaction, which suppresses the IRF3-IFN-I response and enhances NF-κB activation. Moreover, we demonstrate that combining STING agonists with TLR2 agonist pretreatment significantly improves antitumor efficacy in murine syngeneic and humanized models. Our findings uncover a protumoral aspect of STING activation mediated by cell-intrinsic PD-L1 and propose a promising strategy to boost antitumor immunity by fine-tuning STING signaling outputs.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"38 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143582537","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 : 2025-03-10DOI: 10.1016/j.ccell.2025.02.010
Jianzhou Chen, Antonin Levy, Ai-Ling Tian, Xuehan Huang, Guoxin Cai, Marine Fidelle, Conrad Rauber, Pierre Ly, Eugénie Pizzato, Lisa Sitterle, Gianmarco Piccinno, Peng Liu, Sylvère Durand, Misha Mao, Liwei Zhao, Valerio Iebba, Hannah Felchle, Anne-Laure Mallard de La Varende, Julius Clemens Fischer, Simon Thomas, Eric Deutsch
{"title":"Low-dose irradiation of the gut improves the efficacy of PD-L1 blockade in metastatic cancer patients","authors":"Jianzhou Chen, Antonin Levy, Ai-Ling Tian, Xuehan Huang, Guoxin Cai, Marine Fidelle, Conrad Rauber, Pierre Ly, Eugénie Pizzato, Lisa Sitterle, Gianmarco Piccinno, Peng Liu, Sylvère Durand, Misha Mao, Liwei Zhao, Valerio Iebba, Hannah Felchle, Anne-Laure Mallard de La Varende, Julius Clemens Fischer, Simon Thomas, Eric Deutsch","doi":"10.1016/j.ccell.2025.02.010","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.02.010","url":null,"abstract":"The mechanisms governing the abscopal effects of local radiotherapy in cancer patients remain an open conundrum. Here, we show that off-target intestinal low-dose irradiation (ILDR) increases the clinical benefits of immune checkpoint inhibitors or chemotherapy in eight retrospective cohorts of cancer patients and in tumor-bearing mice. The abscopal effects of ILDR depend on dosimetry (≥1 and ≤3 Gy) and on the metabolic and immune host-microbiota interaction at baseline allowing CD8<sup>+</sup> T cell activation without exhaustion. Various strains of <em>Christensenella minuta</em> selectively boost the anti-cancer efficacy of ILDR and PD-L1 blockade, allowing emigration of intestinal PD-L1-expressing dendritic cells to tumor-draining lymph nodes. An interventional phase 2 study provides the proof-of-concept that ILDR can circumvent resistance to first- or second-line immunotherapy in cancer patients. Prospective clinical trials are warranted to define optimal dosimetry and indications for ILDR to maximize its therapeutic potential.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"38 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143582532","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 : 2025-03-10DOI: 10.1016/j.ccell.2025.02.020
Martina Molgora, Marco Colonna
{"title":"Targeting brain macrophages: NF-κB as a therapeutic gateway in melanoma brain metastasis","authors":"Martina Molgora, Marco Colonna","doi":"10.1016/j.ccell.2025.02.020","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.02.020","url":null,"abstract":"Melanoma brain metastasis (MBM) is associated with poor prognosis. In this issue of <em>Cancer Cell</em>, Rodriguez-Baena et al. identify nuclear factor κB (NF-κB) (Rela) as a driver of pro-tumoral microglia in MBM. While <em>Rela</em> deletion reprograms microglia, enhancing proinflammatory and anti-metastasis T cell responses, RELA activation in human macrophages correlates with immunotherapy resistance.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"15 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143582496","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 : 2025-03-10DOI: 10.1016/j.ccell.2025.02.007
Chang-Ching Lin, Ariella B. Hanker
{"title":"A CDK4-selective inhibitor puts the brakes on cancer cells","authors":"Chang-Ching Lin, Ariella B. Hanker","doi":"10.1016/j.ccell.2025.02.007","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.02.007","url":null,"abstract":"In this issue of <em>Cancer Cell</em>, Palmer et al. describe the discovery and preclinical testing of the first-in-class CDK4-selective inhibitor atirmociclib. By sparing CDK6, atirmociclib has the potential to ameliorate dose-limiting hematological toxicities that limit drug exposure and treatment continuity and, by extension, the antitumor efficacy of dual CDK4/6 inhibitors.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"68 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143582497","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 : 2025-03-10DOI: 10.1016/j.ccell.2025.02.011
Mao Yang, Yuhao Zhao, Chen Li, Xiaoling Weng, Zhizhen Li, Wu Guo, Wenning Jia, Feiling Feng, Jiaming Hu, Haonan Sun, Bo Wang, Huaifeng Li, Ming Li, Ting Wang, Wei Zhang, Xiaoqing Jiang, Zongli Zhang, Fubao Liu, Hai Hu, Xiangsong Wu, Yingbin Liu
{"title":"Multimodal integration of liquid biopsy and radiology for the noninvasive diagnosis of gallbladder cancer and benign disorders","authors":"Mao Yang, Yuhao Zhao, Chen Li, Xiaoling Weng, Zhizhen Li, Wu Guo, Wenning Jia, Feiling Feng, Jiaming Hu, Haonan Sun, Bo Wang, Huaifeng Li, Ming Li, Ting Wang, Wei Zhang, Xiaoqing Jiang, Zongli Zhang, Fubao Liu, Hai Hu, Xiangsong Wu, Yingbin Liu","doi":"10.1016/j.ccell.2025.02.011","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.02.011","url":null,"abstract":"Gallbladder cancer (GBC) frequently mimics gallbladder benign lesions (GBBLs) in radiological images, leading to preoperative misdiagnoses. To address this challenge, we initiated a prospective, multicenter clinical trial (ChicCTR2100049249) and proposed a multimodal, non-invasive diagnostic model to distinguish GBC from GBBLs. A total of 301 patients diagnosed with gallbladder-occupying lesions (GBOLs) from 11 medical centers across 7 provinces in China were enrolled and divided into a discovery cohort and an independent external validation cohort. An artificial intelligence (AI)-based integrated model, GBCseeker, is created using cell-free DNA (cfDNA) genetic signatures, radiomic features, and clinical information. It achieves high accuracy in distinguishing GBC from GBBL patients (93.33% in the discovery cohort and 87.76% in the external validation cohort), reduces surgeons’ diagnostic errors by 56.24%, and reclassifies GBOL patients into three categories to guide surgical options. Overall, our study establishes a tool for the preoperative diagnosis of GBC, facilitating surgical decision-making.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"21 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143582534","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 : 2025-03-10DOI: 10.1016/j.ccell.2025.02.022
Zhenyu Dai, Melody Smith
{"title":"Epigenetic enhancement of adoptive T cell immunotherapy","authors":"Zhenyu Dai, Melody Smith","doi":"10.1016/j.ccell.2025.02.022","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.02.022","url":null,"abstract":"Isshiki et al. and Porazzi et al. report that inhibiting enhancer of zeste homolog 1 (EZH1) and EZH2 enhances chimeric antigen receptor (CAR)/T cell receptor (TCR)-based therapies by reprogramming tumors to be more immunogenic and improving T cell phenotype and demonstrate the efficacy of this combination in preclinical models across hematologic and solid cancers. Clinical trials are ongoing to evaluate its safety and therapeutic potential.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"38 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143582538","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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