Pub Date : 2026-01-13Epub Date: 2025-12-15DOI: 10.1016/j.immuni.2025.11.014
Xiao Huang, Dan Feng, Sneha Mitra, Emma S Andretta, Nima B Hooshdaran, Aazam P Ghelani, Eric Y Wang, Joe N Frost, Victoria R Lawless, Aparna Vancheswaran, Qingwen Jiang, Cheryl Mai, Karuna Ganesh, Christina S Leslie, Alexander Y Rudensky
Enrichment of regulatory T (Treg) cells in solid organ cancers is generally associated with poor prognosis; however, colorectal cancer (CRC) stands out as a notable exception. Here, we examined the heterogeneity of tumoral Treg cells in CRC and identified two distinct tumoral Treg subsets with differential Il10 expression. Selective depletion of interleukin-10-expressing (IL-10⁺) Treg cells promoted tumor growth by lifting the restraint on IL-17 production from effector CD4+ T cells, thereby directly stimulating tumor cell proliferation; depletion of IL-10- Treg cells led to pronounced tumor regression. In human CRC, IL-10⁺ and IL-10- Treg abundance correlated with favorable and unfavorable prognosis, respectively. Accordingly, IL-10⁺ and IL-10- Treg cells exhibited opposite enrichment patterns in adjacent normal colon tissues and tumors. Transcriptionally similar Treg subsets were observed across different human barrier tissue tumors. This functional dichotomy between Treg subsets may enable selective targeting of the pro-tumoral subset while preserving its anti-tumoral counterpart in CRC and other barrier tissue cancers.
{"title":"Opposing functions of distinct regulatory T cell subsets in colorectal cancer.","authors":"Xiao Huang, Dan Feng, Sneha Mitra, Emma S Andretta, Nima B Hooshdaran, Aazam P Ghelani, Eric Y Wang, Joe N Frost, Victoria R Lawless, Aparna Vancheswaran, Qingwen Jiang, Cheryl Mai, Karuna Ganesh, Christina S Leslie, Alexander Y Rudensky","doi":"10.1016/j.immuni.2025.11.014","DOIUrl":"10.1016/j.immuni.2025.11.014","url":null,"abstract":"<p><p>Enrichment of regulatory T (Treg) cells in solid organ cancers is generally associated with poor prognosis; however, colorectal cancer (CRC) stands out as a notable exception. Here, we examined the heterogeneity of tumoral Treg cells in CRC and identified two distinct tumoral Treg subsets with differential Il10 expression. Selective depletion of interleukin-10-expressing (IL-10⁺) Treg cells promoted tumor growth by lifting the restraint on IL-17 production from effector CD4<sup>+</sup> T cells, thereby directly stimulating tumor cell proliferation; depletion of IL-10<sup>-</sup> Treg cells led to pronounced tumor regression. In human CRC, IL-10⁺ and IL-10<sup>-</sup> Treg abundance correlated with favorable and unfavorable prognosis, respectively. Accordingly, IL-10⁺ and IL-10<sup>-</sup> Treg cells exhibited opposite enrichment patterns in adjacent normal colon tissues and tumors. Transcriptionally similar Treg subsets were observed across different human barrier tissue tumors. This functional dichotomy between Treg subsets may enable selective targeting of the pro-tumoral subset while preserving its anti-tumoral counterpart in CRC and other barrier tissue cancers.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":" ","pages":"145-160.e9"},"PeriodicalIF":26.3,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12895308/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145767840","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 : 2026-01-13DOI: 10.1016/j.immuni.2025.12.006
Elizabeth Wickman, Maksim Mamonkin
IL-9 is canonically associated with anti-helminth and allergic immunity. However, in this issue of Immunity, Jiang et al. and Castelli et al. demonstrate how integrating IL-9 signaling in T cells enhances their persistence and anti-tumor function in solid cancer models.
{"title":"To the nines: IL-9 boosts T cell function","authors":"Elizabeth Wickman, Maksim Mamonkin","doi":"10.1016/j.immuni.2025.12.006","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.12.006","url":null,"abstract":"IL-9 is canonically associated with anti-helminth and allergic immunity. However, in this issue of <em>Immunity</em>, Jiang et al. and Castelli et al. demonstrate how integrating IL-9 signaling in T cells enhances their persistence and anti-tumor function in solid cancer models.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"146 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145955167","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 : 2026-01-13Epub Date: 2025-12-31DOI: 10.1016/j.immuni.2025.11.021
Minke W Lucas, Elizabeth M Burton, Petros Dimitriadis, Alexander C Huang, Georgina V Long, Tara C Mitchell, Rodabe N Amaria, Christian U Blank
Personalized escalation and de-escalation of immune checkpoint inhibitor (ICI) regimens may help to overcome upfront resistance and mitigate the risk for immune-related adverse events (irAEs). Here, we examined the association between pathological response and irAEs per ICI regimen. Meta-analysis of neoadjuvant ICI trials in melanoma illustrated a pattern of increased toxicity and efficacy with the addition and/or higher dosing of anti-CTLA-4 to anti-PD-1. We subgrouped anti-PD-1, low-dose anti-CTLA-4 + anti-PD-1, high-dose anti-CTLA-4 + anti-PD-1, and anti-PD-1 + anti-LAG-3 cohorts according to the baseline interferon-gamma (IFN-γ) signature and analyzed these for response and toxicity rates. Whereas in IFN-γ high subgroups the addition of (high-dose) anti-CTLA-4 increased toxicity but not efficacy, the addition of high-dose anti-CTLA-4 to anti-PD-1 increased efficacy in the IFN-γ low subgroup, while toxicity remained low. Our findings suggest that baseline immune signatures may be used to separate risk for toxicity from risk for non-response, with implications for patient stratification and treatment regimens.
{"title":"Immune signature-based uncoupling of checkpoint inhibitor efficacy and toxicity.","authors":"Minke W Lucas, Elizabeth M Burton, Petros Dimitriadis, Alexander C Huang, Georgina V Long, Tara C Mitchell, Rodabe N Amaria, Christian U Blank","doi":"10.1016/j.immuni.2025.11.021","DOIUrl":"10.1016/j.immuni.2025.11.021","url":null,"abstract":"<p><p>Personalized escalation and de-escalation of immune checkpoint inhibitor (ICI) regimens may help to overcome upfront resistance and mitigate the risk for immune-related adverse events (irAEs). Here, we examined the association between pathological response and irAEs per ICI regimen. Meta-analysis of neoadjuvant ICI trials in melanoma illustrated a pattern of increased toxicity and efficacy with the addition and/or higher dosing of anti-CTLA-4 to anti-PD-1. We subgrouped anti-PD-1, low-dose anti-CTLA-4 + anti-PD-1, high-dose anti-CTLA-4 + anti-PD-1, and anti-PD-1 + anti-LAG-3 cohorts according to the baseline interferon-gamma (IFN-γ) signature and analyzed these for response and toxicity rates. Whereas in IFN-γ high subgroups the addition of (high-dose) anti-CTLA-4 increased toxicity but not efficacy, the addition of high-dose anti-CTLA-4 to anti-PD-1 increased efficacy in the IFN-γ low subgroup, while toxicity remained low. Our findings suggest that baseline immune signatures may be used to separate risk for toxicity from risk for non-response, with implications for patient stratification and treatment regimens.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":" ","pages":"29-33.e2"},"PeriodicalIF":26.3,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145889222","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 : 2026-01-13Epub Date: 2025-12-30DOI: 10.1016/j.immuni.2025.12.001
Hassan Jamaleddine, Bryan T Grenfell, Andrea L Graham, Judith N Mandl
The ability of viruses to adapt and evolve as they spread through a population remains a global concern. Immune responses drive viral evolution, but our understanding of how specific selective pressures from distinct mediators of innate and adaptive immune responses within individual hosts influence long-term pathogen evolutionary trajectories is limited. Here, we argue that there is a critical need for experiments that bridge individual host studies on the one hand and population-level epi-evolutionary studies on the other. Current frameworks that investigate how immune parameters individually affect viral abundance or clearance need to be more frequently coupled with sequencing data across viral genomes. Such integration would enable the identification of potentially distinct immune-mediated selection pressures on viruses, thereby better informing the design of future cross-scale experimental models. Resolving how immune factors influence the emergence of novel viral variants will be essential to better predict and effectively manage viral evolution.
{"title":"From host to population: Bridging the viral immuno-evolutionary gap.","authors":"Hassan Jamaleddine, Bryan T Grenfell, Andrea L Graham, Judith N Mandl","doi":"10.1016/j.immuni.2025.12.001","DOIUrl":"10.1016/j.immuni.2025.12.001","url":null,"abstract":"<p><p>The ability of viruses to adapt and evolve as they spread through a population remains a global concern. Immune responses drive viral evolution, but our understanding of how specific selective pressures from distinct mediators of innate and adaptive immune responses within individual hosts influence long-term pathogen evolutionary trajectories is limited. Here, we argue that there is a critical need for experiments that bridge individual host studies on the one hand and population-level epi-evolutionary studies on the other. Current frameworks that investigate how immune parameters individually affect viral abundance or clearance need to be more frequently coupled with sequencing data across viral genomes. Such integration would enable the identification of potentially distinct immune-mediated selection pressures on viruses, thereby better informing the design of future cross-scale experimental models. Resolving how immune factors influence the emergence of novel viral variants will be essential to better predict and effectively manage viral evolution.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":" ","pages":"17-28"},"PeriodicalIF":26.3,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145878309","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: 10.1016/j.immuni.2025.12.002
Ayelet Peres, Amit A. Upadhyay, Vered Klein, Swati Saha, Oscar L. Rodriguez, Zachary M. Vanwinkle, Kirti Karunakaran, Amanda Metz, William Lauer, Mark C. Lin, Timothy Melton, Lukas Granholm, Pazit Polak, Samuel M. Peterson, Eric J. Peterson, Nagarajan Raju, Kaitlyn Shields, Steven Schultze, Thang Ton, Adam J. Ericsen, Stacey A. Lapp, Francois Villinger, Mats Ohlin, Christopher A. Cottrell, Rama R. Amara, Cynthia A. Derdeyn, Shane Crotty, William R. Schief, Gunilla B. Karlsson Hedestam, Melissa L. Smith, William Lees, Corey T. Watson, Gur Yaari, Steven E. Bosinger
Rhesus macaques (RMs) are a vital model for studying human disease and are invaluable to preclinical vaccine research, particularly for the study of broadly neutralizing antibody responses. Such studies require robust genetic resources for antibody-encoding genes within the immunoglobulin (IG) loci. The complexity of the IG loci has historically made them challenging to characterize accurately. To address this, we developed experimental and computational methodologies to generate a collection of integrated antibody repertoire and long-read genomic sequencing data in 106 Indian-origin RMs. We created a resource of IG heavy- and light-chain variable (V), diversity (D), and joining (J) alleles, as well as leader, intronic, and recombination signal sequences (RSSs). This includes the curation of 1,095 previously unidentified alleles, unveiling tremendous diversity and expanding existing IG allele sets by 40%. This publicly available, continually updated resource (https://vdjbase.org/reference_book/Rhesus_Macaque) provides the foundation for advancing RM immunogenomics, vaccine discovery, and translational research.
{"title":"Population-level genomic analysis of immunoglobulin loci variation in rhesus macaques reveals extensive germline diversity","authors":"Ayelet Peres, Amit A. Upadhyay, Vered Klein, Swati Saha, Oscar L. Rodriguez, Zachary M. Vanwinkle, Kirti Karunakaran, Amanda Metz, William Lauer, Mark C. Lin, Timothy Melton, Lukas Granholm, Pazit Polak, Samuel M. Peterson, Eric J. Peterson, Nagarajan Raju, Kaitlyn Shields, Steven Schultze, Thang Ton, Adam J. Ericsen, Stacey A. Lapp, Francois Villinger, Mats Ohlin, Christopher A. Cottrell, Rama R. Amara, Cynthia A. Derdeyn, Shane Crotty, William R. Schief, Gunilla B. Karlsson Hedestam, Melissa L. Smith, William Lees, Corey T. Watson, Gur Yaari, Steven E. Bosinger","doi":"10.1016/j.immuni.2025.12.002","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.12.002","url":null,"abstract":"Rhesus macaques (RMs) are a vital model for studying human disease and are invaluable to preclinical vaccine research, particularly for the study of broadly neutralizing antibody responses. Such studies require robust genetic resources for antibody-encoding genes within the immunoglobulin (IG) loci. The complexity of the IG loci has historically made them challenging to characterize accurately. To address this, we developed experimental and computational methodologies to generate a collection of integrated antibody repertoire and long-read genomic sequencing data in 106 Indian-origin RMs. We created a resource of IG heavy- and light-chain variable (V), diversity (D), and joining (J) alleles, as well as leader, intronic, and recombination signal sequences (RSSs). This includes the curation of 1,095 previously unidentified alleles, unveiling tremendous diversity and expanding existing IG allele sets by 40%. This publicly available, continually updated resource (<span><span>https://vdjbase.org/reference_book/Rhesus_Macaque</span><svg aria-label=\"Opens in new window\" focusable=\"false\" height=\"20\" viewbox=\"0 0 8 8\"><path d=\"M1.12949 2.1072V1H7V6.85795H5.89111V2.90281L0.784057 8L0 7.21635L5.11902 2.1072H1.12949Z\"></path></svg></span>) provides the foundation for advancing RM immunogenomics, vaccine discovery, and translational research.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"77 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145902345","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-26DOI: 10.1016/j.immuni.2025.11.022
Jing Chen, Siling Du, Wenxuan Cheng, Junedh M. Amrute, Min Woo Kim, Ray A. Ohara, Jichang Han, Suin Jo, Leah Kim, Zhenxiao Wang, Hansoo Song, J. Luke Postoak, Sunkyung Kim, Gwendalyn J. Randolph, Jonathan Kipnis, Theresa L. Murphy, Kenneth M. Murphy
{"title":"Transcription factor Maf promotes expression of repressor Zeb2 to drive microglia development in primitive hematopoiesis","authors":"Jing Chen, Siling Du, Wenxuan Cheng, Junedh M. Amrute, Min Woo Kim, Ray A. Ohara, Jichang Han, Suin Jo, Leah Kim, Zhenxiao Wang, Hansoo Song, J. Luke Postoak, Sunkyung Kim, Gwendalyn J. Randolph, Jonathan Kipnis, Theresa L. Murphy, Kenneth M. Murphy","doi":"10.1016/j.immuni.2025.11.022","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.11.022","url":null,"abstract":"","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"9 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145845094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-19DOI: 10.1016/j.immuni.2025.11.020
Beatrice Zitti, Florent Duval, Pratyaksha Wirapati, Mehdi Hicham, Yuxuan Xie, Juhyun Oh, Jan Hoelzl, Philippa Meiser, Marco Varrone, Hannah M. Peterson, Chiara Cianciaruso, Ruben Bill, Felix Bayerl, Evangelia Bolli, Anne-Gaëlle Goubet, Máté Kiss, Sheri McDowell, Phil Cheng, Dan Celestini, Julie Terzic, Thomas Zwahlen, Nagham Alouche, Nawel Zouggari, David Tarussio, Stephanie Tissot, Paula Nunes-Hasler, Mari Mino-Kenudson, Michael Lanuti, William C. Faquin, Peter M. Sadow, Jean-Christophe Tille, Sana Intidhar Labidi-Galy, Christopher S. Garris, Stephanie Hugues, Tatiana V. Petrova, Burkhard Ludewig, Sergio Quezada, Sanjiv Luther, Thorsten R. Mempel, Giovanni Ciriello, Sara I. Pai, Olivier Michielin, Jan P. Böttcher, Ralph Weissleder, Mikael J. Pittet
{"title":"Positioning and reversible suppression of CCR7+ dendritic cells in perivascular tumor niches shape cancer immunity","authors":"Beatrice Zitti, Florent Duval, Pratyaksha Wirapati, Mehdi Hicham, Yuxuan Xie, Juhyun Oh, Jan Hoelzl, Philippa Meiser, Marco Varrone, Hannah M. Peterson, Chiara Cianciaruso, Ruben Bill, Felix Bayerl, Evangelia Bolli, Anne-Gaëlle Goubet, Máté Kiss, Sheri McDowell, Phil Cheng, Dan Celestini, Julie Terzic, Thomas Zwahlen, Nagham Alouche, Nawel Zouggari, David Tarussio, Stephanie Tissot, Paula Nunes-Hasler, Mari Mino-Kenudson, Michael Lanuti, William C. Faquin, Peter M. Sadow, Jean-Christophe Tille, Sana Intidhar Labidi-Galy, Christopher S. Garris, Stephanie Hugues, Tatiana V. Petrova, Burkhard Ludewig, Sergio Quezada, Sanjiv Luther, Thorsten R. Mempel, Giovanni Ciriello, Sara I. Pai, Olivier Michielin, Jan P. Böttcher, Ralph Weissleder, Mikael J. Pittet","doi":"10.1016/j.immuni.2025.11.020","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.11.020","url":null,"abstract":"","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"27 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145784805","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-11DOI: 10.1016/j.immuni.2025.11.015
Stijn Verwaerde, Jean-François Hastir, Sjoerd T.T. Schetters, Ursula Smole, Leen Seys, Antonio P. Baptista, Kieran English, Martijn J. Schuijs, Helena Aegerter, Karel F.A. Van Damme, Aimée Bugler-Lamb, Nikita Gerebtsov, Wendy Toussaint, Tatsuma Ban, Tomohiko Tamura, Florent Ginhoux, Zhaoyuan Liu, Wouter Saelens, Hamida Hammad, Martin Guilliams, Bart N. Lambrecht
{"title":"Innate type 2 lymphocytes trigger an inflammatory switch in alveolar macrophages","authors":"Stijn Verwaerde, Jean-François Hastir, Sjoerd T.T. Schetters, Ursula Smole, Leen Seys, Antonio P. Baptista, Kieran English, Martijn J. Schuijs, Helena Aegerter, Karel F.A. Van Damme, Aimée Bugler-Lamb, Nikita Gerebtsov, Wendy Toussaint, Tatsuma Ban, Tomohiko Tamura, Florent Ginhoux, Zhaoyuan Liu, Wouter Saelens, Hamida Hammad, Martin Guilliams, Bart N. Lambrecht","doi":"10.1016/j.immuni.2025.11.015","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.11.015","url":null,"abstract":"","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"22 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145731622","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-10DOI: 10.1016/j.immuni.2025.11.018
Chantal Wientjens, Maria Doverman, Jelena Zurkovic, Tushar More, Jayagopi Surendar, Svetozar Nesic, Carola Sarici, Timon D. Utecht, Johanna Pohl, Jonathan Pollock, David Voehringer, Karsten Hiller, Christoph Thiele, Christoph Wilhelm
Type 2 innate lymphoid cells (ILC2s) are essential for maintaining and protecting barrier tissues, but they also drive chronic inflammation, a process associated with altered metabolic activity. Identifying and targeting the metabolic pathways driving ILC2-mediated inflammation could restore tissue homeostasis. Here, we find that in allergic airway inflammation, pathogenic ILC2s rely on cystine for enhanced metabolic flexibility and survival. Cystine acquisition fuels glutathione (GSH) synthesis, which, together with increased expression of glutathione peroxidase 4 (GPX4) and thioredoxin reductase 1 (TXNRD1), confers resistance to ferroptosis by counteracting lipid peroxidation and reactive oxygen species (ROS). This adaptation enables accelerated lipid acquisition and metabolism, fostering ILC2 and T helper type 2 (Th2) cell expansion. Conversely, ablation of GPX4 and TXNRD1 in ILC2s or pharmacological inhibition of TXNRD1 constrains lipid metabolism and prevents ILC2 accumulation in allergen-induced airway inflammation. This demonstrates that increased reliance on antioxidant systems represents a metabolic vulnerability that can be exploited therapeutically to treat asthma.
{"title":"Tolerance to ferroptosis facilitates lipid metabolism and pathogenic type 2 immunity in allergic airway inflammation","authors":"Chantal Wientjens, Maria Doverman, Jelena Zurkovic, Tushar More, Jayagopi Surendar, Svetozar Nesic, Carola Sarici, Timon D. Utecht, Johanna Pohl, Jonathan Pollock, David Voehringer, Karsten Hiller, Christoph Thiele, Christoph Wilhelm","doi":"10.1016/j.immuni.2025.11.018","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.11.018","url":null,"abstract":"Type 2 innate lymphoid cells (ILC2s) are essential for maintaining and protecting barrier tissues, but they also drive chronic inflammation, a process associated with altered metabolic activity. Identifying and targeting the metabolic pathways driving ILC2-mediated inflammation could restore tissue homeostasis. Here, we find that in allergic airway inflammation, pathogenic ILC2s rely on cystine for enhanced metabolic flexibility and survival. Cystine acquisition fuels glutathione (GSH) synthesis, which, together with increased expression of glutathione peroxidase 4 (GPX4) and thioredoxin reductase 1 (TXNRD1), confers resistance to ferroptosis by counteracting lipid peroxidation and reactive oxygen species (ROS). This adaptation enables accelerated lipid acquisition and metabolism, fostering ILC2 and T helper type 2 (Th2) cell expansion. Conversely, ablation of GPX4 and TXNRD1 in ILC2s or pharmacological inhibition of TXNRD1 constrains lipid metabolism and prevents ILC2 accumulation in allergen-induced airway inflammation. This demonstrates that increased reliance on antioxidant systems represents a metabolic vulnerability that can be exploited therapeutically to treat asthma.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"223 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145717912","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-09DOI: 10.1016/j.immuni.2025.11.012
Qiang Dong, Chengcheng Jin
TET2 mutations can drive clonal hematopoiesis (CH), but their impact on tumor immunity remains unresolved. Recently in Cancer Cell, Herbrich et al. reported that TET2-mutant CH reprograms tumor-associated macrophages to enhance antigen presentation and immune-checkpoint therapy efficacy in solid tumors.
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