Pub Date : 2026-01-28DOI: 10.1038/s41591-025-04183-8
Ricardo Fernandes, Behnam Jabbarizadeh, Adnan Rajeh, Megan M Y Hong, Kelly J. Baines, Scott Ernst, Eric Winquist, Anorin Shadi Ali, Susanne Penny, Rene Figueredo, Seema Nair Parvathy, John G. Lenehan, Devanand M. Pinto, Michael S. Silverman, Saman Maleki Vareki
Immune checkpoint inhibitors (ICIs) improve outcomes in metastatic renal cell carcinoma (mRCC) but are hindered by immune-related adverse events (irAEs). Modulation of the gut microbiome may enhance efficacy and mitigate toxicity, yet the safety and mechanisms of healthy donor fecal microbiota transplantation (FMT) in mRCC remain unexplored. In this phase 1 trial, 20 treatment-naive patients with mRCC received encapsulated healthy donor FMT (LND101) combined with ipilimumab/nivolumab (n = 16), pembrolizumab/axitinib (n = 3) or pembrolizumab/lenvatinib (n = 1). The primary endpoint was safety, defined by the incidence and severity of irAEs. Secondary endpoints included clinical response (Response Evaluation Criteria in Solid Tumors version 1.1), gut microbiome and immune correlates and patient-reported quality of life. The safety endpoint was met with 50% (10/20) of patients experiencing grade 3 irAEs and no serious FMT-related toxicities or grade 4 or 5 irAEs. Among evaluable patients, the objective response rate was 50% (9/18), including two complete responses (11%, 2/18). Notably, most treatment responders did not develop any grade 3 or higher irAEs. Alpha (α) diversity improvement and durable engraftment of taxa and metabolic functions associated with anti-inflammatory properties correlated with reduced toxicity and improved response. Conversely, patients experiencing grade 3 irAEs exhibited expansion of Segatella copri, particularly with ipilimumab/nivolumab, and elevated levels of donor-derived microbial enzymes previously linked to pro-inflammatory activity. Resilience to toxicity correlated with the maintenance of protective metabolites and increased levels of immune regulatory cells, whereas the presence of grade 3 irAEs and S. copri enrichment was associated with high immune dysregulation. These findings demonstrate the safety and potential for functional microbiome engraftment to optimize response and minimize toxicity in ICI-treated mRCC. ClinicalTrials.gov identifier: NCT04163289.
{"title":"Fecal microbiota transplantation plus immunotherapy in metastatic renal cell carcinoma: the phase 1 PERFORM trial","authors":"Ricardo Fernandes, Behnam Jabbarizadeh, Adnan Rajeh, Megan M Y Hong, Kelly J. Baines, Scott Ernst, Eric Winquist, Anorin Shadi Ali, Susanne Penny, Rene Figueredo, Seema Nair Parvathy, John G. Lenehan, Devanand M. Pinto, Michael S. Silverman, Saman Maleki Vareki","doi":"10.1038/s41591-025-04183-8","DOIUrl":"https://doi.org/10.1038/s41591-025-04183-8","url":null,"abstract":"Immune checkpoint inhibitors (ICIs) improve outcomes in metastatic renal cell carcinoma (mRCC) but are hindered by immune-related adverse events (irAEs). Modulation of the gut microbiome may enhance efficacy and mitigate toxicity, yet the safety and mechanisms of healthy donor fecal microbiota transplantation (FMT) in mRCC remain unexplored. In this phase 1 trial, 20 treatment-naive patients with mRCC received encapsulated healthy donor FMT (LND101) combined with ipilimumab/nivolumab (n = 16), pembrolizumab/axitinib (n = 3) or pembrolizumab/lenvatinib (n = 1). The primary endpoint was safety, defined by the incidence and severity of irAEs. Secondary endpoints included clinical response (Response Evaluation Criteria in Solid Tumors version 1.1), gut microbiome and immune correlates and patient-reported quality of life. The safety endpoint was met with 50% (10/20) of patients experiencing grade 3 irAEs and no serious FMT-related toxicities or grade 4 or 5 irAEs. Among evaluable patients, the objective response rate was 50% (9/18), including two complete responses (11%, 2/18). Notably, most treatment responders did not develop any grade 3 or higher irAEs. Alpha (α) diversity improvement and durable engraftment of taxa and metabolic functions associated with anti-inflammatory properties correlated with reduced toxicity and improved response. Conversely, patients experiencing grade 3 irAEs exhibited expansion of Segatella copri, particularly with ipilimumab/nivolumab, and elevated levels of donor-derived microbial enzymes previously linked to pro-inflammatory activity. Resilience to toxicity correlated with the maintenance of protective metabolites and increased levels of immune regulatory cells, whereas the presence of grade 3 irAEs and S. copri enrichment was associated with high immune dysregulation. These findings demonstrate the safety and potential for functional microbiome engraftment to optimize response and minimize toxicity in ICI-treated mRCC. ClinicalTrials.gov identifier: NCT04163289.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"86 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146057195","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 : 2026-01-28DOI: 10.1038/s41591-026-04233-9
Jennifer M Kwon, Francina Munell, Laure Le Goff, Kotaro Yuge, Tamaki Kato, Claude Cances, Liesbeth De Waele, Ian R Woodcock, Eugenio M Mercuri, Crystal M Proud, Basil T Darras, Leslie H Hayes, Maryam Oskoui, Jeannie Visootsak, Gemma Williams, Andreja Ilić, Lina Yang, W Ludo van der Pol
{"title":"Author Correction: Intrathecal onasemnogene abeparvovec for treatment-experienced patients with spinal muscular atrophy: a phase 3b, open-label trial.","authors":"Jennifer M Kwon, Francina Munell, Laure Le Goff, Kotaro Yuge, Tamaki Kato, Claude Cances, Liesbeth De Waele, Ian R Woodcock, Eugenio M Mercuri, Crystal M Proud, Basil T Darras, Leslie H Hayes, Maryam Oskoui, Jeannie Visootsak, Gemma Williams, Andreja Ilić, Lina Yang, W Ludo van der Pol","doi":"10.1038/s41591-026-04233-9","DOIUrl":"https://doi.org/10.1038/s41591-026-04233-9","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":50.0,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146086470","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 : 2026-01-28DOI: 10.1038/s41591-026-04236-6
Muhannad Abu-Remaileh,Laura A Stransky,Nikita Bhalerao,Nitin H Shirole,Qinqin Jiang,Eddy Saad,Marc Machaalani,Sean M Vigeant,Hilina Woldemichael,Charles Xu,Jing Lu,Hairong Wei,Zhihong Liu,William Sun,Kei Enomoto,Toni K Choueiri,Jason R Pitarresi,Steven A Carr,Namrata D Udeshi,William G Kaelin
{"title":"Publisher Correction: argeting of HIF2-driven cachexia in kidney cancer.","authors":"Muhannad Abu-Remaileh,Laura A Stransky,Nikita Bhalerao,Nitin H Shirole,Qinqin Jiang,Eddy Saad,Marc Machaalani,Sean M Vigeant,Hilina Woldemichael,Charles Xu,Jing Lu,Hairong Wei,Zhihong Liu,William Sun,Kei Enomoto,Toni K Choueiri,Jason R Pitarresi,Steven A Carr,Namrata D Udeshi,William G Kaelin","doi":"10.1038/s41591-026-04236-6","DOIUrl":"https://doi.org/10.1038/s41591-026-04236-6","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"1 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146070055","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 : 2026-01-27DOI: 10.1038/s41591-025-04177-6
Edgar Gonzalez-Kozlova,Robert Sweeney,Igor Figueiredo,Kevin Tuballes,Sinem Ozbey,Pauline Hamon,Matthew D Park,Giorgio Ioannou,Yohei Nose,Ruiwei Guo,Paula Restrepo,Mark Buckup,Vladimir Roudko,Clotilde Hennequin,Jessica Le Berichel,Nicholas Venturini,Laszlo Halasz,Leanna Troncoso,Alexandra Tabachnikova,Christie Chang,Amanda Reid,Haley Brown,Theodore Chin,Rafael Cabal,Raphaël Mattiuz,Shingo Eikawa,Diane Marie Del Valle,Tina Ruth Gonsalves,Nelson M LaMarche,Hajra Jamal,Alona Lansky,Nancy Yi,Daniella Nelson,Jarod Morgenroth-Rebin,Raphael Merand,Bryan Villagomez,Darwin D'Souza,Emir Radkevich,Kai Nie,Zhihong Chen,Yasuko Tada,Hiroyoshi Nishikawa,Stephen C Ward,Maria Isabel Fiel,Rachel Brody,Parissa Tabrizian,Ganesh Gunasekaran,Alice O Kamphorst,Noah Cohen,Maria Curotto de Lafaille,Olivia Hapanowicz,Natalie Lucas,Kathy Wu,Nicola James,John C Lin,Gavin Thurston,Myron Schwartz,Nathalie Fiaschi,Seunghee Kim-Schulze,Miriam Merad,Thomas U Marron,Sacha Gnjatic
Tumor-infiltrating T cells have been the primary focus of cancer immunotherapy; however, accumulating evidence points to a critical role for B cells and plasma cells in shaping responses to immune checkpoint blockade. In this study, we investigated the humoral immune response in 38 patients with hepatocellular carcinoma treated with neoadjuvant anti-programmed cell death protein 1 (PD-1) therapy. In responders, defined by more than 50% tumor necrosis, we observed on-treatment enrichment of clonally expanded IgG1+ plasma cells within the tumor. Clonal tracking revealed that anti-PD-1 treatment expanded preexisting B cell clones associated with favorable clinical outcomes. Moreover, serum from responders contained IgG1 antibodies specific to cancer/testis antigens, including NY-ESO-1, and these humoral responses were linked to tumor-reactive T cell activity. We independently validated these findings across seven additional cohorts, encompassing single-cell and bulk sequencing data from 500 patients, spatial transcriptomics from seven patients and survival analyses from 1,582 patients. Our findings apply to recently approved treatments, such as PD-1 and vascular endothelial growth factor A (VEGF-A) blockade, but not to chemotherapy alone, suggesting broad relevance to individuals treated with immunotherapy. Collectively, our results demonstrate that PD-1 blockade induces tumor-specific IgG1+ plasma cell responses that complement cellular immunity and contribute to clinical benefit, underscoring a coordinated humoral-cellular axis in effective antitumor immunity.
{"title":"Humoral IgG1 responses to tumor antigens underpin clinical outcomes in immune checkpoint blockade.","authors":"Edgar Gonzalez-Kozlova,Robert Sweeney,Igor Figueiredo,Kevin Tuballes,Sinem Ozbey,Pauline Hamon,Matthew D Park,Giorgio Ioannou,Yohei Nose,Ruiwei Guo,Paula Restrepo,Mark Buckup,Vladimir Roudko,Clotilde Hennequin,Jessica Le Berichel,Nicholas Venturini,Laszlo Halasz,Leanna Troncoso,Alexandra Tabachnikova,Christie Chang,Amanda Reid,Haley Brown,Theodore Chin,Rafael Cabal,Raphaël Mattiuz,Shingo Eikawa,Diane Marie Del Valle,Tina Ruth Gonsalves,Nelson M LaMarche,Hajra Jamal,Alona Lansky,Nancy Yi,Daniella Nelson,Jarod Morgenroth-Rebin,Raphael Merand,Bryan Villagomez,Darwin D'Souza,Emir Radkevich,Kai Nie,Zhihong Chen,Yasuko Tada,Hiroyoshi Nishikawa,Stephen C Ward,Maria Isabel Fiel,Rachel Brody,Parissa Tabrizian,Ganesh Gunasekaran,Alice O Kamphorst,Noah Cohen,Maria Curotto de Lafaille,Olivia Hapanowicz,Natalie Lucas,Kathy Wu,Nicola James,John C Lin,Gavin Thurston,Myron Schwartz,Nathalie Fiaschi,Seunghee Kim-Schulze,Miriam Merad,Thomas U Marron,Sacha Gnjatic","doi":"10.1038/s41591-025-04177-6","DOIUrl":"https://doi.org/10.1038/s41591-025-04177-6","url":null,"abstract":"Tumor-infiltrating T cells have been the primary focus of cancer immunotherapy; however, accumulating evidence points to a critical role for B cells and plasma cells in shaping responses to immune checkpoint blockade. In this study, we investigated the humoral immune response in 38 patients with hepatocellular carcinoma treated with neoadjuvant anti-programmed cell death protein 1 (PD-1) therapy. In responders, defined by more than 50% tumor necrosis, we observed on-treatment enrichment of clonally expanded IgG1+ plasma cells within the tumor. Clonal tracking revealed that anti-PD-1 treatment expanded preexisting B cell clones associated with favorable clinical outcomes. Moreover, serum from responders contained IgG1 antibodies specific to cancer/testis antigens, including NY-ESO-1, and these humoral responses were linked to tumor-reactive T cell activity. We independently validated these findings across seven additional cohorts, encompassing single-cell and bulk sequencing data from 500 patients, spatial transcriptomics from seven patients and survival analyses from 1,582 patients. Our findings apply to recently approved treatments, such as PD-1 and vascular endothelial growth factor A (VEGF-A) blockade, but not to chemotherapy alone, suggesting broad relevance to individuals treated with immunotherapy. Collectively, our results demonstrate that PD-1 blockade induces tumor-specific IgG1+ plasma cell responses that complement cellular immunity and contribute to clinical benefit, underscoring a coordinated humoral-cellular axis in effective antitumor immunity.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"8 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146056398","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 : 2026-01-27DOI: 10.1038/s41591-026-04202-2
Fawad A Khan,Margaret T Gopaul,Elizabeth J Howard,Jennifer Robblee,Ann H Tilton,Margot Savoy
{"title":"Professional medical associations as catalytic pathways for advancing women in academic medicine and promoting leadership.","authors":"Fawad A Khan,Margaret T Gopaul,Elizabeth J Howard,Jennifer Robblee,Ann H Tilton,Margot Savoy","doi":"10.1038/s41591-026-04202-2","DOIUrl":"https://doi.org/10.1038/s41591-026-04202-2","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"38 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146056399","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}
{"title":"Student-led efforts promoting inclusivity and belonging in US medical schools.","authors":"Briana Macedo,Felipe Rosero Castro,Danielle Feffer,Andrew Siaw-Asamoah,Karen Campbell,Roy Hamilton,Horace DeLisser,César A Briceño","doi":"10.1038/s41591-025-04195-4","DOIUrl":"https://doi.org/10.1038/s41591-025-04195-4","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"41 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146056400","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 : 2026-01-26DOI: 10.1038/s41591-026-04223-x
Laura Jiménez-Gracia, Davide Maspero, Sergio Aguilar-Fernández, Francesco Craighero, Maria Boulougouri, Max Ruiz, Domenica Marchese, Ginevra Caratù, Jose Liñares-Blanco, Miren Berasategi, Ricardo O. Ramirez Flores, Angela Sanzo-Machuca, Ana M. Corraliza, Hoang A. Tran, Rachelly Normand, Jacquelyn Nestor, Yourae Hong, Tessa Kole, Petra van der Velde, Frederique Alleblas, Flaminia Pedretti, Adrià Aterido, Martin Banchero, German Soriano, Eva Román, Maarten van den Berge, Azucena Salas, Jose Manuel Carrascosa, Antonio Fernández Nebro, Eugeni Domènech, Juan D. Cañete, Jesús Tornero, Javier P. Gisbert, Ernest Choy, Giampiero Girolomoni, Britta Siegmund, Antonio Julià, Violeta Serra, Roberto Elosua, Sabine Tejpar, Silvia Vidal, Martijn C. Nawijn, Ivo Gut, Julio Saez-Rodriguez, Sara Marsal, Alexandra-Chloé Villani, Juan C. Nieto, Holger Heyn
{"title":"Publisher Correction: Interpretable inflammation landscape of circulating immune cells","authors":"Laura Jiménez-Gracia, Davide Maspero, Sergio Aguilar-Fernández, Francesco Craighero, Maria Boulougouri, Max Ruiz, Domenica Marchese, Ginevra Caratù, Jose Liñares-Blanco, Miren Berasategi, Ricardo O. Ramirez Flores, Angela Sanzo-Machuca, Ana M. Corraliza, Hoang A. Tran, Rachelly Normand, Jacquelyn Nestor, Yourae Hong, Tessa Kole, Petra van der Velde, Frederique Alleblas, Flaminia Pedretti, Adrià Aterido, Martin Banchero, German Soriano, Eva Román, Maarten van den Berge, Azucena Salas, Jose Manuel Carrascosa, Antonio Fernández Nebro, Eugeni Domènech, Juan D. Cañete, Jesús Tornero, Javier P. Gisbert, Ernest Choy, Giampiero Girolomoni, Britta Siegmund, Antonio Julià, Violeta Serra, Roberto Elosua, Sabine Tejpar, Silvia Vidal, Martijn C. Nawijn, Ivo Gut, Julio Saez-Rodriguez, Sara Marsal, Alexandra-Chloé Villani, Juan C. Nieto, Holger Heyn","doi":"10.1038/s41591-026-04223-x","DOIUrl":"https://doi.org/10.1038/s41591-026-04223-x","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"3 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146048349","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 : 2026-01-23DOI: 10.1038/s41591-025-04198-1
Tej D Azad,Harlan M Krumholz,Suchi Saria
{"title":"Principles to guide clinical AI readiness and move from benchmarks to real-world evaluation.","authors":"Tej D Azad,Harlan M Krumholz,Suchi Saria","doi":"10.1038/s41591-025-04198-1","DOIUrl":"https://doi.org/10.1038/s41591-025-04198-1","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"75 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146034026","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/s41591-025-04136-1
{"title":"Immune cells in circulation serve as living biomarkers for inflammatory diseases.","authors":"","doi":"10.1038/s41591-025-04136-1","DOIUrl":"https://doi.org/10.1038/s41591-025-04136-1","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"142 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146021603","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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