Cancer CellPub Date : 2025-03-20DOI: 10.1016/j.ccell.2025.03.002
Michael V. Berridge, Renata Zobalova, Stepana Boukalova, Andrés Caicedo, Stuart A. Rushworth, Jiri Neuzil
{"title":"Horizontal mitochondrial transfer in cancer biology: Potential clinical relevance","authors":"Michael V. Berridge, Renata Zobalova, Stepana Boukalova, Andrés Caicedo, Stuart A. Rushworth, Jiri Neuzil","doi":"10.1016/j.ccell.2025.03.002","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.03.002","url":null,"abstract":"Recent research highlights horizontal mitochondrial transfer as a key biological phenomenon linked to cancer onset and progression. The transfer of mitochondria and their genomes between cancer and non-cancer cells shifts our understanding of intercellular gene trafficking, increasing the metabolic fitness of cancer cells and modulating antitumor immune responses. This process not only facilitates tumor progression but also presents potential therapeutic opportunities.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"26 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143660407","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 : 2025-03-20DOI: 10.1016/j.ccell.2025.02.027
Duygu Kuzuoglu-Ozturk, Hao G. Nguyen, Lingru Xue, Emma Figueredo, Vishvak Subramanyam, Isabelle Liu, Kenya Bonitto, Ashish Noronha, Adrianna Dabrowska, Janet E. Cowan, Juan A. Oses-Prieto, Alma L. Burlingame, Stephen T. Worland, Peter R. Carroll, Davide Ruggero
{"title":"Small-molecule RNA therapeutics to target prostate cancer","authors":"Duygu Kuzuoglu-Ozturk, Hao G. Nguyen, Lingru Xue, Emma Figueredo, Vishvak Subramanyam, Isabelle Liu, Kenya Bonitto, Ashish Noronha, Adrianna Dabrowska, Janet E. Cowan, Juan A. Oses-Prieto, Alma L. Burlingame, Stephen T. Worland, Peter R. Carroll, Davide Ruggero","doi":"10.1016/j.ccell.2025.02.027","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.02.027","url":null,"abstract":"Tuning protein expression by targeting RNA structure using small molecules is an unexplored avenue for cancer treatment. To understand whether this vulnerability could be therapeutically targeted in the most lethal form of prostate cancer, castration-resistant prostate cancer (CRPC), we use a clinical small molecule, zotatifin, that targets the RNA helicase and translation factor eukaryotic initiation factor 4A (eIF4A). Zotatifin represses tumorigenesis in patient-derived and xenograft models and prolonged survival <em>in vivo</em> alongside hormone therapy. Genome-wide transcriptome, translatome, and proteomic analysis reveals two important translational targets: androgen receptor (AR), a key oncogene in CRPC, and hypoxia-inducible factor 1A (HIF1A), an essential cancer modulator in hypoxia. We solve the structure of the 5′ UTRs of these oncogenic mRNAs and strikingly observe complex structural remodeling of these select mRNAs by this small molecule. Remarkably, tumors treated with zotatifin become more sensitive to anti-androgen therapy and radiotherapy. Therefore, “translatome therapy” provides additional strategies to treat the deadliest cancers.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"36 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143660415","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 : 2025-03-13DOI: 10.1016/j.ccell.2025.02.018
Lisa Mayr, Sina Neyazi, Kallen Schwark, Maria Trissal, Alexander Beck, Jenna Labelle, Sebastian K. Eder, Liesa Weiler-Wichtl, Joana G. Marques, Carlos A.O. de Biagi-Junior, Costanza Lo Cascio, Owen Chapman, Sunita Sridhar, Rishaan Kenkre, Aditi Dutta, Shanqing Wang, Jessica Wang, Olivia Hack, Andrezza Nascimento, Cuong M. Nguyen, Mariella G. Filbin
{"title":"Effective targeting of PDGFRA-altered high-grade glioma with avapritinib","authors":"Lisa Mayr, Sina Neyazi, Kallen Schwark, Maria Trissal, Alexander Beck, Jenna Labelle, Sebastian K. Eder, Liesa Weiler-Wichtl, Joana G. Marques, Carlos A.O. de Biagi-Junior, Costanza Lo Cascio, Owen Chapman, Sunita Sridhar, Rishaan Kenkre, Aditi Dutta, Shanqing Wang, Jessica Wang, Olivia Hack, Andrezza Nascimento, Cuong M. Nguyen, Mariella G. Filbin","doi":"10.1016/j.ccell.2025.02.018","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.02.018","url":null,"abstract":"PDGFRA is crucial to tumorigenesis and frequently genomically altered in high-grade glioma (HGG). In a comprehensive dataset of pediatric HGG (<em>n</em> = 261), we detect <em>PDGFRA</em> mutations and/or amplifications in 15% of cases, suggesting PDGFRA as a therapeutic target. We reveal that the PDGFRA/KIT inhibitor avapritinib shows (1) selectivity for PDGFRA inhibition, (2) distinct patterns of subcellular effects, (3) <em>in vitro</em> and <em>in vivo</em> activity in patient-derived HGG models, and (4) effective blood-brain barrier penetration in mice and humans. Furthermore, we report preliminary clinical real-world experience using avapritinib in pediatric and young adult patients with predominantly recurrent/refractory <em>PDGFRA</em>-altered HGG (<em>n</em> = 8). Our early data demonstrate that avapritinib is well tolerated and results in radiographic response in 3/7 cases, suggesting a potential role for avapritinib in the treatment of HGG with specific <em>PDGFRA</em> alterations<strong>.</strong> Overall, these translational results underscore the therapeutic potential of PDGFRA inhibition with avapritinib in HGG.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"39 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143608519","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 : 2025-03-13DOI: 10.1016/j.ccell.2025.02.019
Grégoire Marret, Mercedes Herrera, Lillian L. Siu
{"title":"Turning the kaleidoscope: Innovations shaping the future of clinical trial design","authors":"Grégoire Marret, Mercedes Herrera, Lillian L. Siu","doi":"10.1016/j.ccell.2025.02.019","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.02.019","url":null,"abstract":"Current clinical trials are based on rigid designs and drug-centric approaches that can stifle flexibility and innovation. With advances in molecular biology and technology, there is an urgent call to revitalize trial designs to meet these evolving demands. We propose a reshaped, prismatic vision of clinical trials combining different knowledge layers, synergized with modern computational approaches. This paradigm based on iterative learning will enable a more adaptive and precise framework for oncology drug development.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"17 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143608589","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 : 2025-03-13DOI: 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}
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