Pub Date : 2026-01-26DOI: 10.1038/s43018-025-01103-0
Jason L. Vassy, Anna M. Dornisch, Roshan Karunamuni, Michael Gatzen, Christopher J. Kachulis, Niall J. Lennon, Charles A. Brunette, Morgan E. Danowski, Richard L. Hauger, Isla P. Garraway, Adam S. Kibel, Kyung M. Lee, Julie A. Lynch, Kara N. Maxwell, Dmitry Ratner, Brent S. Rose, Craig C. Teerlink, George J. Xu, Sean E. Hofherr, Katherine A. Lafferty, Katie Larkin, Edyta Malolepsza, Candace J. Patterson, Diana M. Toledo, Jenny L. Donovan, Freddie C. Hamdy, Richard M. Martin, David E. Neal, Emma L. Turner, Ole A. Andreassen, Anders M. Dale, Ian G. Mills, Aswin Abraham, Jyotsna Batra, Judith Clements, Olivier Cussenot, Cezary Cybulski, Rosalind A. Eeles, Jay H. Fowke, Eli Marie Grindedal, Henrik Grönberg, Robert J. Hamilton, Jasmine Lim, Yong-Jie Lu, Robert J. MacInnis, Christiane Maier, Lorelei A. Mucci, Luc Multigner, Susan L. Neuhausen, Sune F. Nielsen, Marie-Élise Parent, Jong Y. Park, Gyorgy Petrovics, Anna Plym, Azad Razack, Barry S. Rosenstein, Johanna Schleutker, Karina Dalsgaard Sørensen, Paul A. Townsend, Ruth C. Travis, Ana Vega, Catharine M. L. West, Fredrik Wiklund, Wei Zheng, Profile Steering Committee, IMPACT Study Steering Committee and Collaborators, PRACTICAL Consortium, VA Million Veteran Program, Tyler M. Seibert
Precision healthcare aims to tailor disease prevention and early detection to individual risk. Prostate cancer screening may benefit from genomics-informed approaches. We developed and validated the P-CARE model, a prostate cancer risk prediction tool combining a polygenic score, family history and genetic ancestry, using data from over 585,000 male participants in the Million Veteran Program. The model was externally validated in diverse cohorts and implemented via a blended genome–exome assay for clinical use. Here we show that the P-CARE model identifies clinically meaningful gradients of prostate cancer risk among men, with higher scores associated with increased risk of any, metastatic and fatal prostate cancer. The model is now being used in a clinical trial of precision prostate cancer screening. This work demonstrates the potential for genomics-enabled health systems to improve prostate cancer screening and prevention in men. ClinicalTrials.gov registration: NCT05926102 . Vassy, Dornisch and colleagues developed a genomics-based prostate cancer risk model to support a randomized clinical trial of precision screening in a national healthcare system.
{"title":"Genomic risk model to implement precision prostate cancer screening in clinical care: the ProGRESS study","authors":"Jason L. Vassy, Anna M. Dornisch, Roshan Karunamuni, Michael Gatzen, Christopher J. Kachulis, Niall J. Lennon, Charles A. Brunette, Morgan E. Danowski, Richard L. Hauger, Isla P. Garraway, Adam S. Kibel, Kyung M. Lee, Julie A. Lynch, Kara N. Maxwell, Dmitry Ratner, Brent S. Rose, Craig C. Teerlink, George J. Xu, Sean E. Hofherr, Katherine A. Lafferty, Katie Larkin, Edyta Malolepsza, Candace J. Patterson, Diana M. Toledo, Jenny L. Donovan, Freddie C. Hamdy, Richard M. Martin, David E. Neal, Emma L. Turner, Ole A. Andreassen, Anders M. Dale, Ian G. Mills, Aswin Abraham, Jyotsna Batra, Judith Clements, Olivier Cussenot, Cezary Cybulski, Rosalind A. Eeles, Jay H. Fowke, Eli Marie Grindedal, Henrik Grönberg, Robert J. Hamilton, Jasmine Lim, Yong-Jie Lu, Robert J. MacInnis, Christiane Maier, Lorelei A. Mucci, Luc Multigner, Susan L. Neuhausen, Sune F. Nielsen, Marie-Élise Parent, Jong Y. Park, Gyorgy Petrovics, Anna Plym, Azad Razack, Barry S. Rosenstein, Johanna Schleutker, Karina Dalsgaard Sørensen, Paul A. Townsend, Ruth C. Travis, Ana Vega, Catharine M. L. West, Fredrik Wiklund, Wei Zheng, Profile Steering Committee, IMPACT Study Steering Committee and Collaborators, PRACTICAL Consortium, VA Million Veteran Program, Tyler M. Seibert","doi":"10.1038/s43018-025-01103-0","DOIUrl":"10.1038/s43018-025-01103-0","url":null,"abstract":"Precision healthcare aims to tailor disease prevention and early detection to individual risk. Prostate cancer screening may benefit from genomics-informed approaches. We developed and validated the P-CARE model, a prostate cancer risk prediction tool combining a polygenic score, family history and genetic ancestry, using data from over 585,000 male participants in the Million Veteran Program. The model was externally validated in diverse cohorts and implemented via a blended genome–exome assay for clinical use. Here we show that the P-CARE model identifies clinically meaningful gradients of prostate cancer risk among men, with higher scores associated with increased risk of any, metastatic and fatal prostate cancer. The model is now being used in a clinical trial of precision prostate cancer screening. This work demonstrates the potential for genomics-enabled health systems to improve prostate cancer screening and prevention in men. ClinicalTrials.gov registration: NCT05926102 . Vassy, Dornisch and colleagues developed a genomics-based prostate cancer risk model to support a randomized clinical trial of precision screening in a national healthcare system.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"7 2","pages":"352-367"},"PeriodicalIF":28.5,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146053006","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}
Pub Date : 2026-01-22DOI: 10.1038/s43018-025-01079-x
Systemic delivery of oncolytic viruses has long been limited by rapid immune clearance, short circulation times and restricted spread within tumors. To overcome these challenges, we engineered an immune-cloaked, ultrasound-inducible oncolytic virus platform. By evading immune clearance and triggering pyroptosis to amplify viral replication within tumors, this approach enhances immune activation and drives potent tumor regression in preclinical models.
{"title":"Programmable oncolytic viruses for systemic cancer therapy","authors":"","doi":"10.1038/s43018-025-01079-x","DOIUrl":"10.1038/s43018-025-01079-x","url":null,"abstract":"Systemic delivery of oncolytic viruses has long been limited by rapid immune clearance, short circulation times and restricted spread within tumors. To overcome these challenges, we engineered an immune-cloaked, ultrasound-inducible oncolytic virus platform. By evading immune clearance and triggering pyroptosis to amplify viral replication within tumors, this approach enhances immune activation and drives potent tumor regression in preclinical models.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"7 1","pages":"10-11"},"PeriodicalIF":28.5,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146030425","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}
Systemic delivery of oncolytic viruses (OVs) is limited by neutralizing antibodies and poor intratumoral bioavailability. Here we developed genetically engineered, immune-compatible cell membranes expressing a chimeric antigen receptor to cloak OVs, creating a tumor-targeted viral delivery platform (iNV-GOV) that shields virions from immune recognition while guiding them to tumors. The OV payload encodes an N-terminal gasdermin under a heat-shock promoter enabling ultrasound-induced mild hyperthermia to trigger tumor-specific pyroptosis, accelerate oncolysis and promote rapid viral release from lysed tumor cells, thereby amplifying infection of neighboring tumor populations. Following systemic administration, iNV-GOV efficiently targets and infects tumor cells, induces pyroptosis upon ultrasound activation and elicits robust antitumor immunity in patient-derived xenograft models in humanized mice. Collectively, this systemically injectable, tumor-targeted OV platform enables rapid and continuous intratumoral viral propagation and represents a promising strategy for treating a wide range of cancers. Chen et al. report the design and characterization of a systemically injectable oncolytic virus with tumor-targeting and low-immunogenic properties, engineered to induce tumor cell pyroptosis under local mild hyperthermia.
{"title":"Genetic engineering of systemically injectable oncolytic viruses for pyroptosis-accelerated cancer virotherapy","authors":"Xiaohong Chen, Minqi Yang, Yuxuan Chen, Yao Zhang, Shuang Wang, Jiaqi Meng, Zunqiao Zhu, Wen Li, Wei Wei, Yuan Ping, Tingbo Liang","doi":"10.1038/s43018-025-01078-y","DOIUrl":"10.1038/s43018-025-01078-y","url":null,"abstract":"Systemic delivery of oncolytic viruses (OVs) is limited by neutralizing antibodies and poor intratumoral bioavailability. Here we developed genetically engineered, immune-compatible cell membranes expressing a chimeric antigen receptor to cloak OVs, creating a tumor-targeted viral delivery platform (iNV-GOV) that shields virions from immune recognition while guiding them to tumors. The OV payload encodes an N-terminal gasdermin under a heat-shock promoter enabling ultrasound-induced mild hyperthermia to trigger tumor-specific pyroptosis, accelerate oncolysis and promote rapid viral release from lysed tumor cells, thereby amplifying infection of neighboring tumor populations. Following systemic administration, iNV-GOV efficiently targets and infects tumor cells, induces pyroptosis upon ultrasound activation and elicits robust antitumor immunity in patient-derived xenograft models in humanized mice. Collectively, this systemically injectable, tumor-targeted OV platform enables rapid and continuous intratumoral viral propagation and represents a promising strategy for treating a wide range of cancers. Chen et al. report the design and characterization of a systemically injectable oncolytic virus with tumor-targeting and low-immunogenic properties, engineered to induce tumor cell pyroptosis under local mild hyperthermia.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"7 1","pages":"207-223"},"PeriodicalIF":28.5,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145989923","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}
Pub Date : 2026-01-16DOI: 10.1038/s43018-026-01119-0
Federico Giovannoni, Craig A. Strathdee, Camilo Faust Akl, Brian M. Andersen, Zhaorong Li, Hong-Gyun Lee, María Florencia Torti, Joseph M. Rone, Pere Duart-Abadia, Martina Molgora, Linxing Kong, Michael Floyd, Jian Teng, Yulia Gyulakian, Peter Grzesik, Terry Farkaly, Agnieszka Denslow, Sonia Feau, Irene Rodriguez-Sanchez, Judith Jacques, Marco Colonna, Edward M. Kennedy, Tooba Cheema, Lorena Lerner, Christophe Quéva, Francisco J. Quintana
{"title":"Author Correction: Retargeted oncolytic viruses engineered to remodel the tumor microenvironment for glioblastoma immunotherapy","authors":"Federico Giovannoni, Craig A. Strathdee, Camilo Faust Akl, Brian M. Andersen, Zhaorong Li, Hong-Gyun Lee, María Florencia Torti, Joseph M. Rone, Pere Duart-Abadia, Martina Molgora, Linxing Kong, Michael Floyd, Jian Teng, Yulia Gyulakian, Peter Grzesik, Terry Farkaly, Agnieszka Denslow, Sonia Feau, Irene Rodriguez-Sanchez, Judith Jacques, Marco Colonna, Edward M. Kennedy, Tooba Cheema, Lorena Lerner, Christophe Quéva, Francisco J. Quintana","doi":"10.1038/s43018-026-01119-0","DOIUrl":"10.1038/s43018-026-01119-0","url":null,"abstract":"","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"7 1","pages":"247-247"},"PeriodicalIF":28.5,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s43018-026-01119-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145989787","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-16DOI: 10.1038/s43018-025-01110-1
Julian M. Yabut, Daniel J. Drucker
Glucagon-like peptide-1 (GLP-1) medicines reduce food intake, body weight, insulin resistance and inflammation, thus improving outcomes for people with type 2 diabetes and obesity and potentially contributing to decreased cancer incidence. GLP-1 medicines acting through weight loss-dependent and weight loss-independent mechanisms hold potential for suppression of tumorigenesis and reduction of rates of obesity-associated cancer. In this Perspective, we summarize data on cancer incidence from trials and registries in individuals with type 2 diabetes, describe the actions of GLP-1 medicines on preclinical cancer models and highlight possible direct and indirect mechanisms linking GLP-1R signaling to cancer development and progression. Yabut and Drucker discuss clinical and preclinical evidence about the potential roles of GLP-1 medicines on cancer incidence, development and therapy and speculate about their mechanism on cancer cells and the tumor microenvironment.
{"title":"Glucagon-like peptide-1 medicines and cancer","authors":"Julian M. Yabut, Daniel J. Drucker","doi":"10.1038/s43018-025-01110-1","DOIUrl":"10.1038/s43018-025-01110-1","url":null,"abstract":"Glucagon-like peptide-1 (GLP-1) medicines reduce food intake, body weight, insulin resistance and inflammation, thus improving outcomes for people with type 2 diabetes and obesity and potentially contributing to decreased cancer incidence. GLP-1 medicines acting through weight loss-dependent and weight loss-independent mechanisms hold potential for suppression of tumorigenesis and reduction of rates of obesity-associated cancer. In this Perspective, we summarize data on cancer incidence from trials and registries in individuals with type 2 diabetes, describe the actions of GLP-1 medicines on preclinical cancer models and highlight possible direct and indirect mechanisms linking GLP-1R signaling to cancer development and progression. Yabut and Drucker discuss clinical and preclinical evidence about the potential roles of GLP-1 medicines on cancer incidence, development and therapy and speculate about their mechanism on cancer cells and the tumor microenvironment.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"7 2","pages":"260-271"},"PeriodicalIF":28.5,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145989947","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}
Pub Date : 2026-01-16DOI: 10.1038/s43018-025-01107-w
Lichun Ma, Barbara Xiong, Meng Liu, Kai Tan
The concept of cellular neighborhoods, defined as recurring structures within the tissue with characteristic cell compositions and interactions, has transformed our understanding of the complexity and dynamics of tumor ecosystems. Recent advances in spatial omics and computational modeling have enabled high-resolution mapping of these neighborhoods, providing unprecedented insights into their roles in shaping tumor heterogeneity, evolution and therapeutic responses. Despite these advances, a unified framework for interpreting cellular neighborhoods remains lacking. This Perspective synthesizes emerging concepts and insights, focusing on the definition and classification of cellular neighborhoods in cancer, computational methods for identifying and comparing them, and their clinical relevance. Tan and colleagues discuss recent advances in spatial omics and computational models that inform the classification and clinical relevance of cellular neighborhoods in cancer.
{"title":"Cellular neighborhoods in cancer","authors":"Lichun Ma, Barbara Xiong, Meng Liu, Kai Tan","doi":"10.1038/s43018-025-01107-w","DOIUrl":"10.1038/s43018-025-01107-w","url":null,"abstract":"The concept of cellular neighborhoods, defined as recurring structures within the tissue with characteristic cell compositions and interactions, has transformed our understanding of the complexity and dynamics of tumor ecosystems. Recent advances in spatial omics and computational modeling have enabled high-resolution mapping of these neighborhoods, providing unprecedented insights into their roles in shaping tumor heterogeneity, evolution and therapeutic responses. Despite these advances, a unified framework for interpreting cellular neighborhoods remains lacking. This Perspective synthesizes emerging concepts and insights, focusing on the definition and classification of cellular neighborhoods in cancer, computational methods for identifying and comparing them, and their clinical relevance. Tan and colleagues discuss recent advances in spatial omics and computational models that inform the classification and clinical relevance of cellular neighborhoods in cancer.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"7 1","pages":"16-28"},"PeriodicalIF":28.5,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145990004","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}
Pub Date : 2026-01-09DOI: 10.1038/s43018-025-01072-4
William C. Pilcher, Lijun Yao, Edgar Gonzalez-Kozlova, Yered Pita-Juarez, Dimitra Karagkouni, Chaitanya R. Acharya, Marina E. Michaud, Mark Hamilton, Shivani Nanda, Yizhe Song, Kazuhito Sato, Julia T. Wang, Sarthak Satpathy, Yuling Ma, Jessica Schulman, Darwin D’Souza, Reyka G. Jayasinghe, Denis Ohlstrom, Katherine E. Ferguson, Giulia Cheloni, Mojtaba Bakhtiari, Nick Pabustan, Kai Nie, Jennifer A. Foltz, Isabella Saldarriaga, Rania Alaaeldin, Eva Lepisto, Rachel Chen, Mark A. Fiala, Beena E. Thomas, April Cook, Junia Vieira Dos Santos, Chiang I-ling, Igor Figueiredo, Julie Fortier, Michael Slade, Stephen T. Oh, Michael P. Rettig, Emilie Anderson, Ying Li, Surendra Dasari, Michael A. Strausbauch, Vernadette A. Simon, Immune Atlas Consortium, Emir Radkevich, Adeeb H. Rahman, Zhihong Chen, Alessandro Lagana, John F. DiPersio, Jacalyn Rosenblatt, Seunghee Kim-Schulze, Sagar Lonial, Shaji Kumar, Swati S. Bhasin, Taxiarchis Kourelis, Madhav V. Dhodapkar, Ravi Vij, David Avigan, Hearn J. Cho, George Mulligan, Li Ding, Sacha Gnjatic, Ioannis S. Vlachos, Manoj Bhasin
Multiple myeloma (MM) remains incurable despite advances in treatment options. Although tumor subtypes and specific DNA abnormalities are linked to worse prognosis, the impact of immune dysfunction on disease emergence and/or treatment sensitivity remains unclear. We developed an Immune Atlas of MM by generating profiles of 1,397,272 single cells from the bone marrow (BM) of 337 newly diagnosed participants and characterized immune and hematopoietic cell populations. Cytogenetic risk-based analysis revealed heterogeneous associations with T cells of BM, with 17p13 deletion showing distinct enrichment of a type 1 interferon signature. The disease progression-based analysis revealed the presence of a proinflammatory immune senescence-associated secretory phenotype in rapidly progressing participants. Furthermore, signaling analyses suggested active intercellular communication involving a proliferation-inducing ligand and B cell maturation antigen, potentially promoting tumor growth and survival. Lastly, using independent discovery and validation cohorts, we demonstrated that integrating immune cell signatures with known tumor cytogenetics and individual characteristics significantly improves stratification for the prediction of survival. Pilcher et al. present a single-cell transcriptomics-based immune atlas of participants with newly diagnosed multiple myeloma, reporting on the association of cell types, gene expression and intercellular interactions with disease progression phenotypes.
{"title":"A single-cell atlas characterizes dysregulation of the bone marrow immune microenvironment associated with outcomes in multiple myeloma","authors":"William C. Pilcher, Lijun Yao, Edgar Gonzalez-Kozlova, Yered Pita-Juarez, Dimitra Karagkouni, Chaitanya R. Acharya, Marina E. Michaud, Mark Hamilton, Shivani Nanda, Yizhe Song, Kazuhito Sato, Julia T. Wang, Sarthak Satpathy, Yuling Ma, Jessica Schulman, Darwin D’Souza, Reyka G. Jayasinghe, Denis Ohlstrom, Katherine E. Ferguson, Giulia Cheloni, Mojtaba Bakhtiari, Nick Pabustan, Kai Nie, Jennifer A. Foltz, Isabella Saldarriaga, Rania Alaaeldin, Eva Lepisto, Rachel Chen, Mark A. Fiala, Beena E. Thomas, April Cook, Junia Vieira Dos Santos, Chiang I-ling, Igor Figueiredo, Julie Fortier, Michael Slade, Stephen T. Oh, Michael P. Rettig, Emilie Anderson, Ying Li, Surendra Dasari, Michael A. Strausbauch, Vernadette A. Simon, Immune Atlas Consortium, Emir Radkevich, Adeeb H. Rahman, Zhihong Chen, Alessandro Lagana, John F. DiPersio, Jacalyn Rosenblatt, Seunghee Kim-Schulze, Sagar Lonial, Shaji Kumar, Swati S. Bhasin, Taxiarchis Kourelis, Madhav V. Dhodapkar, Ravi Vij, David Avigan, Hearn J. Cho, George Mulligan, Li Ding, Sacha Gnjatic, Ioannis S. Vlachos, Manoj Bhasin","doi":"10.1038/s43018-025-01072-4","DOIUrl":"10.1038/s43018-025-01072-4","url":null,"abstract":"Multiple myeloma (MM) remains incurable despite advances in treatment options. Although tumor subtypes and specific DNA abnormalities are linked to worse prognosis, the impact of immune dysfunction on disease emergence and/or treatment sensitivity remains unclear. We developed an Immune Atlas of MM by generating profiles of 1,397,272 single cells from the bone marrow (BM) of 337 newly diagnosed participants and characterized immune and hematopoietic cell populations. Cytogenetic risk-based analysis revealed heterogeneous associations with T cells of BM, with 17p13 deletion showing distinct enrichment of a type 1 interferon signature. The disease progression-based analysis revealed the presence of a proinflammatory immune senescence-associated secretory phenotype in rapidly progressing participants. Furthermore, signaling analyses suggested active intercellular communication involving a proliferation-inducing ligand and B cell maturation antigen, potentially promoting tumor growth and survival. Lastly, using independent discovery and validation cohorts, we demonstrated that integrating immune cell signatures with known tumor cytogenetics and individual characteristics significantly improves stratification for the prediction of survival. Pilcher et al. present a single-cell transcriptomics-based immune atlas of participants with newly diagnosed multiple myeloma, reporting on the association of cell types, gene expression and intercellular interactions with disease progression phenotypes.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"7 1","pages":"224-246"},"PeriodicalIF":28.5,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s43018-025-01072-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145945223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-09DOI: 10.1038/s43018-025-01085-z
Guangwen Yuan, Ge Lou, Jundong Li, Mei Xu, Xiaowei Liu, Danbo Wang, Keqiang Zhang, Tao Zhu, Xiumin Li, Yi Huang, Wei Duan, Ke Wang, Qi Zhou, Guiling Li, Chen Yang, Jiajing Zhang, Haolin Sun, Renhong Tang, Qingshui Li, Lingying Wu
In the SCORES study ( NCT04908787 ), women with ovarian cancer that progressed within 6 months after completing platinum-based therapy were randomized (2:1) to receive suvemcitug (1.5 mg kg−1), an antibody to vascular endothelial growth factor or placebo every 2 weeks, with chemotherapy (paclitaxel, topotecan or PEGylated liposomal doxorubicin). The primary endpoint was progression-free survival (PFS). The key secondary endpoint was overall survival (OS). Other secondary endpoints included objective response rate, disease control rate, duration of response, quality of life, safety, pharmacokinetics and antidrug antibodies. Between June 5, 2021 and October 11, 2024, 421 participants were randomized (49.4% and 49.4% previously exposed to antiangiogenic agents and poly(ADP-ribose) polymerase inhibitors, respectively). Median PFS was 5.5 and 2.7 months in the suvemcitug and placebo arms, respectively (hazard ratio: 0.46, 95% confidence interval (CI): 0.35–0.60, P < 0.001), meeting the primary endpoint. Median OS was 15.3 versus 14.0 months, respectively (hazard ratio: 0.77, 95% CI: 0.60–0.99, P = 0.03). Decreased neutrophil count and decreased white blood cell count were the most common grade ≥3 treatment-emergent adverse events (TEAEs) in the suvemcitug arm. No suvemcitug-related grade 5 TEAE occurred. In conclusion, the addition of suvemcitug to chemotherapy significantly improved PFS and OS, with tolerable toxicities. Wu and colleagues present the efficacy and safety results from the phase 3 SCORES trial evaluating suvemcitug plus chemotherapy in persons with platinum-refractory or resistant recurrent ovarian cancer.
在SCORES研究（NCT04908787）中，在完成铂基治疗后6个月内进展的卵巢癌妇女被随机（2:1）每2周接受suvemcitug (1.5 mg kg-1)，血管内皮生长因子抗体或安慰剂，化疗（紫杉醇，拓扑替康或聚乙二醇化脂质体阿霉素）。主要终点为无进展生存期（PFS）。主要次要终点是总生存期（OS）。其他次要终点包括客观缓解率、疾病控制率、缓解持续时间、生活质量、安全性、药代动力学和抗药物抗体。在2021年6月5日至2024年10月11日期间，421名参与者被随机分配（49.4%和49.4%分别暴露于抗血管生成药物和聚（adp -核糖）聚合酶抑制剂）。苏维西库特和安慰剂组的中位PFS分别为5.5个月和2.7个月(风险比：0.46,95%可信区间（CI）： 0.35-0.60， P
{"title":"Suvemcitug plus chemotherapy in women with platinum-resistant recurrent ovarian cancer: the SCORES randomized, double-blinded, phase 3 trial","authors":"Guangwen Yuan, Ge Lou, Jundong Li, Mei Xu, Xiaowei Liu, Danbo Wang, Keqiang Zhang, Tao Zhu, Xiumin Li, Yi Huang, Wei Duan, Ke Wang, Qi Zhou, Guiling Li, Chen Yang, Jiajing Zhang, Haolin Sun, Renhong Tang, Qingshui Li, Lingying Wu","doi":"10.1038/s43018-025-01085-z","DOIUrl":"10.1038/s43018-025-01085-z","url":null,"abstract":"In the SCORES study ( NCT04908787 ), women with ovarian cancer that progressed within 6 months after completing platinum-based therapy were randomized (2:1) to receive suvemcitug (1.5 mg kg−1), an antibody to vascular endothelial growth factor or placebo every 2 weeks, with chemotherapy (paclitaxel, topotecan or PEGylated liposomal doxorubicin). The primary endpoint was progression-free survival (PFS). The key secondary endpoint was overall survival (OS). Other secondary endpoints included objective response rate, disease control rate, duration of response, quality of life, safety, pharmacokinetics and antidrug antibodies. Between June 5, 2021 and October 11, 2024, 421 participants were randomized (49.4% and 49.4% previously exposed to antiangiogenic agents and poly(ADP-ribose) polymerase inhibitors, respectively). Median PFS was 5.5 and 2.7 months in the suvemcitug and placebo arms, respectively (hazard ratio: 0.46, 95% confidence interval (CI): 0.35–0.60, P < 0.001), meeting the primary endpoint. Median OS was 15.3 versus 14.0 months, respectively (hazard ratio: 0.77, 95% CI: 0.60–0.99, P = 0.03). Decreased neutrophil count and decreased white blood cell count were the most common grade ≥3 treatment-emergent adverse events (TEAEs) in the suvemcitug arm. No suvemcitug-related grade 5 TEAE occurred. In conclusion, the addition of suvemcitug to chemotherapy significantly improved PFS and OS, with tolerable toxicities. Wu and colleagues present the efficacy and safety results from the phase 3 SCORES trial evaluating suvemcitug plus chemotherapy in persons with platinum-refractory or resistant recurrent ovarian cancer.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"7 1","pages":"182-193"},"PeriodicalIF":28.5,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s43018-025-01085-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145945160","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cancer immunotherapies have revolutionized cancer treatment, yet many patients fail to respond. Activating innate immunity offers a promising approach to enhance therapeutic efficacy, but the signaling kinases directly regulating this process to boost antitumor responses remain elusive. Here we conduct an in vivo kinome CRISPR screen and identify CDK10 as a key suppressor of tumor immune surveillance. Mechanistically, CDK10 phosphorylates DNMT1 and RAP80 to reduce the accumulation of double-stranded RNA and R-loops, which alleviates the activation of innate immune pathways mediated by MDA5 and cGAS. Kinase inhibitor screens identify NVP-AST487 and ponatinib as selective CDK10 inhibitors. Both genetic and pharmacological inhibition of CDK10 activates MDA5 and cGAS pathways, fostering an immunoactive tumor microenvironment that enhances cancer immunotherapy in multiple mouse tumor models. Clinically, low CDK10 expression in tumors correlates with better immunotherapy responses. These findings establish CDK10 as a pivotal modulator of tumor immunity and a potential therapeutic target. Xu et al. report that CDK10 drives immune evasion by reducing nucleic acid sensors-mediated innate immune response in tumor cells and that its inhibition improves response to immune-checkpoint blockade in preclinical cancer models.
{"title":"CDK10 suppresses nucleic acid sensors-mediated antitumor immunity","authors":"Gaoshan Xu, Fusheng Guo, Chuan He, Xiyong Wang, Bolin Xiang, Lifang Fan, Baoxiang Chen, Jiakun Peng, Yishuang Sun, Jie Shi, Xixin Xing, Yingmeng Yao, Panpan Dai, Haiou Li, Wenjun Xiong, Hudan Liu, Rui Xiao, Guoliang Qing, Congqing Jiang, Baishan Jiang, Xiaoguang Lei, Jinfang Zhang","doi":"10.1038/s43018-025-01100-3","DOIUrl":"10.1038/s43018-025-01100-3","url":null,"abstract":"Cancer immunotherapies have revolutionized cancer treatment, yet many patients fail to respond. Activating innate immunity offers a promising approach to enhance therapeutic efficacy, but the signaling kinases directly regulating this process to boost antitumor responses remain elusive. Here we conduct an in vivo kinome CRISPR screen and identify CDK10 as a key suppressor of tumor immune surveillance. Mechanistically, CDK10 phosphorylates DNMT1 and RAP80 to reduce the accumulation of double-stranded RNA and R-loops, which alleviates the activation of innate immune pathways mediated by MDA5 and cGAS. Kinase inhibitor screens identify NVP-AST487 and ponatinib as selective CDK10 inhibitors. Both genetic and pharmacological inhibition of CDK10 activates MDA5 and cGAS pathways, fostering an immunoactive tumor microenvironment that enhances cancer immunotherapy in multiple mouse tumor models. Clinically, low CDK10 expression in tumors correlates with better immunotherapy responses. These findings establish CDK10 as a pivotal modulator of tumor immunity and a potential therapeutic target. Xu et al. report that CDK10 drives immune evasion by reducing nucleic acid sensors-mediated innate immune response in tumor cells and that its inhibition improves response to immune-checkpoint blockade in preclinical cancer models.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"7 2","pages":"283-303"},"PeriodicalIF":28.5,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145934350","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}
Pub Date : 2026-01-08DOI: 10.1038/s43018-025-01093-z
Kadriye Nehir Cosgun, Huda Jumaa, Mark E. Robinson, Zhangliang Cheng, Salim Oulghazi, Kohei Kume, David Fonseca Arce, Nikol Agadzhanian, Klaus M. Kistner, Etienne Leveille, Elsa Drivet, Fang Yu, Zhijian Qian, Joo Y. Song, Wing-Chung Chan, Liang Xu, Gang Xiao, M. Mark Taketo, Shalin Kothari, Matthew S. Davids, Hilde Schjerven, Julia Jellusova, Markus Müschen
As part of canonical Wnt signaling, T cell factor (TCF)–β-catenin complexes promote MYC-dependent proliferation. Lesions of the β-catenin protein degradation machinery are common oncogenic drivers. Here, we show that B cell acute lymphoblastic leukemia (B-ALL) lacks these mutations and critically depends on unencumbered β-catenin protein degradation. Compared to solid tumors, we found that mouse and human B-ALL express β-catenin protein at much lower levels; β-catenin protein was constitutively phosphorylated by glycogen synthase kinase 3B (GSK3β) and poised for proteasomal degradation. Instead of TCF–β-catenin complexes to activate MYC, β-catenin paired with B lymphoid Ikaros and NuRD complex factors, resulting in MYC repression and acute cell death. To leverage β-catenin protein degradation as a previously unrecognized vulnerability in B-ALL, we validated GSK3β inhibition in patient-derived xenograft models in vivo. CRISPR screens confirmed β-catenin protein degradation as a central mechanistic target of established GSK3β inhibitors. As several GSK3β inhibitors achieved favorable safety profiles in clinical trials, our results provide a rationale for repurposing these compounds for persons with refractory B cell malignancies. Cosgun et al. show that, in B cell leukemia, β-catenin expression is maintained at low levels through glycogen synthase kinase 3B (GSK3β)-mediated phosphorylation. Inhibition of GSK3β results in β-catenin–Ikaros–NuRD complex formation, leading to B-ALL cell death through MYC repression.
{"title":"Targeting β-catenin degradation with GSK3β inhibitors induces cell death in acute lymphoblastic leukemia","authors":"Kadriye Nehir Cosgun, Huda Jumaa, Mark E. Robinson, Zhangliang Cheng, Salim Oulghazi, Kohei Kume, David Fonseca Arce, Nikol Agadzhanian, Klaus M. Kistner, Etienne Leveille, Elsa Drivet, Fang Yu, Zhijian Qian, Joo Y. Song, Wing-Chung Chan, Liang Xu, Gang Xiao, M. Mark Taketo, Shalin Kothari, Matthew S. Davids, Hilde Schjerven, Julia Jellusova, Markus Müschen","doi":"10.1038/s43018-025-01093-z","DOIUrl":"10.1038/s43018-025-01093-z","url":null,"abstract":"As part of canonical Wnt signaling, T cell factor (TCF)–β-catenin complexes promote MYC-dependent proliferation. Lesions of the β-catenin protein degradation machinery are common oncogenic drivers. Here, we show that B cell acute lymphoblastic leukemia (B-ALL) lacks these mutations and critically depends on unencumbered β-catenin protein degradation. Compared to solid tumors, we found that mouse and human B-ALL express β-catenin protein at much lower levels; β-catenin protein was constitutively phosphorylated by glycogen synthase kinase 3B (GSK3β) and poised for proteasomal degradation. Instead of TCF–β-catenin complexes to activate MYC, β-catenin paired with B lymphoid Ikaros and NuRD complex factors, resulting in MYC repression and acute cell death. To leverage β-catenin protein degradation as a previously unrecognized vulnerability in B-ALL, we validated GSK3β inhibition in patient-derived xenograft models in vivo. CRISPR screens confirmed β-catenin protein degradation as a central mechanistic target of established GSK3β inhibitors. As several GSK3β inhibitors achieved favorable safety profiles in clinical trials, our results provide a rationale for repurposing these compounds for persons with refractory B cell malignancies. Cosgun et al. show that, in B cell leukemia, β-catenin expression is maintained at low levels through glycogen synthase kinase 3B (GSK3β)-mediated phosphorylation. Inhibition of GSK3β results in β-catenin–Ikaros–NuRD complex formation, leading to B-ALL cell death through MYC repression.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"7 1","pages":"150-168"},"PeriodicalIF":28.5,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s43018-025-01093-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145934332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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