Pub Date : 2026-01-05DOI: 10.1038/s43018-025-01084-0
Nils Bessler, Amber K L Wezenaar, Hendrikus C R Ariese, Celina Honhoff, Noëlle Dommann, Ellen J Wehrens, Cristian Ruiz Moreno, Thijs J M van den Broek, Raphaël V U Collot, Daan J Kloosterman, Farid Keramati, Mieke Roosen, Sam de Blank, Esmée van Vliet, Mario Barrera Román, Lucrezia C D E Gatti, Ali Ertürk, Jürgen Kuball, Zsolt Sebestyén, Marcel Kool, Sara Patrizi, Evelina Miele, Annette Künkele, Mariëtte E G Kranendonk, Annelisa M Cornel, Stefan Nierkens, Christian Mayer, Hendrik G Stunnenberg, Anna Alemany, Maria Alieva, Anne C Rios
Diffuse midline glioma (DMG) is a highly aggressive and untreatable pediatric cancer primarily arising in the pontine brainstem region, necessitating the development of representative models for treatment advance. Here we developed an FGF4-driven human brainstem organoid model, which we used to genetically engineer H3.3K27M-altered DMG. We demonstrated that brainstem pontine glial specification is critical for DMG tumorigenesis, yielding infiltrative tumors that recapitulate patient-representative intratumoral heterogeneity. Prolonged GD2 chimeric antigen receptor (CAR) T cell treatment mirrored clinical outcomes and revealed extensive transcriptional heterogeneity, from which both potent effector and dysfunctional CAR T cell populations could be identified. Furthermore, incorporation of myeloid cells generated DMG-specific microglia that reduced treatment efficacy and revealed CAR T cell functional states most vulnerable to microglia-mediated immunosuppression. Thus, we present a representative DMG model offering a months-long experimental window in vitro, which we leveraged to delineate CAR T cell functionality and microglial impact, aiding therapy development for this devastating disease.
{"title":"De novo H3.3K27M-altered diffuse midline glioma in human brainstem organoids to dissect GD2 CAR T cell function.","authors":"Nils Bessler, Amber K L Wezenaar, Hendrikus C R Ariese, Celina Honhoff, Noëlle Dommann, Ellen J Wehrens, Cristian Ruiz Moreno, Thijs J M van den Broek, Raphaël V U Collot, Daan J Kloosterman, Farid Keramati, Mieke Roosen, Sam de Blank, Esmée van Vliet, Mario Barrera Román, Lucrezia C D E Gatti, Ali Ertürk, Jürgen Kuball, Zsolt Sebestyén, Marcel Kool, Sara Patrizi, Evelina Miele, Annette Künkele, Mariëtte E G Kranendonk, Annelisa M Cornel, Stefan Nierkens, Christian Mayer, Hendrik G Stunnenberg, Anna Alemany, Maria Alieva, Anne C Rios","doi":"10.1038/s43018-025-01084-0","DOIUrl":"https://doi.org/10.1038/s43018-025-01084-0","url":null,"abstract":"<p><p>Diffuse midline glioma (DMG) is a highly aggressive and untreatable pediatric cancer primarily arising in the pontine brainstem region, necessitating the development of representative models for treatment advance. Here we developed an FGF4-driven human brainstem organoid model, which we used to genetically engineer H3.3K27M-altered DMG. We demonstrated that brainstem pontine glial specification is critical for DMG tumorigenesis, yielding infiltrative tumors that recapitulate patient-representative intratumoral heterogeneity. Prolonged GD2 chimeric antigen receptor (CAR) T cell treatment mirrored clinical outcomes and revealed extensive transcriptional heterogeneity, from which both potent effector and dysfunctional CAR T cell populations could be identified. Furthermore, incorporation of myeloid cells generated DMG-specific microglia that reduced treatment efficacy and revealed CAR T cell functional states most vulnerable to microglia-mediated immunosuppression. Thus, we present a representative DMG model offering a months-long experimental window in vitro, which we leveraged to delineate CAR T cell functionality and microglial impact, aiding therapy development for this devastating disease.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":28.5,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145906190","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 : 2026-01-05DOI: 10.1038/s43018-025-01094-y
Zhenghan Wang, Yassmin Elbanna, Inês Godet, Siting Gan, Lila Peters, George Lampe, Yanyan Chen, Joao Xavier, Morgan Huse, Joan Massagué
Different forms of epithelial-to-mesenchymal transition (EMT) manifest during tumor progression. Little is known about the mechanistic basis and functional role of these distinct EMTs. We explored this question in lung adenocarcinoma (LUAD) primitive progenitors, which are competent to enter dormancy in response to transforming growth factor-β (TGFβ) upon metastatic dissemination. The TGFβ response in these cells includes growth arrest and a full EMT that subsequently transitions into an atypical mesenchymal state of round morphology and lacking actin stress fibers. TGFβ drives this transition by inducing expression of the actin depolymerizing protein gelsolin, which converts a migratory, stress-fiber-rich phenotype into a cortical actin-rich, spheroidal state. This transition lowers the biomechanical stiffness of metastatic progenitors and protects them from killing by cytotoxic lymphocytes. Gelsolin-deficient LUAD progenitors can enter dormancy but succumb to immune surveillance. Thus, quiescent LUAD metastatic progenitors undergo an atypical EMT to avert immune surveillance during TGFβ-driven metastatic dormancy. Wang et al. report that LUAD cells entering dormancy transition into a TGFβ-induced atypical mesenchymal state characterized by a soft spheroidal morphology and strong EMT signature, which protects disseminated cancer cells from immune clearance.
{"title":"TGFβ induces an atypical EMT to evade immune mechanosurveillance in lung adenocarcinoma dormant metastasis","authors":"Zhenghan Wang, Yassmin Elbanna, Inês Godet, Siting Gan, Lila Peters, George Lampe, Yanyan Chen, Joao Xavier, Morgan Huse, Joan Massagué","doi":"10.1038/s43018-025-01094-y","DOIUrl":"10.1038/s43018-025-01094-y","url":null,"abstract":"Different forms of epithelial-to-mesenchymal transition (EMT) manifest during tumor progression. Little is known about the mechanistic basis and functional role of these distinct EMTs. We explored this question in lung adenocarcinoma (LUAD) primitive progenitors, which are competent to enter dormancy in response to transforming growth factor-β (TGFβ) upon metastatic dissemination. The TGFβ response in these cells includes growth arrest and a full EMT that subsequently transitions into an atypical mesenchymal state of round morphology and lacking actin stress fibers. TGFβ drives this transition by inducing expression of the actin depolymerizing protein gelsolin, which converts a migratory, stress-fiber-rich phenotype into a cortical actin-rich, spheroidal state. This transition lowers the biomechanical stiffness of metastatic progenitors and protects them from killing by cytotoxic lymphocytes. Gelsolin-deficient LUAD progenitors can enter dormancy but succumb to immune surveillance. Thus, quiescent LUAD metastatic progenitors undergo an atypical EMT to avert immune surveillance during TGFβ-driven metastatic dormancy. Wang et al. report that LUAD cells entering dormancy transition into a TGFβ-induced atypical mesenchymal state characterized by a soft spheroidal morphology and strong EMT signature, which protects disseminated cancer cells from immune clearance.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"7 1","pages":"131-149"},"PeriodicalIF":28.5,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s43018-025-01094-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145906217","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/s43018-025-01081-3
Eric Haines, Michael Burke, Rachel Catterall, Victor De Jesus, Daniel Hidalgo, Bin Li, Joseph D. Manna, Ao Yang, Jill Cavanaugh, Sarah R. Wessell, Marta Sanchez-Martin, Alexander Ivliev, Wilmin Bartolini, Sergio Santillana, Jeffrey Ecsedy, Michelle X. Zhang, Sabine K. Ruppel
MAPK pathway alterations are the most common oncogenic drivers. Among the approved therapies targeting this pathway are RAS, MEK and RAF inhibitors. However, therapeutic resistance and toxicities have limited their clinical success. Here, to overcome these liabilities, we developed IK-595, a potent MEK–RAF molecular glue. IK-595 traps MEK in an inactive complex with all RAF isoforms. In addition, IK-595 precludes CRAF-mediated MEK reactivation and ARAF heterodimerization, allowing for prolonged target engagement and durable MAPK pathway inhibition. This translates into superior antitumor activity across a wide range of cancer model indications harboring MAPK pathway alterations. A key advantage of IK-595 is its ability to achieve transient high plasma exposure affording a larger therapeutic window. The unique mechanism of action and improved tolerability positions IK-595 as an ideal combination partner. IK-595 is an MEK–RAF molecular glue that prolongs pathway inhibition while providing a broader therapeutic window as monotherapy and in combination. Haines et al. developed an MEK–RAF molecular glue called IK-595 that blocks MAPK pathway activation in RAS-mutant and BRAF-mutant cancer cells. IK-595 exhibited high tolerability and strong antitumor effects in preclinical models across cancer types.
{"title":"The MEK–RAF molecular glue IK-595 has potent antitumor activity across RAS/MAPK pathway-altered cancers","authors":"Eric Haines, Michael Burke, Rachel Catterall, Victor De Jesus, Daniel Hidalgo, Bin Li, Joseph D. Manna, Ao Yang, Jill Cavanaugh, Sarah R. Wessell, Marta Sanchez-Martin, Alexander Ivliev, Wilmin Bartolini, Sergio Santillana, Jeffrey Ecsedy, Michelle X. Zhang, Sabine K. Ruppel","doi":"10.1038/s43018-025-01081-3","DOIUrl":"10.1038/s43018-025-01081-3","url":null,"abstract":"MAPK pathway alterations are the most common oncogenic drivers. Among the approved therapies targeting this pathway are RAS, MEK and RAF inhibitors. However, therapeutic resistance and toxicities have limited their clinical success. Here, to overcome these liabilities, we developed IK-595, a potent MEK–RAF molecular glue. IK-595 traps MEK in an inactive complex with all RAF isoforms. In addition, IK-595 precludes CRAF-mediated MEK reactivation and ARAF heterodimerization, allowing for prolonged target engagement and durable MAPK pathway inhibition. This translates into superior antitumor activity across a wide range of cancer model indications harboring MAPK pathway alterations. A key advantage of IK-595 is its ability to achieve transient high plasma exposure affording a larger therapeutic window. The unique mechanism of action and improved tolerability positions IK-595 as an ideal combination partner. IK-595 is an MEK–RAF molecular glue that prolongs pathway inhibition while providing a broader therapeutic window as monotherapy and in combination. Haines et al. developed an MEK–RAF molecular glue called IK-595 that blocks MAPK pathway activation in RAS-mutant and BRAF-mutant cancer cells. IK-595 exhibited high tolerability and strong antitumor effects in preclinical models across cancer types.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"7 1","pages":"116-130"},"PeriodicalIF":28.5,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145892248","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/s43018-025-01052-8
Evripidis Gavathiotis
RAS–MAPK pathway inhibitors are limited by pathway reactivation and toxicity. A study now introduces IK-595, a MEK–RAF molecular glue that stabilizes MEK in an inactive complex with RAF isoforms, enabling durable inhibition of ERK signaling and anti-tumor activity in various cancers in which RAS or RAF is altered, including those resistant to current standard-of-care therapies.
{"title":"A molecular glue halts RAS–MAPK signaling","authors":"Evripidis Gavathiotis","doi":"10.1038/s43018-025-01052-8","DOIUrl":"10.1038/s43018-025-01052-8","url":null,"abstract":"RAS–MAPK pathway inhibitors are limited by pathway reactivation and toxicity. A study now introduces IK-595, a MEK–RAF molecular glue that stabilizes MEK in an inactive complex with RAF isoforms, enabling durable inhibition of ERK signaling and anti-tumor activity in various cancers in which RAS or RAF is altered, including those resistant to current standard-of-care therapies.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"7 1","pages":"4-6"},"PeriodicalIF":28.5,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145891867","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/s43018-025-01068-0
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}
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