Pub Date : 2025-11-11DOI: 10.1016/j.immuni.2025.10.016
Vassilis Glaros, Taras Kreslavsky
Until recently, the existence of long-lived IgE-secreting plasma cells was debated. Using timestamping in mouse models of type 2 inflammation, two studies in this issue of Immunity reveal the long-term persistence of IgE-secreting plasma cells in secondary lymphoid organs rather than in the bone marrow.
{"title":"Hidden survivors: Long-lived IgE-secreting plasma cells in the spleen","authors":"Vassilis Glaros, Taras Kreslavsky","doi":"10.1016/j.immuni.2025.10.016","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.10.016","url":null,"abstract":"Until recently, the existence of long-lived IgE-secreting plasma cells was debated. Using timestamping in mouse models of type 2 inflammation, two studies in this issue of <em>Immunity</em> reveal the long-term persistence of IgE-secreting plasma cells in secondary lymphoid organs rather than in the bone marrow.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"164 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145485666","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 : 2025-11-11DOI: 10.1016/j.immuni.2025.10.015
Zheng Jin, Bo Zhu
Immunosuppressive monocyte-derived macrophages are key targets in cancer therapy; however, the mechanisms of their replenishment and functional plasticity remain elusive. In a recent issue of Nature, Hedge et al. challenge the conventional view that immunosuppressive macrophages are acquired exclusively through tumor microenvironment reprogramming; instead, their study demonstrates that the developmental fate of these macrophages is predisposed in the bone marrow.
{"title":"Tame the Hydra’s head: Targeting bone marrow maladaptive myelopoiesis to reverse macrophage-mediated immunosuppression in cancer","authors":"Zheng Jin, Bo Zhu","doi":"10.1016/j.immuni.2025.10.015","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.10.015","url":null,"abstract":"Immunosuppressive monocyte-derived macrophages are key targets in cancer therapy; however, the mechanisms of their replenishment and functional plasticity remain elusive. In a recent issue of <em>Nature</em>, Hedge et al. challenge the conventional view that immunosuppressive macrophages are acquired exclusively through tumor microenvironment reprogramming; instead, their study demonstrates that the developmental fate of these macrophages is predisposed in the bone marrow.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"14 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145485667","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 : 2025-11-11DOI: 10.1016/j.immuni.2025.10.018
Hocheol Shin, Joon Seok Park
Gut microbial metabolites modulate immune responses to tumors. In this issue of Immunity, Bachem et al.1 demonstrate that microbiota-derived butyrate cooperates with the transcription factor Foxo1 to promote CD8+ T cell stemness and enhance responsiveness to immune checkpoint inhibitors in melanoma.
{"title":"Fermenting T cell stemness for cancer immunity","authors":"Hocheol Shin, Joon Seok Park","doi":"10.1016/j.immuni.2025.10.018","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.10.018","url":null,"abstract":"Gut microbial metabolites modulate immune responses to tumors. In this issue of <em>Immunity</em>, Bachem et al.<span><span><sup>1</sup></span></span> demonstrate that microbiota-derived butyrate cooperates with the transcription factor Foxo1 to promote CD8<sup>+</sup> T cell stemness and enhance responsiveness to immune checkpoint inhibitors in melanoma.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"105 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145485665","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 : 2025-11-11Epub Date: 2025-10-21DOI: 10.1016/j.immuni.2025.09.018
Pinar Cakmak, Jennifer H Lun, Aakanksha Singh, Jadranka Macas, Jonathan Schupp, Jonas Schuck, Zeina Mahmoud, Miriam Köhler, Tatjana Starzetz, Michael C Burger, Eike Steidl, Lucie Marie Hasse, Elke Hattingen, Karl H Plate, Yvonne Reiss, Katharina Imkeller
Adult-type diffuse gliomas, the most common primary brain tumors, respond poorly to immune-based therapies and are considered immunologically "cold" tumors. Here, we examined the features and clinical relevance of glioma intratumoral tertiary lymphoid structures (TLSs) using spatial transcriptome and proteome profiling. In a cohort of 642 gliomas, TLSs were present in 15% of tumors and associated with a remodeled perivascular space and spatial redistribution of extracellular matrix components. Three distinct TLS subtypes could be defined based on differing cellular composition and immune activity. While all subtypes lacked classical germinal center architecture, certain TLSs exhibited features of dynamic immune functions, including clonal T and B cell expansion, generation of IgA⁺ and IgG⁺ plasma cells, and dendritic cell-T cell interactions. The presence of TLSs with active immune response features correlated with improved overall survival. Thus, a functional adaptive immune response is detectable in some gliomas, with implications for stratification and treatment.
{"title":"Spatial immune profiling defines a subset of human gliomas with functional tertiary lymphoid structures.","authors":"Pinar Cakmak, Jennifer H Lun, Aakanksha Singh, Jadranka Macas, Jonathan Schupp, Jonas Schuck, Zeina Mahmoud, Miriam Köhler, Tatjana Starzetz, Michael C Burger, Eike Steidl, Lucie Marie Hasse, Elke Hattingen, Karl H Plate, Yvonne Reiss, Katharina Imkeller","doi":"10.1016/j.immuni.2025.09.018","DOIUrl":"10.1016/j.immuni.2025.09.018","url":null,"abstract":"<p><p>Adult-type diffuse gliomas, the most common primary brain tumors, respond poorly to immune-based therapies and are considered immunologically \"cold\" tumors. Here, we examined the features and clinical relevance of glioma intratumoral tertiary lymphoid structures (TLSs) using spatial transcriptome and proteome profiling. In a cohort of 642 gliomas, TLSs were present in 15% of tumors and associated with a remodeled perivascular space and spatial redistribution of extracellular matrix components. Three distinct TLS subtypes could be defined based on differing cellular composition and immune activity. While all subtypes lacked classical germinal center architecture, certain TLSs exhibited features of dynamic immune functions, including clonal T and B cell expansion, generation of IgA⁺ and IgG⁺ plasma cells, and dendritic cell-T cell interactions. The presence of TLSs with active immune response features correlated with improved overall survival. Thus, a functional adaptive immune response is detectable in some gliomas, with implications for stratification and treatment.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":" ","pages":"2847-2863.e8"},"PeriodicalIF":26.3,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145345140","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 : 2025-11-11DOI: 10.1016/j.immuni.2025.10.010
Maria Backhaus, Kai Markus Schneider
Sympathetic signaling has been implicated in colitis, but the precise circuits remain unclear. In this issue of Immunity, Sharma et al. demonstrate that myeloid cell-specific loss of DNA-demethylation dampens sympathetic signaling-driven colitis exacerbation in an IL-1β-dependent manner.
{"title":"Myeloid TET2 tips the balance of neuro-epithelial crosstalk","authors":"Maria Backhaus, Kai Markus Schneider","doi":"10.1016/j.immuni.2025.10.010","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.10.010","url":null,"abstract":"Sympathetic signaling has been implicated in colitis, but the precise circuits remain unclear. In this issue of <em>Immunity</em>, Sharma et al. demonstrate that myeloid cell-specific loss of DNA-demethylation dampens sympathetic signaling-driven colitis exacerbation in an IL-1β-dependent manner.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"39 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145485672","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 : 2025-11-11DOI: 10.1016/j.immuni.2025.10.017
Justine Fiefvet, Lidia Yshii
Regulatory T cells can play conflicting roles in autoimmune inflammation. In this issue of Immunity, Benamar et al. reveal that gut-microbiota-induced Notch3+ regulatory T cells migrate to the central nervous system in multiple sclerosis and transition to inflammatory Th17-like cells.
{"title":"A Notch too far: Treg plasticity in multiple sclerosis","authors":"Justine Fiefvet, Lidia Yshii","doi":"10.1016/j.immuni.2025.10.017","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.10.017","url":null,"abstract":"Regulatory T cells can play conflicting roles in autoimmune inflammation. In this issue of <em>Immunity</em>, Benamar et al. reveal that gut-microbiota-induced Notch3<sup>+</sup> regulatory T cells migrate to the central nervous system in multiple sclerosis and transition to inflammatory Th17-like cells.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"1 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145485867","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 : 2025-11-07DOI: 10.1016/j.immuni.2025.10.008
Ester Marina-Zárate, Henry J. Sutton, Paul G. Lopez, Tasha K. Altheide, Michael Bick, Iszac Burton, Elana Ben-Akiva, Katarzyna Kaczmarek Michaels, Kesha Hyacinth, Brandon S. Healy, Deuk Lim, Lars Hangartner, Dennis R. Burton, Diane G. Carnathan, Guido Silvestri, William R. Schief, Darrell J. Irvine, Shane Crotty
Durability of T follicular helper (Tfh) cell responses is pivotal for generating high affinity antibodies. We characterized Tfh cell responses to HIV Env immunization longitudinally in non-human primates, analyzing >500,000 CD4+ T cells from 192 lymph node (LN) samples collected over 60 weeks, including >36,000 vaccine-specific Tfh cells. An escalating-dose priming regimen elicited higher and more sustained Tfh cell responses in LNs, compared with conventional bolus immunization. Multiple vaccine-specific germinal center (GC)-Tfh subpopulations, including interleukin (IL)4hi and IL21hi GC-Tfh cells, were continually present. Antigen-specific Tfh clones persisted within GCs for over 6 months, maintaining stable gene expression profiles and showing no signs of exhaustion. Vaccine-specific Tfh proliferation signatures were detectable for 27+ weeks after priming. Tfh subpopulations correlated with HIV Env-specific antibody and neutralization titers. Additionally, substantial Tfh clonal migration occurred between LNs. Thus, complex populations of GC-Tfh can enhance antibody responses and survive for 48 weeks in GC responses without new antigen delivery, with implications for immunization regimens.
{"title":"Highly functional and prolonged germinal center T follicular helper cell responses are associated with enhanced neutralizing antibody development","authors":"Ester Marina-Zárate, Henry J. Sutton, Paul G. Lopez, Tasha K. Altheide, Michael Bick, Iszac Burton, Elana Ben-Akiva, Katarzyna Kaczmarek Michaels, Kesha Hyacinth, Brandon S. Healy, Deuk Lim, Lars Hangartner, Dennis R. Burton, Diane G. Carnathan, Guido Silvestri, William R. Schief, Darrell J. Irvine, Shane Crotty","doi":"10.1016/j.immuni.2025.10.008","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.10.008","url":null,"abstract":"Durability of T follicular helper (Tfh) cell responses is pivotal for generating high affinity antibodies. We characterized Tfh cell responses to HIV Env immunization longitudinally in non-human primates, analyzing >500,000 CD4<sup>+</sup> T cells from 192 lymph node (LN) samples collected over 60 weeks, including >36,000 vaccine-specific Tfh cells. An escalating-dose priming regimen elicited higher and more sustained Tfh cell responses in LNs, compared with conventional bolus immunization. Multiple vaccine-specific germinal center (GC)-Tfh subpopulations, including interleukin (IL)4<sup>hi</sup> and IL21<sup>hi</sup> GC-Tfh cells, were continually present. Antigen-specific Tfh clones persisted within GCs for over 6 months, maintaining stable gene expression profiles and showing no signs of exhaustion. Vaccine-specific Tfh proliferation signatures were detectable for 27+ weeks after priming. Tfh subpopulations correlated with HIV Env-specific antibody and neutralization titers. Additionally, substantial Tfh clonal migration occurred between LNs. Thus, complex populations of GC-Tfh can enhance antibody responses and survive for 48 weeks in GC responses without new antigen delivery, with implications for immunization regimens.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"39 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145454664","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 : 2025-11-04DOI: 10.1016/j.immuni.2025.10.006
Zhoujie Ding, Mark R. Dowling, Adam K. Wade-Vallance, Alexandra R. Dvorscek, Catherine Pitt, Jesse Mulder, Kristy O’Donnell, Craig McKenzie, Alexandra Bosak Karaviotis, Julia Scrofani, Olaf Perdijk, Danika L. Hill, Isaak Quast, David M. Tarlinton, Christopher D.C. Allen, Marcus J. Robinson
Long-term allergies can exhibit persistent concentrations of circulating immunoglobulin E (IgE). Here, we examined the lifespan of IgE antibody-secreting cells (ASCs) to determine whether the IgE that sustains allergies receives contributions from long-lived cells or relies more heavily on constant ASC production. In mouse aeroallergy, IgE ASCs localized to the lungs, mediastinal lymph nodes, spleen, and bone marrow (BM). IgE ASC production continued for months after allergen exposure ceased. We identified long-lived IgE ASCs residing predominantly outside the BM, with a half-life exceeding 49 days; in contrast, most IgE ASCs had a 3-day half-life. Long-lived IgE ASCs matured phenotypically, became quiescent, retained their surface B cell receptors, but showed low expression of the BM homing receptor CXCR4. They were hierarchically more reliant on the navitoclax-sensitive anti-apoptotic molecules BCL2, BCLXL, and BCLW than MCL1. Thus, continual production of short-lived IgE ASCs and retention of long-lived IgE ASCs outside the BM together drive IgE persistence, perpetuating allergic disease.
{"title":"Long-lived IgE plasma cells persist in secondary lymphoid tissues using a navitoclax-sensitive survival program","authors":"Zhoujie Ding, Mark R. Dowling, Adam K. Wade-Vallance, Alexandra R. Dvorscek, Catherine Pitt, Jesse Mulder, Kristy O’Donnell, Craig McKenzie, Alexandra Bosak Karaviotis, Julia Scrofani, Olaf Perdijk, Danika L. Hill, Isaak Quast, David M. Tarlinton, Christopher D.C. Allen, Marcus J. Robinson","doi":"10.1016/j.immuni.2025.10.006","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.10.006","url":null,"abstract":"Long-term allergies can exhibit persistent concentrations of circulating immunoglobulin E (IgE). Here, we examined the lifespan of IgE antibody-secreting cells (ASCs) to determine whether the IgE that sustains allergies receives contributions from long-lived cells or relies more heavily on constant ASC production. In mouse aeroallergy, IgE ASCs localized to the lungs, mediastinal lymph nodes, spleen, and bone marrow (BM). IgE ASC production continued for months after allergen exposure ceased. We identified long-lived IgE ASCs residing predominantly outside the BM, with a half-life exceeding 49 days; in contrast, most IgE ASCs had a 3-day half-life. Long-lived IgE ASCs matured phenotypically, became quiescent, retained their surface B cell receptors, but showed low expression of the BM homing receptor CXCR4. They were hierarchically more reliant on the navitoclax-sensitive anti-apoptotic molecules BCL2, BCL<sub>XL</sub>, and BCL<sub>W</sub> than MCL1. Thus, continual production of short-lived IgE ASCs and retention of long-lived IgE ASCs outside the BM together drive IgE persistence, perpetuating allergic disease.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"88 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145434686","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 : 2025-11-03DOI: 10.1016/j.immuni.2025.10.012
Deepika Sharma, Ankit Malik, Veronica Locher, Shaina McGrath, Sarah Zabala, Hardik Grover, Cezary Ciszewski, Li Chen, Daping Yang, Isaac M. Chiu, Bana Jabri
Deciphering multicellular interactions is essential to understanding immune-mediated diseases. Myeloid cells can coordinate inflammatory responses and are central to immune crosstalk with neuronal, epithelial, and stromal cells. Here, we show that myeloid-specific loss of ten-eleven-translocation methylcytosine dioxygenase 2 (TET2) protected against colitis by limiting enterochromaffin (EC) cell differentiation and subsequent serotonin release. This protective effect was mediated by elevated interleukin (IL)-1β production by myeloid cells, which signals to tyrosine hydroxylase (TH)-positive neurons under inflammatory conditions. Neuronal IL-1R signaling dampened neuronal-epithelial interactions and consequent α₁-adrenergic signaling, thereby reducing EC differentiation. Conversely, physiological stress exacerbated colitis by enhancing catecholaminergic signals, which increased EC differentiation and serotonin production following mucosal injury. Thus, myeloid-derived IL-1β and stress exert opposing control over colitis severity through the α₁-adrenergic-EC axis, uncovering a neuro-immune-epithelial circuit that shapes intestinal inflammation.
{"title":"A myeloid Tet2-IL-1β axis modulates intestinal inflammation by restricting catecholaminergic stimulation of enterochromaffin cell differentiation","authors":"Deepika Sharma, Ankit Malik, Veronica Locher, Shaina McGrath, Sarah Zabala, Hardik Grover, Cezary Ciszewski, Li Chen, Daping Yang, Isaac M. Chiu, Bana Jabri","doi":"10.1016/j.immuni.2025.10.012","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.10.012","url":null,"abstract":"Deciphering multicellular interactions is essential to understanding immune-mediated diseases. Myeloid cells can coordinate inflammatory responses and are central to immune crosstalk with neuronal, epithelial, and stromal cells. Here, we show that myeloid-specific loss of ten-eleven-translocation methylcytosine dioxygenase 2 (TET2) protected against colitis by limiting enterochromaffin (EC) cell differentiation and subsequent serotonin release. This protective effect was mediated by elevated interleukin (IL)-1β production by myeloid cells, which signals to tyrosine hydroxylase (TH)-positive neurons under inflammatory conditions. Neuronal IL-1R signaling dampened neuronal-epithelial interactions and consequent α₁-adrenergic signaling, thereby reducing EC differentiation. Conversely, physiological stress exacerbated colitis by enhancing catecholaminergic signals, which increased EC differentiation and serotonin production following mucosal injury. Thus, myeloid-derived IL-1β and stress exert opposing control over colitis severity through the α₁-adrenergic-EC axis, uncovering a neuro-immune-epithelial circuit that shapes intestinal inflammation.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"156 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145427924","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 : 2025-11-03DOI: 10.1016/j.immuni.2025.10.004
Annabell Bachem, Michele Clarke, Geraldine Kong, Ilaryia Tarasova, Lachlan Dryburgh, Lindsay Kosack, Ariane R. Lee, Lewis D. Newland, Teagan Wagner, Emma Bawden, Kah Min Yap, Michael D. Wilson, Sven Engel, Kayla R. Wilson, Brendan E. Russ, Kshitij Tandon, Peter Kar Han Lau, Grant McArthur, Vanessa R. Marcelino, Paul A. Beavis, Sammy Bedoui
A range of microbiota species correlate with improved cancer outcomes in patients and confer protection in pre-clinical mouse models. Here, we examined how microbiota regulate CD8+ T cell immunity against melanoma. Spontaneous control of cutaneous melanoma in mice correlated with metabolic pathways required for microbial synthesis of short-chain fatty acids (SCFAs) shared between several microbiota species. Diet-induced enforcement of SCFA production by the gut microbiota reduced melanoma progression and enriched tumor-specific stem-like CD127+CD8+ T cells in the tumor-draining lymph node (tdLN). The SCFA butyrate induced a FOXO1-driven stemness program and directly promoted the differentiation of tumor-specific CD127+CD8+ T cells in the tdLN. Metabolic flux modeling predicted enhanced microbial production of butyrate in melanoma patients with complete therapeutic responses to immune checkpoint blockade (ICB), and butyrate induced transcriptional features of ICB responsiveness in CD8+ T cells. Our findings suggest a critical role for metabolite production shared across several microbiota species in the preservation of stem-like tumor-specific CD8+ T cells.
{"title":"Microbiota-derived butyrate promotes a FOXO1-induced stemness program and preserves CD8+ T cell immunity against melanoma","authors":"Annabell Bachem, Michele Clarke, Geraldine Kong, Ilaryia Tarasova, Lachlan Dryburgh, Lindsay Kosack, Ariane R. Lee, Lewis D. Newland, Teagan Wagner, Emma Bawden, Kah Min Yap, Michael D. Wilson, Sven Engel, Kayla R. Wilson, Brendan E. Russ, Kshitij Tandon, Peter Kar Han Lau, Grant McArthur, Vanessa R. Marcelino, Paul A. Beavis, Sammy Bedoui","doi":"10.1016/j.immuni.2025.10.004","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.10.004","url":null,"abstract":"A range of microbiota species correlate with improved cancer outcomes in patients and confer protection in pre-clinical mouse models. Here, we examined how microbiota regulate CD8<sup>+</sup> T cell immunity against melanoma. Spontaneous control of cutaneous melanoma in mice correlated with metabolic pathways required for microbial synthesis of short-chain fatty acids (SCFAs) shared between several microbiota species. Diet-induced enforcement of SCFA production by the gut microbiota reduced melanoma progression and enriched tumor-specific stem-like CD127<sup>+</sup>CD8<sup>+</sup> T cells in the tumor-draining lymph node (tdLN). The SCFA butyrate induced a FOXO1-driven stemness program and directly promoted the differentiation of tumor-specific CD127<sup>+</sup>CD8<sup>+</sup> T cells in the tdLN. Metabolic flux modeling predicted enhanced microbial production of butyrate in melanoma patients with complete therapeutic responses to immune checkpoint blockade (ICB), and butyrate induced transcriptional features of ICB responsiveness in CD8<sup>+</sup> T cells. Our findings suggest a critical role for metabolite production shared across several microbiota species in the preservation of stem-like tumor-specific CD8<sup>+</sup> T cells.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"80 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145427925","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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