Pub Date : 2026-01-02DOI: 10.1038/s43018-025-01068-0
Nadeem Riaz, Tyler J. Alban, Robert I. Haddad, Michelle Saul, Vladimir Makarov, Yingjie Zhu, Ezra E. W. Cohen, Robert L. Ferris, Peter Mu-Hsing Chang, Jin-Ching Lin, Amanda Psyrri, Prerana Bangalore Parthasarathy, Ardijana Novaj, Mruniya Gawali, Douglas Hoen, Phineas Hamilton, Natalie L. Silver, Ivan Juric, Daniel Chawla, Ana Gradissimo, Jennifer Ko, Daniel J. McGrail, Craig B. Davis, Nancy Y. Lee, Timothy A. Chan
Immune checkpoint blockade-based multimodal therapy is widely used across oncology; yet drivers of resistance in most cancer types are not well understood. Here, we comprehensively characterized the tumor genome, microenvironment and microbiome in a phase 3 international randomized trial ( NCT02952586 ) to identify factors that shape outcomes to anti-PD-L1 avelumab plus standard-of-care chemoradiotherapy versus placebo/chemoradiotherapy in individuals with locally advanced head and neck cancer. Patients receiving avelumab whose tumors contained distinct immunologic and genetic features had superior outcomes compared to those receiving placebo. By contrast, patients with increased myeloid/neutrophil activities had worse outcomes with avelumab than those treated with placebo. Strikingly, these tumors possessed telltale intratumoral bacteria, elevated tumor-associated neutrophils, high systemic neutrophil-to-lymphocyte ratios and suppressed adaptive immunity. We define tumor ecosystems associated with benefit to chemoimmunotherapy. Our data demonstrate how intratumoral bacteria affect immune checkpoint blockade response within a randomized trial. These discoveries enhance our understanding of combination immunotherapy, provide a useful multiomic resource and identify unanticipated interactions that may guide future therapeutic strategies. Chan and colleagues report that tumor ecosystem and microbiome features are associated with response to anti-PD-L1 avelumab plus chemoradiotherapy in patients with locally advanced head and neck cancer.
{"title":"Tumor ecosystem and microbiome features associated with efficacy and resistance to avelumab plus chemoradiotherapy in head and neck cancer","authors":"Nadeem Riaz, Tyler J. Alban, Robert I. Haddad, Michelle Saul, Vladimir Makarov, Yingjie Zhu, Ezra E. W. Cohen, Robert L. Ferris, Peter Mu-Hsing Chang, Jin-Ching Lin, Amanda Psyrri, Prerana Bangalore Parthasarathy, Ardijana Novaj, Mruniya Gawali, Douglas Hoen, Phineas Hamilton, Natalie L. Silver, Ivan Juric, Daniel Chawla, Ana Gradissimo, Jennifer Ko, Daniel J. McGrail, Craig B. Davis, Nancy Y. Lee, Timothy A. Chan","doi":"10.1038/s43018-025-01068-0","DOIUrl":"10.1038/s43018-025-01068-0","url":null,"abstract":"Immune checkpoint blockade-based multimodal therapy is widely used across oncology; yet drivers of resistance in most cancer types are not well understood. Here, we comprehensively characterized the tumor genome, microenvironment and microbiome in a phase 3 international randomized trial ( NCT02952586 ) to identify factors that shape outcomes to anti-PD-L1 avelumab plus standard-of-care chemoradiotherapy versus placebo/chemoradiotherapy in individuals with locally advanced head and neck cancer. Patients receiving avelumab whose tumors contained distinct immunologic and genetic features had superior outcomes compared to those receiving placebo. By contrast, patients with increased myeloid/neutrophil activities had worse outcomes with avelumab than those treated with placebo. Strikingly, these tumors possessed telltale intratumoral bacteria, elevated tumor-associated neutrophils, high systemic neutrophil-to-lymphocyte ratios and suppressed adaptive immunity. We define tumor ecosystems associated with benefit to chemoimmunotherapy. Our data demonstrate how intratumoral bacteria affect immune checkpoint blockade response within a randomized trial. These discoveries enhance our understanding of combination immunotherapy, provide a useful multiomic resource and identify unanticipated interactions that may guide future therapeutic strategies. Chan and colleagues report that tumor ecosystem and microbiome features are associated with response to anti-PD-L1 avelumab plus chemoradiotherapy in patients with locally advanced head and neck cancer.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"7 1","pages":"98-115"},"PeriodicalIF":28.5,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145892604","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 : 2026-01-02DOI: 10.1038/s43018-025-01067-1
Natalie L. Silver, Jin Dai, Travis D. Kerr, Jessica Altemus, Rekha Garg, Hannah Simmons, Tyler Alban, Laura Noel-Romas, Vladimir Makarov, David J. H. Shih, Shwetha V. Kumar, Akeem Santos, Rehan Akbani, Adam Burgener, Mohammed Dwidar, Neil Gross, Andrew G. Sikora, Elias J. Sayour, Apollo Stacy, Christian Jobin, Timothy A. Chan, Renata Ferrarotto, Daniel J. McGrail
Despite the promise of immune checkpoint blockade (ICB) in head and neck squamous cell carcinoma (HNSCC), mediators of response are poorly understood. To address this, here we analyzed oropharyngeal HNSCCs treated with neoadjuvant durvalumab (anti-PDL1) alone or in combination with tremelimumab (anti-CTLA4) from the CIAO clinical trial ( NCT03144778 ). We found that only the total abundance of intratumoral bacteria predicted ICB response, which was validated in multiple independent cohorts. High intratumoral bacteria abundance was associated with an immunosuppressive tumor microenvironment, characterized by an accumulation of neutrophils coupled with depletion of T cells and other adaptive immune cells. Experimental elevation or reduction in intratumoral bacteria abundance in orthotopic models of HNSCC in female mice recapitulated immunological associations observed in participant tumors. Increasing intratumoral bacteria abundance was sufficient to induce resistance to anti-PDL1 ICB, irrespective of bacterial species tested. Together, these findings demonstrate that high intratumoral bacteria abundance is a key suppressor of antitumor immunity and promotes immunotherapy resistance. McGrail and colleagues report that high intratumoral bacteria abundance is associated with an immunosuppressive microenvironment and resistance to immune checkpoint blockade in head and neck squamous cell carcinoma.
{"title":"Intratumoral bacteria are immunosuppressive and promote immunotherapy resistance in head and neck squamous cell carcinoma","authors":"Natalie L. Silver, Jin Dai, Travis D. Kerr, Jessica Altemus, Rekha Garg, Hannah Simmons, Tyler Alban, Laura Noel-Romas, Vladimir Makarov, David J. H. Shih, Shwetha V. Kumar, Akeem Santos, Rehan Akbani, Adam Burgener, Mohammed Dwidar, Neil Gross, Andrew G. Sikora, Elias J. Sayour, Apollo Stacy, Christian Jobin, Timothy A. Chan, Renata Ferrarotto, Daniel J. McGrail","doi":"10.1038/s43018-025-01067-1","DOIUrl":"10.1038/s43018-025-01067-1","url":null,"abstract":"Despite the promise of immune checkpoint blockade (ICB) in head and neck squamous cell carcinoma (HNSCC), mediators of response are poorly understood. To address this, here we analyzed oropharyngeal HNSCCs treated with neoadjuvant durvalumab (anti-PDL1) alone or in combination with tremelimumab (anti-CTLA4) from the CIAO clinical trial ( NCT03144778 ). We found that only the total abundance of intratumoral bacteria predicted ICB response, which was validated in multiple independent cohorts. High intratumoral bacteria abundance was associated with an immunosuppressive tumor microenvironment, characterized by an accumulation of neutrophils coupled with depletion of T cells and other adaptive immune cells. Experimental elevation or reduction in intratumoral bacteria abundance in orthotopic models of HNSCC in female mice recapitulated immunological associations observed in participant tumors. Increasing intratumoral bacteria abundance was sufficient to induce resistance to anti-PDL1 ICB, irrespective of bacterial species tested. Together, these findings demonstrate that high intratumoral bacteria abundance is a key suppressor of antitumor immunity and promotes immunotherapy resistance. McGrail and colleagues report that high intratumoral bacteria abundance is associated with an immunosuppressive microenvironment and resistance to immune checkpoint blockade in head and neck squamous cell carcinoma.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"7 1","pages":"80-97"},"PeriodicalIF":28.5,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12823012/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145891955","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 : 2026-01-02DOI: 10.1038/s43018-025-01074-2
Sachin R. Jhawar, Daniel Spakowicz
Tumor-infiltrating microorganisms have been presented as an unappreciated component of the tumor microenvironment, but there are few examples of their influence on tumor phenotypes or response to therapies. The total amount of bacteria is now shown to influence immunotherapy outcomes in head and neck squamous cell carcinoma.
{"title":"Tumor bacterial burden dictates immunotherapy fate in head and neck cancer","authors":"Sachin R. Jhawar, Daniel Spakowicz","doi":"10.1038/s43018-025-01074-2","DOIUrl":"10.1038/s43018-025-01074-2","url":null,"abstract":"Tumor-infiltrating microorganisms have been presented as an unappreciated component of the tumor microenvironment, but there are few examples of their influence on tumor phenotypes or response to therapies. The total amount of bacteria is now shown to influence immunotherapy outcomes in head and neck squamous cell carcinoma.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"7 1","pages":"7-9"},"PeriodicalIF":28.5,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145892268","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 : 2025-12-22DOI: 10.1038/s43018-025-01069-z
Jiaxin Ge, Joshua Urban, Sarah R. DiNapoli, Bum Seok Lee, Taha Ahmedna, Tushar D. Nichakawade, Brian J. Mog, Steve Lu, Xuyang Li, Nikita Marcou, Stephanie Glavaris, Jacqueline Douglass, Jin Liu, Maximilian F. Konig, Evangeline Watson, Maria Popoli, J. David Peske, Sima Rozati, Cole H. Sterling, Nina Wagner-Johnston, Richard F. Ambinder, Kathy Gabrielson, Charles G. Mullighan, Nickolas Papadopoulos, Chetan Bettegowda, Drew M. Pardoll, Shibin Zhou, Surojit Sur, Kenneth W. Kinzler, Bert Vogelstein, Suman Paul
Antibody–drug conjugates (ADCs) have been remarkably successful in treating solid and hematological malignancies. Generation of ADCs for T cell cancers is challenging because the ADCs must selectively target cancerous T cells while sparing some normal T cells necessary for immune function. T cells express one of two TRBC alleles: TRBC1 or TRBC2. Normal T cells are composed of about 40% TRBC1-expressing and 60% TRBC2-expressing cells. In contrast, T cell malignancies are characterized by the clonal expression of either TRBC1 or TRBC2. Selective targeting of TRBC1 or TRBC2 enables the killing of cancer cells but preserves about 60–40% of the normal T cells. To enable such a therapy for cancers expressing TRBC2, here we developed a high-affinity anti-TRBC2 antibody. An ADC generated with this antibody and a pyrrolobenzodiazepine dimer payload showed specific killing of TRBC2+ cancers in vitro and in mouse models. The anti-TRBC2 ADC provides a promising, off-the-shelf therapy for patients with T cell cancers. Paul and colleagues report the development and characterization of an antibody–drug conjugate targeting TRBC2 for the treatment of T cell malignancies.
{"title":"TRBC2-targeting antibody–drug conjugates for the treatment of T cell cancers","authors":"Jiaxin Ge, Joshua Urban, Sarah R. DiNapoli, Bum Seok Lee, Taha Ahmedna, Tushar D. Nichakawade, Brian J. Mog, Steve Lu, Xuyang Li, Nikita Marcou, Stephanie Glavaris, Jacqueline Douglass, Jin Liu, Maximilian F. Konig, Evangeline Watson, Maria Popoli, J. David Peske, Sima Rozati, Cole H. Sterling, Nina Wagner-Johnston, Richard F. Ambinder, Kathy Gabrielson, Charles G. Mullighan, Nickolas Papadopoulos, Chetan Bettegowda, Drew M. Pardoll, Shibin Zhou, Surojit Sur, Kenneth W. Kinzler, Bert Vogelstein, Suman Paul","doi":"10.1038/s43018-025-01069-z","DOIUrl":"10.1038/s43018-025-01069-z","url":null,"abstract":"Antibody–drug conjugates (ADCs) have been remarkably successful in treating solid and hematological malignancies. Generation of ADCs for T cell cancers is challenging because the ADCs must selectively target cancerous T cells while sparing some normal T cells necessary for immune function. T cells express one of two TRBC alleles: TRBC1 or TRBC2. Normal T cells are composed of about 40% TRBC1-expressing and 60% TRBC2-expressing cells. In contrast, T cell malignancies are characterized by the clonal expression of either TRBC1 or TRBC2. Selective targeting of TRBC1 or TRBC2 enables the killing of cancer cells but preserves about 60–40% of the normal T cells. To enable such a therapy for cancers expressing TRBC2, here we developed a high-affinity anti-TRBC2 antibody. An ADC generated with this antibody and a pyrrolobenzodiazepine dimer payload showed specific killing of TRBC2+ cancers in vitro and in mouse models. The anti-TRBC2 ADC provides a promising, off-the-shelf therapy for patients with T cell cancers. Paul and colleagues report the development and characterization of an antibody–drug conjugate targeting TRBC2 for the treatment of T cell malignancies.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 12","pages":"2011-2024"},"PeriodicalIF":28.5,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145802623","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 : 2025-12-10DOI: 10.1038/s43018-025-01082-2
Michelle Monje, Frank Winkler
Over the past decade, multiple lines of inquiry have converged on the appreciation that the nervous system plays crucial roles in cancer pathophysiology. Key conceptual advances will mark 2025 as a milestone year in which the ‘emerging’ cancer neuroscience field developed into an established field. Here, we discuss the latest developments.
{"title":"Key developments in the cancer neuroscience field","authors":"Michelle Monje, Frank Winkler","doi":"10.1038/s43018-025-01082-2","DOIUrl":"10.1038/s43018-025-01082-2","url":null,"abstract":"Over the past decade, multiple lines of inquiry have converged on the appreciation that the nervous system plays crucial roles in cancer pathophysiology. Key conceptual advances will mark 2025 as a milestone year in which the ‘emerging’ cancer neuroscience field developed into an established field. Here, we discuss the latest developments.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 12","pages":"1928-1929"},"PeriodicalIF":28.5,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145724885","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 : 2025-12-10DOI: 10.1038/s43018-025-01055-5
Bertrand Routy, Edmond Rafie, Arielle Elkrief
Antibiotic-related dysbiosis has emerged as a major, yet potentially modifiable, barrier to immune-checkpoint inhibitor (ICI) efficacy in patients with cancer. Although antibiotic stewardship remains the primary recommendation, the advent of point-of-care microbiome profiling tools and targeted, preventative or restorative interventions may offer strategies to counter antibiotic-related dysbiosis and improve outcomes.
{"title":"Antibiotic-related dysbiosis in cancer immunotherapy: from preclinical insights to practice-changing evidence","authors":"Bertrand Routy, Edmond Rafie, Arielle Elkrief","doi":"10.1038/s43018-025-01055-5","DOIUrl":"10.1038/s43018-025-01055-5","url":null,"abstract":"Antibiotic-related dysbiosis has emerged as a major, yet potentially modifiable, barrier to immune-checkpoint inhibitor (ICI) efficacy in patients with cancer. Although antibiotic stewardship remains the primary recommendation, the advent of point-of-care microbiome profiling tools and targeted, preventative or restorative interventions may offer strategies to counter antibiotic-related dysbiosis and improve outcomes.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 12","pages":"1909-1912"},"PeriodicalIF":28.5,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145724790","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 : 2025-12-10DOI: 10.1038/s43018-025-01077-z
Sandra Misale
The initial discovery of an inhibitor of KRAS G12C revolutionized the KRAS field. Since then, more-potent G12C-specific inhibitors, newer allele-specific inhibitors and combinations based on KRAS targeting have advanced through clinical trials, which has led to approval by the US Food and Drug Administration of the first KRAS–EGFR inhibition combinations.
{"title":"The evolving landscape of RAS-targeted therapies","authors":"Sandra Misale","doi":"10.1038/s43018-025-01077-z","DOIUrl":"10.1038/s43018-025-01077-z","url":null,"abstract":"The initial discovery of an inhibitor of KRAS G12C revolutionized the KRAS field. Since then, more-potent G12C-specific inhibitors, newer allele-specific inhibitors and combinations based on KRAS targeting have advanced through clinical trials, which has led to approval by the US Food and Drug Administration of the first KRAS–EGFR inhibition combinations.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 12","pages":"1913-1915"},"PeriodicalIF":28.5,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145724835","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 : 2025-12-10DOI: 10.1038/s43018-025-01086-y
Hana Aliee, Leire Bejarano-Bosque, Roger Castells-Graells, Deborah Caswell, Mirco Julian Friedrich, Carino Gurjao, Li Ren Kong, Shuang Liu, Simone Minnie, Reineke A. Schoot, Zefang Tang
Twelve early-career researchers who started their independent research groups in 2025 reflect on their experiences from this first year of the journey, describe the opportunities they have had and the challenges they have faced, and share their hopes and plans for the future.
{"title":"The 2025 generation","authors":"Hana Aliee, Leire Bejarano-Bosque, Roger Castells-Graells, Deborah Caswell, Mirco Julian Friedrich, Carino Gurjao, Li Ren Kong, Shuang Liu, Simone Minnie, Reineke A. Schoot, Zefang Tang","doi":"10.1038/s43018-025-01086-y","DOIUrl":"10.1038/s43018-025-01086-y","url":null,"abstract":"Twelve early-career researchers who started their independent research groups in 2025 reflect on their experiences from this first year of the journey, describe the opportunities they have had and the challenges they have faced, and share their hopes and plans for the future.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 12","pages":"1930-1934"},"PeriodicalIF":28.5,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145724821","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 : 2025-12-10DOI: 10.1038/s43018-025-01080-4
Melanie Senior
Bispecific antibodies and ADCs battle for the limelight, CAR-T therapy sees late surge and China’s growth continues.
双特异性抗体和adc争夺风头，CAR-T疗法姗姗来迟，中国的增长仍在继续。
{"title":"Cancer drug approvals and setbacks in 2025","authors":"Melanie Senior","doi":"10.1038/s43018-025-01080-4","DOIUrl":"10.1038/s43018-025-01080-4","url":null,"abstract":"Bispecific antibodies and ADCs battle for the limelight, CAR-T therapy sees late surge and China’s growth continues.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 12","pages":"1902-1904"},"PeriodicalIF":28.5,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145724841","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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