Pub Date : 2026-01-30DOI: 10.1016/j.immuni.2026.01.013
Dianyu Chen, Heping Xu
The meninges, long viewed as passive protective membranes, are now recognized as active immunological interfaces harboring diverse immune populations. Among them, B cells have emerged as dynamic participants in central nervous system (CNS) homeostasis and disorders. Recent studies have identified distinct B cell subsets in the meninges at different developmental and activation stages, including precursors supported by skull marrow-derived progenitors and immunoglobulin A (IgA)⁺ plasma cells influenced by gut microbiota. These meningeal B cells contribute to immune tolerance, barrier protection, and potentially neural development and repair, while also exhibiting context-dependent pathogenic roles in CNS autoimmunity, aging, and neurodegeneration. In this review, we discuss the current knowledge of meningeal B cells and highlight key future research directions aimed at understanding their cellular dynamics, activation and differentiation processes, and the balance between protective and deleterious functions.
{"title":"Meningeal B cells: Emerging players at the brain border","authors":"Dianyu Chen, Heping Xu","doi":"10.1016/j.immuni.2026.01.013","DOIUrl":"https://doi.org/10.1016/j.immuni.2026.01.013","url":null,"abstract":"The meninges, long viewed as passive protective membranes, are now recognized as active immunological interfaces harboring diverse immune populations. Among them, B cells have emerged as dynamic participants in central nervous system (CNS) homeostasis and disorders. Recent studies have identified distinct B cell subsets in the meninges at different developmental and activation stages, including precursors supported by skull marrow-derived progenitors and immunoglobulin A (IgA)⁺ plasma cells influenced by gut microbiota. These meningeal B cells contribute to immune tolerance, barrier protection, and potentially neural development and repair, while also exhibiting context-dependent pathogenic roles in CNS autoimmunity, aging, and neurodegeneration. In this review, we discuss the current knowledge of meningeal B cells and highlight key future research directions aimed at understanding their cellular dynamics, activation and differentiation processes, and the balance between protective and deleterious functions.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"14 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146089433","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 : 2026-01-30DOI: 10.1016/j.immuni.2025.12.013
Katharina Daniel, Leon Ullrich, Denis Ruchnewitz, Matthijs Meijers, Nico Joel Halwe, Ursula Wild, Jan Eberhardt, Jacob Schön, Ricarda Stumpf, Maike Schlotz, Marie Wunsch, Luana Girao Lessa, Elsayed Mohammed Abdelwhab, Maryna Kuryshko, Christopher Dietrich, Andreas Pinger, Anna-Lena Schumacher, Maximilian Germer, Malena Rohde, Christian Kukat, Lutz Gieselmann, Henning Gruell, Donata Hoffmann, Martin Beer, Thomas Erren, Michael Lässig, Christoph Kreer, Florian Klein
{"title":"Pre-existing neutralizing antibodies against cattle-transmitted influenza A virus H5N1 are detectable in unexposed individuals","authors":"Katharina Daniel, Leon Ullrich, Denis Ruchnewitz, Matthijs Meijers, Nico Joel Halwe, Ursula Wild, Jan Eberhardt, Jacob Schön, Ricarda Stumpf, Maike Schlotz, Marie Wunsch, Luana Girao Lessa, Elsayed Mohammed Abdelwhab, Maryna Kuryshko, Christopher Dietrich, Andreas Pinger, Anna-Lena Schumacher, Maximilian Germer, Malena Rohde, Christian Kukat, Lutz Gieselmann, Henning Gruell, Donata Hoffmann, Martin Beer, Thomas Erren, Michael Lässig, Christoph Kreer, Florian Klein","doi":"10.1016/j.immuni.2025.12.013","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.12.013","url":null,"abstract":"","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"29 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146089431","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 : 2026-01-30DOI: 10.1016/j.immuni.2026.01.004
Simon Grassmann, Endi K. Santosa, Hyunu Kim, Isabelle B. Johnson, Adriana M. Mujal, Jean-Benoit LeLuduec, Sherry X. Fan, Mark Owyong, Adrian Straub, Liang Deng, Katharine C. Hsu, Dirk H. Busch, Colleen M. Lau, Joseph C. Sun
{"title":"Stepwise epigenetic signal integration drives adaptive programming of cytotoxic lymphocytes","authors":"Simon Grassmann, Endi K. Santosa, Hyunu Kim, Isabelle B. Johnson, Adriana M. Mujal, Jean-Benoit LeLuduec, Sherry X. Fan, Mark Owyong, Adrian Straub, Liang Deng, Katharine C. Hsu, Dirk H. Busch, Colleen M. Lau, Joseph C. Sun","doi":"10.1016/j.immuni.2026.01.004","DOIUrl":"https://doi.org/10.1016/j.immuni.2026.01.004","url":null,"abstract":"","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"30 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146089432","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 : 2026-01-30DOI: 10.1016/j.immuni.2026.01.016
Paloma Navarro Negredo, Justin You, Max Hauptschein, Adam B. Schroer, Daniel J. Richard, Gita C. Abhiraman, Andy P. Tsai, Eric D. Sun, Giulia Notarangelo, Julliana Ramirez-Matias, Olivia Y. Zhou, Matthew T. Buckley, Karen E. Malacon, Lucy Xu, Juliana Sucharov, Eduardo Ramirez Lopez, Lora Picton, Tony Wyss-Coray, Robert A. Saxton, Ricardo A. Fernandes, Saul A. Villeda, K. Christopher Garcia, Anne Brunet
The immune system could play an important role in the age-related decline in brain function, yet specific immune-based strategies to enhance brain resilience in older individuals are lacking. Here, we combined engineered proteins and direct brain delivery to target immune cell populations within the old brain. We detected T cells with an exhaustion signature in the old brain and targeted them with a potent engineered checkpoint inhibitor (RIPR-PD1). This led to T cell expansion and strong pro-inflammatory responses in many brain cell types, notably microglia. To rescue age-related inflammatory imbalances in microglia, we used the anti-inflammatory cytokine interleukin (IL)-10. IL-10 boosted anti-inflammatory responses in old microglia, but it also triggered pro-inflammatory signaling. An engineered IL-10 variant that uncouples pro- and anti-inflammatory responses positively impacted the transcriptome of multiple cell types, enhanced neurogenesis, and improved cognition in aged mice. Our findings pave the way for immunotherapies for the aged brain.
{"title":"Targeting immune cells in the aged brain reveals that engineered cytokine IL-10 enhances neurogenesis and improves cognition","authors":"Paloma Navarro Negredo, Justin You, Max Hauptschein, Adam B. Schroer, Daniel J. Richard, Gita C. Abhiraman, Andy P. Tsai, Eric D. Sun, Giulia Notarangelo, Julliana Ramirez-Matias, Olivia Y. Zhou, Matthew T. Buckley, Karen E. Malacon, Lucy Xu, Juliana Sucharov, Eduardo Ramirez Lopez, Lora Picton, Tony Wyss-Coray, Robert A. Saxton, Ricardo A. Fernandes, Saul A. Villeda, K. Christopher Garcia, Anne Brunet","doi":"10.1016/j.immuni.2026.01.016","DOIUrl":"https://doi.org/10.1016/j.immuni.2026.01.016","url":null,"abstract":"The immune system could play an important role in the age-related decline in brain function, yet specific immune-based strategies to enhance brain resilience in older individuals are lacking. Here, we combined engineered proteins and direct brain delivery to target immune cell populations within the old brain. We detected T cells with an exhaustion signature in the old brain and targeted them with a potent engineered checkpoint inhibitor (RIPR-PD1). This led to T cell expansion and strong pro-inflammatory responses in many brain cell types, notably microglia. To rescue age-related inflammatory imbalances in microglia, we used the anti-inflammatory cytokine interleukin (IL)-10. IL-10 boosted anti-inflammatory responses in old microglia, but it also triggered pro-inflammatory signaling. An engineered IL-10 variant that uncouples pro- and anti-inflammatory responses positively impacted the transcriptome of multiple cell types, enhanced neurogenesis, and improved cognition in aged mice. Our findings pave the way for immunotherapies for the aged brain.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"180 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146089434","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 : 2026-01-30DOI: 10.1016/j.immuni.2026.01.015
Juliette Gauthier, Maxime Maugendre, Simon Léonard, Yoni Desvois, Maïwenn Pineau, Romain Pinon, Nicolas Hipp, Karin Tarte, Patricia Amé, Sophie Hillion, Laure Michel, Céline Delaloy
{"title":"B cell-intrinsic IL-2 signaling regulates inflammation by promoting IL-10 expression in CD25+ age-associated B cells","authors":"Juliette Gauthier, Maxime Maugendre, Simon Léonard, Yoni Desvois, Maïwenn Pineau, Romain Pinon, Nicolas Hipp, Karin Tarte, Patricia Amé, Sophie Hillion, Laure Michel, Céline Delaloy","doi":"10.1016/j.immuni.2026.01.015","DOIUrl":"https://doi.org/10.1016/j.immuni.2026.01.015","url":null,"abstract":"","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"56 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146089435","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 : 2026-01-29DOI: 10.1016/j.immuni.2026.01.005
Miqdad O. Dhariwala, Ricardo O. Carale, Andrea M. DeRogatis, Henry Rodriguez-Valbuena, Joy N. Okoro, Christina A. Ekstrand, Antonin Weckel, Victoria M. Tran, Irek Habrylo, Rio Barrere-Cain, Oluwasunmisola T. Ojewumi, Allison E. Tammen, Jessica Tsui, Saba Shaikh, Shivaram Yellamilli, Ahmed K. Aladhami, Robin Schwartz, John M. Leech, Geil R. Merana, Kamir J. Hiam-Galvez, Matthias Mack, Joanna Halkias, James M. Gardner, Rachel L. Rutishauser, Gabriela K. Fragiadakis, Matthew H. Spitzer, Alexis J. Combes, Tiffany C. Scharschmidt
{"title":"Commensal-myeloid crosstalk in neonatal skin regulates interleukin-1 signaling and cutaneous type 17 inflammation","authors":"Miqdad O. Dhariwala, Ricardo O. Carale, Andrea M. DeRogatis, Henry Rodriguez-Valbuena, Joy N. Okoro, Christina A. Ekstrand, Antonin Weckel, Victoria M. Tran, Irek Habrylo, Rio Barrere-Cain, Oluwasunmisola T. Ojewumi, Allison E. Tammen, Jessica Tsui, Saba Shaikh, Shivaram Yellamilli, Ahmed K. Aladhami, Robin Schwartz, John M. Leech, Geil R. Merana, Kamir J. Hiam-Galvez, Matthias Mack, Joanna Halkias, James M. Gardner, Rachel L. Rutishauser, Gabriela K. Fragiadakis, Matthew H. Spitzer, Alexis J. Combes, Tiffany C. Scharschmidt","doi":"10.1016/j.immuni.2026.01.005","DOIUrl":"https://doi.org/10.1016/j.immuni.2026.01.005","url":null,"abstract":"","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"44 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146072083","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: 10.1016/j.immuni.2025.12.010
Gillian Dunphy, Irene Adán-Barrientos, Irene Fernández-Delgado, Carolina Villarroya-Beltri, Ignacio Heras-Murillo, Elena Moya-Ruiz, Miguel Sánchez-Álvarez, Aitor Jarit-Cabanillas, Miguel A. del Pozo, Susana Guerra, Francisco Sánchez-Madrid, David Sancho
{"title":"A type I interferon-mitochondrial axis regulates efferocytosis and interferon-stimulated gene induction in macrophages","authors":"Gillian Dunphy, Irene Adán-Barrientos, Irene Fernández-Delgado, Carolina Villarroya-Beltri, Ignacio Heras-Murillo, Elena Moya-Ruiz, Miguel Sánchez-Álvarez, Aitor Jarit-Cabanillas, Miguel A. del Pozo, Susana Guerra, Francisco Sánchez-Madrid, David Sancho","doi":"10.1016/j.immuni.2025.12.010","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.12.010","url":null,"abstract":"","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"279 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146071529","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: 10.1016/j.immuni.2026.01.001
Stephanie A. Gaglione, Rachit S. Mukkamala, Chirag Krishna, Blake E. Smith, Marc H. Wadsworth, Scott A. Jelinsky, Caleb R. Perez, Laura Schmidt-Hong, Erica L. Katz, Kyle J. Gellatly, Lestat R. Ali, Jiao Shen, Patrick V. Holec, Qingyang Henry Zhao, Amanda O. Chan, Ellen J.K. Xu, Kellie M. Kravarik, Julia A. Guzova, Connor S. Dobson, Harshabad Singh, Michael E. Birnbaum
T cells initiate targeted immune responses using T cell receptors (TCRs) to recognize specific antigens. Mapping TCRs to antigens at scale remains a major challenge. Here, we developed an approach to synthesize and functionally screen tens of thousands of TCRs simultaneously. TCR rapid assembly for functional testing (TCRAFT) uses a modular strategy to rapidly and inexpensively construct large pools of TCRs from sequences while maintaining TCRα/β pairing. We applied TCRAFT to reconstruct over 3,800 TCRs from vitiligo blister fluid and mapped these TCRs to specific peptide-major histocompatibility complexes using RAPTR, an activation-based library-on-library screening approach. Vitiligo antigen-specific T cells displayed pronounced clonal expansion and transcriptomic signatures similar to antigen-specific T cells in melanoma, pointing to shared features of disease-relevant T cells in autoimmunity and cancer. Demonstrating scalability, we synthesized and screened over 30,800 TCRs from donors with pancreatic ductal adenocarcinoma to capture antigen-reactive TCRs. Our approach expands the scale and accessibility of TCR-antigen screening, which is critical to understanding immunity and developing new immunotherapies.
{"title":"Scalable TCR synthesis and screening enable antigen reactivity mapping in vitiligo","authors":"Stephanie A. Gaglione, Rachit S. Mukkamala, Chirag Krishna, Blake E. Smith, Marc H. Wadsworth, Scott A. Jelinsky, Caleb R. Perez, Laura Schmidt-Hong, Erica L. Katz, Kyle J. Gellatly, Lestat R. Ali, Jiao Shen, Patrick V. Holec, Qingyang Henry Zhao, Amanda O. Chan, Ellen J.K. Xu, Kellie M. Kravarik, Julia A. Guzova, Connor S. Dobson, Harshabad Singh, Michael E. Birnbaum","doi":"10.1016/j.immuni.2026.01.001","DOIUrl":"https://doi.org/10.1016/j.immuni.2026.01.001","url":null,"abstract":"T cells initiate targeted immune responses using T cell receptors (TCRs) to recognize specific antigens. Mapping TCRs to antigens at scale remains a major challenge. Here, we developed an approach to synthesize and functionally screen tens of thousands of TCRs simultaneously. TCR rapid assembly for functional testing (TCRAFT) uses a modular strategy to rapidly and inexpensively construct large pools of TCRs from sequences while maintaining TCRα/β pairing. We applied TCRAFT to reconstruct over 3,800 TCRs from vitiligo blister fluid and mapped these TCRs to specific peptide-major histocompatibility complexes using RAPTR, an activation-based library-on-library screening approach. Vitiligo antigen-specific T cells displayed pronounced clonal expansion and transcriptomic signatures similar to antigen-specific T cells in melanoma, pointing to shared features of disease-relevant T cells in autoimmunity and cancer. Demonstrating scalability, we synthesized and screened over 30,800 TCRs from donors with pancreatic ductal adenocarcinoma to capture antigen-reactive TCRs. Our approach expands the scale and accessibility of TCR-antigen screening, which is critical to understanding immunity and developing new immunotherapies.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"30 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146057099","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: 10.1016/j.immuni.2025.12.009
Xiu Zhong, Ya Su, Zhiwei Zhou, Yuqiu Sun, Yanjie Hou, Feng Shao, Jingjin Ding
{"title":"Exosite-mediated targeting of GSDMB by dimeric granzyme A in lymphocyte pyroptotic killing","authors":"Xiu Zhong, Ya Su, Zhiwei Zhou, Yuqiu Sun, Yanjie Hou, Feng Shao, Jingjin Ding","doi":"10.1016/j.immuni.2025.12.009","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.12.009","url":null,"abstract":"","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"72 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146048541","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: 10.1016/j.immuni.2025.12.016
Sissi Dolci, Loris Mannino, Eros Rossi, Emanuela Bottani, Francesca Ciarpella, Nicola Piazza, Isabel Karkossa, Marzia Di Chio, Benedetta Savino, Benedetta Lucidi, Giulia Pruonto, Ilaria Barone, Alessandra Campanelli, Francesca Cersosimo, Elisa Setten, Stefano Gianoli, Zulkifal Malik, Giuseppe Busetto, Alex Pezzotta, Alessandra Castagna, Nicolò Martinelli, Silvia Ferretti, Federico Boschi, Adam Doherty, Maria Teresa Scupoli, Chiara Cavallini, Giorgio Malpeli, Alessia Amenta, Ludovica Sagripanti, Vincenzo Silani, Patrizia Cristofori, Eugenio Scanziani, Marco Sandri, Anna Pistocchi, Patrizia Bossolasco, Marco Endrizzi, Kristin Schubert, Guido Francesco Fumagalli, Massimo Locati, Francesco Bifari, Ilaria Decimo
Tumor-associated macrophages (TAMs) enhance cancer progression by promoting angiogenesis, extracellular matrix remodeling, and immune suppression. Nerve infiltration also contributes to tumor growth. However, the role of TAMs in promoting intratumoral nerve growth remains unclear. In this study, we have shown that TAMs express a distinct neural growth gene signature. TAMs actively enhanced neural growth within tumors and directly promoted in vitro neurite outgrowth. We identified secreted phosphoprotein 1 (SPP1) as a required mediator of TAM-driven neural growth and mTORC2 activation. Leveraging this TAM-neural growth function, we explored TAM neuroregenerative potential. Adoptive transfer of TAMs in severe complete-compressive-contusive spinal cord injury (scSCI) increased neuronal survival, axonal regrowth, and motor function recovery. Moreover, TAMs healed scSCI microenvironment and remodeled the cyst. Functional and proteomic analyses confirmed SPP1 and neural Rictor as necessary molecular mediators for TAM-induced regeneration. Our data unveil a role for TAMs in tumor innervation and neural tissue repair.
{"title":"Tumor-associated macrophages enhance peripheral nerve tumor infiltration and spinal cord repair","authors":"Sissi Dolci, Loris Mannino, Eros Rossi, Emanuela Bottani, Francesca Ciarpella, Nicola Piazza, Isabel Karkossa, Marzia Di Chio, Benedetta Savino, Benedetta Lucidi, Giulia Pruonto, Ilaria Barone, Alessandra Campanelli, Francesca Cersosimo, Elisa Setten, Stefano Gianoli, Zulkifal Malik, Giuseppe Busetto, Alex Pezzotta, Alessandra Castagna, Nicolò Martinelli, Silvia Ferretti, Federico Boschi, Adam Doherty, Maria Teresa Scupoli, Chiara Cavallini, Giorgio Malpeli, Alessia Amenta, Ludovica Sagripanti, Vincenzo Silani, Patrizia Cristofori, Eugenio Scanziani, Marco Sandri, Anna Pistocchi, Patrizia Bossolasco, Marco Endrizzi, Kristin Schubert, Guido Francesco Fumagalli, Massimo Locati, Francesco Bifari, Ilaria Decimo","doi":"10.1016/j.immuni.2025.12.016","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.12.016","url":null,"abstract":"Tumor-associated macrophages (TAMs) enhance cancer progression by promoting angiogenesis, extracellular matrix remodeling, and immune suppression. Nerve infiltration also contributes to tumor growth. However, the role of TAMs in promoting intratumoral nerve growth remains unclear. In this study, we have shown that TAMs express a distinct neural growth gene signature. TAMs actively enhanced neural growth within tumors and directly promoted <ce:italic>in vitro</ce:italic> neurite outgrowth. We identified secreted phosphoprotein 1 (SPP1) as a required mediator of TAM-driven neural growth and mTORC2 activation. Leveraging this TAM-neural growth function, we explored TAM neuroregenerative potential. Adoptive transfer of TAMs in severe complete-compressive-contusive spinal cord injury (scSCI) increased neuronal survival, axonal regrowth, and motor function recovery. Moreover, TAMs healed scSCI microenvironment and remodeled the cyst. Functional and proteomic analyses confirmed SPP1 and neural Rictor as necessary molecular mediators for TAM-induced regeneration. Our data unveil a role for TAMs in tumor innervation and neural tissue repair.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"102 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146048412","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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