Pub Date : 2026-01-08DOI: 10.1038/s43018-025-01097-9
Pilar M. Moreno-Sanchez, Mahsa Rezaeipour, Else Marit Inderberg, Michael Platten, Anna Golebiewska
Plasticity is a hallmark of aggressive tumors, including glioblastoma (GBM), enabling tumor cells and the tumor microenvironment (TME) to adapt to diverse niches and evade treatment. Here, we discuss how innate and adaptive immune players cooperate in time and space to create an immunosuppressive TME that supports GBM growth and confers resistance to conventional treatments and immunotherapies. We highlight how therapeutic interventions reshape the TME, underscoring the need for targeted approaches to overcome resistance. We introduce the concepts of local TME priming and TME rewiring as necessary foundations for achieving more effective and durable clinical responses in the future. In this Review, Golebiewska and colleagues summarize the main features of the immunosuppressive microenvironment in glioblastoma (GBM) and discuss how different therapeutic approaches reshape GBM immunity.
{"title":"Immunosuppressive mechanisms and therapeutic interventions shaping glioblastoma immunity","authors":"Pilar M. Moreno-Sanchez, Mahsa Rezaeipour, Else Marit Inderberg, Michael Platten, Anna Golebiewska","doi":"10.1038/s43018-025-01097-9","DOIUrl":"10.1038/s43018-025-01097-9","url":null,"abstract":"Plasticity is a hallmark of aggressive tumors, including glioblastoma (GBM), enabling tumor cells and the tumor microenvironment (TME) to adapt to diverse niches and evade treatment. Here, we discuss how innate and adaptive immune players cooperate in time and space to create an immunosuppressive TME that supports GBM growth and confers resistance to conventional treatments and immunotherapies. We highlight how therapeutic interventions reshape the TME, underscoring the need for targeted approaches to overcome resistance. We introduce the concepts of local TME priming and TME rewiring as necessary foundations for achieving more effective and durable clinical responses in the future. In this Review, Golebiewska and colleagues summarize the main features of the immunosuppressive microenvironment in glioblastoma (GBM) and discuss how different therapeutic approaches reshape GBM immunity.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"7 1","pages":"29-42"},"PeriodicalIF":28.5,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145934319","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 : 2026-01-06DOI: 10.1038/s43018-025-01099-7
Philip Bucher, Nadine Brückner, Jule Kortendieck, Melanie Grimm, Jan T. Schleicher, Karlotta Bartels, Steffen Hardy, Martina Rausch, Hannah Wurzer, Meike Thiemann, Celina May, Mara Mitstorfer, Dennis Letzgus, Julia Quach, Carolin Schneider, Denis A. Ispan, Irene Gonzalez-Menendez, Nayan Jain, Yu-Jui Ho, Jiangqing Chen, Francisco J. Sánchez-Rivera, Jie Sun, Leticia Quintanilla-Martinez, Christoph Trautwein, Bettina Weigelin, Manfred Claassen, Michel Sadelain, Judith Feucht, Josef Leibold
Insufficient functional T cell persistence impedes therapeutic success of chimeric antigen receptor (CAR) therapies. Here we performed a CAR-adapted base-editing screen of PIK3CD, a key regulator of T cell function, metabolism and fate. We identified point mutations that beneficially modulate CAR T cell profiles in 4-1BBz and 28z CAR T cells, respectively. We found that point mutations with differing effects on phosphatidylinositol-3-kinase delta (PI3Kδ) signaling activity were advantageous in distinct CAR contexts: The PI3Kδ-activating substitution E81K enhanced proliferation, metabolic fitness and effector function of 4-1BBz CARs, promoting long-term functional persistence and enhanced therapeutic efficacy in vivo. Conversely, the PI3Kδ-attenuating substitution L32P improved T cell memory formation and functionality of 28z CAR T cells. Together, our approach of rational optimization of activation-dependent signaling through targeted allelic reprogramming (ROADSTAR) illustrates the importance of CAR design-specific fine-tuning of intrinsic T cell signaling and demonstrates the potential of base editing for next-generation cellular therapies. By performing a CAR-adapted base-editing screen of phosphatidylinositol-3-kinase delta (PI3Kδ, PIK3CD), Bucher et al. identify mutations affecting endogenous PI3K–AKT signaling that enhances CAR T cell antitumor potency.
功能性T细胞持久性不足阻碍了嵌合抗原受体（CAR）治疗的成功。在这里，我们对PIK3CD进行了car适应的碱基编辑筛选，PIK3CD是T细胞功能、代谢和命运的关键调节因子。我们分别在4-1BBz和28z CAR - T细胞中发现了有利于调节CAR - T细胞谱的点突变。我们发现对磷脂酰肌醇-3-激酶δ (PI3Kδ)信号活性有不同影响的点突变在不同的CAR环境中是有利的：PI3Kδ激活替代E81K增强了4-1BBz CAR的增殖、代谢适应度和效应功能，促进了长期的功能持久性，增强了体内的治疗效果。相反，pi3k δ衰减替代L32P改善了28z CAR - T细胞的T细胞记忆形成和功能。总之，我们通过靶向等位基因重编程（ROADSTAR）对激活依赖性信号进行合理优化的方法说明了CAR设计特异性微调固有T细胞信号的重要性，并展示了碱基编辑在下一代细胞治疗中的潜力。
{"title":"CAR-adapted PIK3CD base editing enhances T cell anti-tumor potency","authors":"Philip Bucher, Nadine Brückner, Jule Kortendieck, Melanie Grimm, Jan T. Schleicher, Karlotta Bartels, Steffen Hardy, Martina Rausch, Hannah Wurzer, Meike Thiemann, Celina May, Mara Mitstorfer, Dennis Letzgus, Julia Quach, Carolin Schneider, Denis A. Ispan, Irene Gonzalez-Menendez, Nayan Jain, Yu-Jui Ho, Jiangqing Chen, Francisco J. Sánchez-Rivera, Jie Sun, Leticia Quintanilla-Martinez, Christoph Trautwein, Bettina Weigelin, Manfred Claassen, Michel Sadelain, Judith Feucht, Josef Leibold","doi":"10.1038/s43018-025-01099-7","DOIUrl":"10.1038/s43018-025-01099-7","url":null,"abstract":"Insufficient functional T cell persistence impedes therapeutic success of chimeric antigen receptor (CAR) therapies. Here we performed a CAR-adapted base-editing screen of PIK3CD, a key regulator of T cell function, metabolism and fate. We identified point mutations that beneficially modulate CAR T cell profiles in 4-1BBz and 28z CAR T cells, respectively. We found that point mutations with differing effects on phosphatidylinositol-3-kinase delta (PI3Kδ) signaling activity were advantageous in distinct CAR contexts: The PI3Kδ-activating substitution E81K enhanced proliferation, metabolic fitness and effector function of 4-1BBz CARs, promoting long-term functional persistence and enhanced therapeutic efficacy in vivo. Conversely, the PI3Kδ-attenuating substitution L32P improved T cell memory formation and functionality of 28z CAR T cells. Together, our approach of rational optimization of activation-dependent signaling through targeted allelic reprogramming (ROADSTAR) illustrates the importance of CAR design-specific fine-tuning of intrinsic T cell signaling and demonstrates the potential of base editing for next-generation cellular therapies. By performing a CAR-adapted base-editing screen of phosphatidylinositol-3-kinase delta (PI3Kδ, PIK3CD), Bucher et al. identify mutations affecting endogenous PI3K–AKT signaling that enhances CAR T cell antitumor potency.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"7 2","pages":"368-383"},"PeriodicalIF":28.5,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s43018-025-01099-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145911042","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 : 2026-01-05DOI: 10.1038/s43018-025-01102-1
Paolo Strati, Lori Leslie, Parveen Shiraz, Lihua E. Budde, Olalekan O. Oluwole, Matthew Ulrickson, Aravind Ramakrishnan, Teresa Zhang, Jennifer Sun, Francesca Milletti, Justyna Kanska, Rhine Shen, Frank Neumann, Hairong Xu, Krish Patel
CD19-negative relapse occurs in ~30% of persons with relapsed or refractory large B cell lymphoma (LBCL) who respond to axicabtagene ciloleucel (axi-cel; CD19-directed chimeric antigen receptor (CAR) T cell therapy). In this phase 2 single-arm study, 26 participants with chemorefractory LBCL received axi-cel in combination with rituximab. The primary endpoint was investigator-assessed complete response rate; select secondary endpoints included duration of response (DOR), axi-cel pharmacokinetics and safety. The complete response rate was 73%. Median DOR was 26.0 months; 46% of participants had an ongoing response at data cutoff. Peak CAR T cell (normalized by tumor burden) and rituximab area-under-the-curve levels were elevated in participants with complete or ongoing response. Axi-cel plus rituximab treatment led to durable responses with no new safety signals despite persistent B cell aplasia and pharmacokinetics of axi-cel were unaffected, indicating that dual targeting of CD19 and CD20 is a feasible and safe approach to potentially limit antigen escape. ClinicalTrials.gov registration: NCT04002401 . In this phase 2 ZUMA-14 clinical trial, Strati et al. reported the safety and efficacy of axicabtagene ciloleucel plus rituximab in adult participants with chemorefractory large B cell lymphomas and compared the results with previous findings from ZUMA-1 cohort 1.
{"title":"Axicabtagene ciloleucel in combination with rituximab for refractory large B cell lymphoma: the phase 2, single-arm ZUMA-14 trial","authors":"Paolo Strati, Lori Leslie, Parveen Shiraz, Lihua E. Budde, Olalekan O. Oluwole, Matthew Ulrickson, Aravind Ramakrishnan, Teresa Zhang, Jennifer Sun, Francesca Milletti, Justyna Kanska, Rhine Shen, Frank Neumann, Hairong Xu, Krish Patel","doi":"10.1038/s43018-025-01102-1","DOIUrl":"10.1038/s43018-025-01102-1","url":null,"abstract":"CD19-negative relapse occurs in ~30% of persons with relapsed or refractory large B cell lymphoma (LBCL) who respond to axicabtagene ciloleucel (axi-cel; CD19-directed chimeric antigen receptor (CAR) T cell therapy). In this phase 2 single-arm study, 26 participants with chemorefractory LBCL received axi-cel in combination with rituximab. The primary endpoint was investigator-assessed complete response rate; select secondary endpoints included duration of response (DOR), axi-cel pharmacokinetics and safety. The complete response rate was 73%. Median DOR was 26.0 months; 46% of participants had an ongoing response at data cutoff. Peak CAR T cell (normalized by tumor burden) and rituximab area-under-the-curve levels were elevated in participants with complete or ongoing response. Axi-cel plus rituximab treatment led to durable responses with no new safety signals despite persistent B cell aplasia and pharmacokinetics of axi-cel were unaffected, indicating that dual targeting of CD19 and CD20 is a feasible and safe approach to potentially limit antigen escape. ClinicalTrials.gov registration: NCT04002401 . In this phase 2 ZUMA-14 clinical trial, Strati et al. reported the safety and efficacy of axicabtagene ciloleucel plus rituximab in adult participants with chemorefractory large B cell lymphomas and compared the results with previous findings from ZUMA-1 cohort 1.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"7 2","pages":"304-315"},"PeriodicalIF":28.5,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s43018-025-01102-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145906224","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 : 2026-01-05DOI: 10.1038/s43018-025-01063-5
A phase 2 trial demonstrates that cryoablation followed by sintilimab (an anti-PD1 antibody) and lenvatinib yields a 75% objective response rate in chemotherapy-refractory advanced or metastatic intrahepatic cholangiocarcinoma. Multi-omics analyses reveal that enhanced immunogenicity and lymphocyte infiltration underpin the abscopal effect.
{"title":"Cryoablation induces abscopal immunity in intrahepatic cholangiocarcinoma","authors":"","doi":"10.1038/s43018-025-01063-5","DOIUrl":"10.1038/s43018-025-01063-5","url":null,"abstract":"A phase 2 trial demonstrates that cryoablation followed by sintilimab (an anti-PD1 antibody) and lenvatinib yields a 75% objective response rate in chemotherapy-refractory advanced or metastatic intrahepatic cholangiocarcinoma. Multi-omics analyses reveal that enhanced immunogenicity and lymphocyte infiltration underpin the abscopal effect.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"7 1","pages":"12-13"},"PeriodicalIF":28.5,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145906232","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/s43018-025-01096-w
Andrea Pérez González, Cédric Blanpain
Dormant metastases can lead to tumor relapse after many years by successfully escaping immune surveillance. A new study identifies an atypical epithelial-to-mesenchymal transition state that presents low stiffness mediated by actin depolymerization, which prevents immune cell-mediated killing of dormant metastatic lung adenocarcinoma.
{"title":"Cell stiffness regulates immune evasion during metastatic dormancy","authors":"Andrea Pérez González, Cédric Blanpain","doi":"10.1038/s43018-025-01096-w","DOIUrl":"10.1038/s43018-025-01096-w","url":null,"abstract":"Dormant metastases can lead to tumor relapse after many years by successfully escaping immune surveillance. A new study identifies an atypical epithelial-to-mesenchymal transition state that presents low stiffness mediated by actin depolymerization, which prevents immune cell-mediated killing of dormant metastatic lung adenocarcinoma.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"7 1","pages":"1-3"},"PeriodicalIF":28.5,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145906242","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/s43018-025-01066-2
Oncogenic KRAS hijacks chromatin remodeling during pancreatitis-induced tissue regeneration to drive tumorigenesis. We found that the chromatin remodeler SMARCA5 cooperates with oncogenic KRAS to maintain the malignant chromatin state; its deletion blocked tumorigenesis while preserving pancreatic tissue repair.
{"title":"Loss of SMARCA5 redirects pancreatic tumorigenesis toward a regenerative cell fate","authors":"","doi":"10.1038/s43018-025-01066-2","DOIUrl":"10.1038/s43018-025-01066-2","url":null,"abstract":"Oncogenic KRAS hijacks chromatin remodeling during pancreatitis-induced tissue regeneration to drive tumorigenesis. We found that the chromatin remodeler SMARCA5 cooperates with oncogenic KRAS to maintain the malignant chromatin state; its deletion blocked tumorigenesis while preserving pancreatic tissue repair.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"7 1","pages":"14-15"},"PeriodicalIF":28.5,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145906185","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/s43018-025-01087-x
Rebecca A. Burrell, Sanjeev Kumar, Elena Provenzano, Cleopatra Pike, Alimu Dayimu, Stuart A. McIntosh, Vassilis Pitsinis, Polly King, Beatrix Elsberger, Sasi Govindarajulu, Lucy Satherley, Sirwan Hadad, Peter Schmid, Amit Agrawal, Bodiere Akpuluma, Steven Bell, John R. Benson, Carlos Caldas, Danya Cheeseman, Igor Chernukhin, Parto Forouhi, Tulay Gulsen, Eleftheria Kleidi, Karen Pinilla, Wendi Qian, Jean E. Abraham, Jason S. Carroll, Richard D. Baird
The use of progestogens in breast cancer has been controversial. Recent preclinical studies have shown that ligand-bound progesterone receptor interacts directly with the estrogen receptor (ER) and reprograms ER transcriptional activity. Progestogen cotreatment enhances the antitumor activity of antiestrogen therapy in mouse xenografts. We report PIONEER, a 198-participant, three-arm, randomized phase 2b window-of-opportunity study for women with early-stage ER+ breast cancer, which evaluated letrozole with or without megestrol at 40 mg or 160 mg daily. The primary endpoint was the change in tumor proliferation measured by Ki67 immunohistochemistry. Secondary and exploratory endpoints included a comparison of low versus higher dose of megestrol, safety, tolerability and biomarker subgroup analyses. The trial met its primary endpoint, with a greater reduction in proliferation seen when megestrol was added to letrozole. This effect was accompanied by reduced ER genomic binding at canonical binding sites in paired tumor biopsies, indicating reduced ER transcriptional activity. These results support further evaluation of low-dose megestrol, which has two mechanisms for potentially improving breast cancer outcomes in combination with standard antiestrogen therapy: alleviating hot flashes and thereby helping with treatment adherence, as well as a direct antiproliferative effect ( NCT03306472 ). Baird et al. present the phase 2 PIONEER trial findings on the antitumor activity of combining aromatase inhibitor letrozole with megestrol in postmenopausal women with operable estrogen-receptor-positive human epidermal-growth-factor-receptor-2-negative breast cancer.
{"title":"Evaluating progesterone receptor agonist megestrol plus letrozole for women with early-stage estrogen-receptor-positive breast cancer: the window-of-opportunity, randomized, phase 2b, PIONEER trial","authors":"Rebecca A. Burrell, Sanjeev Kumar, Elena Provenzano, Cleopatra Pike, Alimu Dayimu, Stuart A. McIntosh, Vassilis Pitsinis, Polly King, Beatrix Elsberger, Sasi Govindarajulu, Lucy Satherley, Sirwan Hadad, Peter Schmid, Amit Agrawal, Bodiere Akpuluma, Steven Bell, John R. Benson, Carlos Caldas, Danya Cheeseman, Igor Chernukhin, Parto Forouhi, Tulay Gulsen, Eleftheria Kleidi, Karen Pinilla, Wendi Qian, Jean E. Abraham, Jason S. Carroll, Richard D. Baird","doi":"10.1038/s43018-025-01087-x","DOIUrl":"10.1038/s43018-025-01087-x","url":null,"abstract":"The use of progestogens in breast cancer has been controversial. Recent preclinical studies have shown that ligand-bound progesterone receptor interacts directly with the estrogen receptor (ER) and reprograms ER transcriptional activity. Progestogen cotreatment enhances the antitumor activity of antiestrogen therapy in mouse xenografts. We report PIONEER, a 198-participant, three-arm, randomized phase 2b window-of-opportunity study for women with early-stage ER+ breast cancer, which evaluated letrozole with or without megestrol at 40 mg or 160 mg daily. The primary endpoint was the change in tumor proliferation measured by Ki67 immunohistochemistry. Secondary and exploratory endpoints included a comparison of low versus higher dose of megestrol, safety, tolerability and biomarker subgroup analyses. The trial met its primary endpoint, with a greater reduction in proliferation seen when megestrol was added to letrozole. This effect was accompanied by reduced ER genomic binding at canonical binding sites in paired tumor biopsies, indicating reduced ER transcriptional activity. These results support further evaluation of low-dose megestrol, which has two mechanisms for potentially improving breast cancer outcomes in combination with standard antiestrogen therapy: alleviating hot flashes and thereby helping with treatment adherence, as well as a direct antiproliferative effect ( NCT03306472 ). Baird et al. present the phase 2 PIONEER trial findings on the antitumor activity of combining aromatase inhibitor letrozole with megestrol in postmenopausal women with operable estrogen-receptor-positive human epidermal-growth-factor-receptor-2-negative breast cancer.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"7 1","pages":"194-206"},"PeriodicalIF":28.5,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s43018-025-01087-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145906212","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 : 2026-01-05DOI: 10.1038/s43018-025-01098-8
M. Angela Nieto
Angela Nieto received her PhD from Universidad Autónoma in Madrid in 1987. After short postdoctoral stays in Madrid and at the Max Planck Institute for Psychiatry in Munich, she joined the National Institute for Medical Research in London in 1989 and returned to Spain in 1993 to lead a research group at the Cajal Institute. She moved to the Neurosciences Institute in Alicante in 2004 as full professor and head of developmental neurobiology. She currently leads the cell plasticity in health and disease program and coordinates the Spanish National Research Council Cancer Hub.
{"title":"From embryos to cancer","authors":"M. Angela Nieto","doi":"10.1038/s43018-025-01098-8","DOIUrl":"10.1038/s43018-025-01098-8","url":null,"abstract":"Angela Nieto received her PhD from Universidad Autónoma in Madrid in 1987. After short postdoctoral stays in Madrid and at the Max Planck Institute for Psychiatry in Munich, she joined the National Institute for Medical Research in London in 1989 and returned to Spain in 1993 to lead a research group at the Cajal Institute. She moved to the Neurosciences Institute in Alicante in 2004 as full professor and head of developmental neurobiology. She currently leads the cell plasticity in health and disease program and coordinates the Spanish National Research Council Cancer Hub.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"7 2","pages":"249-250"},"PeriodicalIF":28.5,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145906268","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/s43018-025-01084-0
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. Bessler et al. developed a human organoid model for H3.3K27M-altered diffuse midline glioma that recapitulates key tumor features and demonstrated its utility for modeling CAR T cell and microglia functions.
{"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":"10.1038/s43018-025-01084-0","url":null,"abstract":"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. Bessler et al. developed a human organoid model for H3.3K27M-altered diffuse midline glioma that recapitulates key tumor features and demonstrated its utility for modeling CAR T cell and microglia functions.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"7 2","pages":"316-333"},"PeriodicalIF":28.5,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s43018-025-01084-0.pdf","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":"OA","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：