{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,11]],"date-time":"2026-11-11T09:58:03Z","timestamp":1794391083691,"version":"4.9.0"},"reference-count":65,"publisher":"Springer Science and Business Media LLC","issue":"9","license":[{"start":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T00:00:00Z","timestamp":1786406400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T00:00:00Z","timestamp":1786406400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000054","name":"U.S. Department of Health & Human Services | NIH | National Cancer Institute","doi-asserted-by":"publisher","award":["R01CA304090"],"award-info":[{"award-number":["R01CA304090"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"U.S. Department of Health & Human Services | NIH | National Cancer Institute","doi-asserted-by":"publisher","award":["P30CA013696"],"award-info":[{"award-number":["P30CA013696"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01HL148718"],"award-info":[{"award-number":["R01HL148718"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R21AI149657"],"award-info":[{"award-number":["R21AI149657"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["T32AI106711"],"award-info":[{"award-number":["T32AI106711"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Immunol"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Across many solid tumor types, cancer-associated fibroblasts (CAFs) are abundant and heterogeneous, with distinct subpopulations exerting immunomodulatory functions. Here we identify a novel population of immunomodulatory CAFs (imCAFs) in primary lung adenocarcinoma and pulmonary metastases, characterized by cell adhesion molecule L1-like (CHL1) expression and enriched in immune regulation and chemokine signaling programs. Through single-cell and spatial transcriptomics, we demonstrate that imCAFs are spatially colocalized with CXCR3\n                    <jats:sup>+<\/jats:sup>\n                    regulatory T (T\n                    <jats:sub>reg<\/jats:sub>\n                    ) cells, a hyper-suppressive subset accumulating at the tumor border. imCAFs produce CXCL9, driving CXCR3\n                    <jats:sup>+<\/jats:sup>\n                    T\n                    <jats:sub>reg<\/jats:sub>\n                    cell recruitment and promoting an immunosuppressive microenvironment. CXCR3\n                    <jats:sup>+<\/jats:sup>\n                    T\n                    <jats:sub>reg<\/jats:sub>\n                    cells display enhanced proliferative and suppressive capacity and are transcriptionally distinct from CXCR3\n                    <jats:sup>\u2212<\/jats:sup>\n                    counterparts. Genetic ablation of\n                    <jats:italic>Cxcr3<\/jats:italic>\n                    in T\n                    <jats:sub>reg<\/jats:sub>\n                    cells or\n                    <jats:italic>Cxcl9<\/jats:italic>\n                    in stromal cells reduces T\n                    <jats:sub>reg<\/jats:sub>\n                    cell accumulation, enhances CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell activation and decreases tumor burden. Analogous CHL1\n                    <jats:sup>+<\/jats:sup>\n                    imCAF-like fibroblasts in human non-small cell lung cancer colocalize with T\n                    <jats:sub>reg<\/jats:sub>\n                    cells, and elevated\n                    <jats:italic>CHL1<\/jats:italic>\n                    expression is associated with reduced cytotoxicity and decreased progression-free survival, highlighting the imCAF\u2013CXCL9\u2013CXCR3\n                    <jats:sup>+<\/jats:sup>\n                    T\n                    <jats:sub>reg<\/jats:sub>\n                    axis as a promising therapeutic target.\n                  <\/jats:p>","DOI":"10.1038\/s41590-026-02607-2","type":"journal-article","created":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T09:04:00Z","timestamp":1786439040000},"page":"1899-1912","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A novel CAF population coordinates hyper-suppressive regulatory T cell recruitment and localization in lung cancer"],"prefix":"10.1038","volume":"27","author":[{"given":"Olivia R.","family":"Ringham","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Rivera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucas F.","family":"Loffredo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melih Arda","family":"Ozsoy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina M.","family":"Healy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maye F.","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinuo","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noah","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenia","family":"de los Santos-Alexis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elham","family":"Azizi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anjali","family":"Saqi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1902-622X","authenticated-orcid":false,"given":"Matthew B.","family":"Buechler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla P.","family":"Concepcion-Crisol","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0657-0528","authenticated-orcid":false,"given":"Nicholas","family":"Arpaia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,11]]},"reference":[{"key":"2607_CR1","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1016\/j.ccell.2023.12.021","volume":"42","author":"L Cords","year":"2024","unstructured":"Cords, L. et al. Cancer-associated fibroblast phenotypes are associated with patient outcome in non-small cell lung cancer. Cancer Cell 42, 396\u2013412 (2024).","journal-title":"Cancer Cell"},{"key":"2607_CR2","doi-asserted-by":"publisher","first-page":"3108","DOI":"10.3390\/cancers12113108","volume":"12","author":"K Louault","year":"2020","unstructured":"Louault, K., Li, R. R. & DeClerck, Y. A. Cancer-associated fibroblasts: understanding their heterogeneity. Cancers 12, 3108 (2020).","journal-title":"Cancers"},{"key":"2607_CR3","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1111\/imr.12978","volume":"302","author":"R Mhaidly","year":"2021","unstructured":"Mhaidly, R. & Mechta-Grigoriou, F. Role of cancer-associated fibroblast subpopulations in immune infiltration, as a new means of treatment in cancer. Immunol. Rev. 302, 259\u2013272 (2021).","journal-title":"Immunol. Rev."},{"key":"2607_CR4","doi-asserted-by":"publisher","first-page":"1717","DOI":"10.1002\/hep.31792","volume":"73","author":"M Song","year":"2021","unstructured":"Song, M. et al. Cancer-associated fibroblast-mediated cellular crosstalk supports hepatocellular carcinoma progression. Hepatology 73, 1717\u20131735 (2021).","journal-title":"Hepatology"},{"key":"2607_CR5","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1016\/j.ccell.2018.01.011","volume":"33","author":"A Costa","year":"2018","unstructured":"Costa, A. et al. Fibroblast heterogeneity and immunosuppressive environment in human breast cancer. Cancer Cell 33, 463\u2013479 (2018).","journal-title":"Cancer Cell"},{"key":"2607_CR6","doi-asserted-by":"publisher","first-page":"579","DOI":"10.1084\/jem.20162024","volume":"214","author":"D Ohlund","year":"2017","unstructured":"Ohlund, D. et al. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J. Exp. Med. 214, 579\u2013596 (2017).","journal-title":"J. Exp. Med."},{"key":"2607_CR7","doi-asserted-by":"publisher","first-page":"656","DOI":"10.1016\/j.ccell.2022.04.011","volume":"40","author":"H Huang","year":"2022","unstructured":"Huang, H. et al. Mesothelial cell-derived antigen-presenting cancer-associated fibroblasts induce expansion of regulatory T cells in pancreatic cancer. Cancer Cell 40, 656\u2013673 (2022).","journal-title":"Cancer Cell"},{"key":"2607_CR8","doi-asserted-by":"publisher","first-page":"446","DOI":"10.1038\/nature25183","volume":"553","author":"RS Herbst","year":"2018","unstructured":"Herbst, R. S., Morgensztern, D. & Boshoff, C. The biology and management of non-small cell lung cancer. Nature 553, 446\u2013454 (2018).","journal-title":"Nature"},{"key":"2607_CR9","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-025-02318-6","volume":"24","author":"G Xiao","year":"2025","unstructured":"Xiao, G., Wang, X., Xu, Z., Liu, Y. & Jing, J. Lung-specific metastasis: the coevolution of tumor cells and lung microenvironment. Mol. Cancer 24, 118 (2025).","journal-title":"Mol. Cancer"},{"key":"2607_CR10","doi-asserted-by":"publisher","first-page":"e0139073","DOI":"10.1371\/journal.pone.0139073","volume":"10","author":"GA Banat","year":"2015","unstructured":"Banat, G. A. et al. Immune and inflammatory cell composition of human lung cancer stroma. PLoS ONE 10, e0139073 (2015).","journal-title":"PLoS ONE"},{"key":"2607_CR11","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20210815","volume":"219","author":"D Kerdidani","year":"2022","unstructured":"Kerdidani, D. et al. Lung tumor MHCII immunity depends on in situ antigen presentation by fibroblasts. J. Exp. Med. 219, e20210815 (2022).","journal-title":"J. Exp. Med."},{"key":"2607_CR12","doi-asserted-by":"publisher","first-page":"1257","DOI":"10.1016\/j.jaci.2017.12.998","volume":"142","author":"HW Cheng","year":"2018","unstructured":"Cheng, H. W. et al. CCL19-producing fibroblastic stromal cells restrain lung carcinoma growth by promoting local antitumor T-cell responses. J. Allergy Clin. Immunol. 142, 1257\u20131271 (2018).","journal-title":"J. Allergy Clin. Immunol."},{"key":"2607_CR13","doi-asserted-by":"publisher","first-page":"2606","DOI":"10.1158\/2159-8290.CD-21-1714","volume":"12","author":"JA Grout","year":"2022","unstructured":"Grout, J. A. et al. Spatial positioning and matrix programs of cancer-associated fibroblasts promote T-cell exclusion in human lung tumors. Cancer Discov. 12, 2606\u20132625 (2022).","journal-title":"Cancer Discov."},{"key":"2607_CR14","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-35832-6","volume":"14","author":"CJ Hanley","year":"2023","unstructured":"Hanley, C. J. et al. Single-cell analysis reveals prognostic fibroblast subpopulations linked to molecular and immunological subtypes of lung cancer. Nat. Commun. 14, 387 (2023).","journal-title":"Nat. Commun."},{"key":"2607_CR15","doi-asserted-by":"publisher","first-page":"1531","DOI":"10.1016\/j.ccell.2021.09.003","volume":"39","author":"H Hu","year":"2021","unstructured":"Hu, H. et al. Three subtypes of lung cancer fibroblasts define distinct therapeutic paradigms. Cancer Cell 39, 1531\u20131547 (2021).","journal-title":"Cancer Cell"},{"key":"2607_CR16","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1016\/j.ccell.2023.02.014","volume":"41","author":"C Tay","year":"2023","unstructured":"Tay, C., Tanaka, A. & Sakaguchi, S. Tumor-infiltrating regulatory T cells as targets of cancer immunotherapy. Cancer Cell 41, 450\u2013465 (2023).","journal-title":"Cancer Cell"},{"key":"2607_CR17","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-03348-z","volume":"9","author":"AM Givel","year":"2018","unstructured":"Givel, A. M. et al. miR200-regulated CXCL12beta promotes fibroblast heterogeneity and immunosuppression in ovarian cancers. Nat. Commun. 9, 1056 (2018).","journal-title":"Nat. Commun."},{"key":"2607_CR18","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-49282-1","volume":"15","author":"A Varveri","year":"2024","unstructured":"Varveri, A. et al. Immunological synapse formation between T regulatory cells and cancer-associated fibroblasts promotes tumour development. Nat. Commun. 15, 4988 (2024).","journal-title":"Nat. Commun."},{"key":"2607_CR19","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1111\/cas.12099","volume":"104","author":"T Kinoshita","year":"2013","unstructured":"Kinoshita, T. et al. Forkhead box P3 regulatory T cells coexisting with cancer associated fibroblasts are correlated with a poor outcome in lung adenocarcinoma. Cancer Sci. 104, 409\u2013415 (2013).","journal-title":"Cancer Sci."},{"key":"2607_CR20","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20221462","volume":"220","author":"KA Kaiser","year":"2023","unstructured":"Kaiser, K. A., Loffredo, L. F., Santos-Alexis, K. L., Ringham, O. R. & Arpaia, N. Regulation of the alveolar regenerative niche by amphiregulin-producing regulatory T cells. J. Exp. Med. 220, e20221462 (2023).","journal-title":"J. Exp. Med."},{"key":"2607_CR21","doi-asserted-by":"publisher","first-page":"627","DOI":"10.1038\/s41586-024-07660-1","volume":"631","author":"T Tsukui","year":"2024","unstructured":"Tsukui, T., Wolters, P. J. & Sheppard, D. Alveolar fibroblast lineage orchestrates lung inflammation and fibrosis. Nature 631, 627\u2013634 (2024).","journal-title":"Nature"},{"key":"2607_CR22","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1038\/s41586-021-03549-5","volume":"593","author":"MB Buechler","year":"2021","unstructured":"Buechler, M. B. et al. Cross-tissue organization of the fibroblast lineage. Nature 593, 575\u2013579 (2021).","journal-title":"Nature"},{"key":"2607_CR23","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.121252","volume":"3","author":"V Sontake","year":"2018","unstructured":"Sontake, V. et al. Wilms\u2019 tumor 1 drives fibroproliferation and myofibroblast transformation in severe fibrotic lung disease. JCI Insight 3, e121252 (2018).","journal-title":"JCI Insight"},{"key":"2607_CR24","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-15670-5","volume":"7","author":"DM Habiel","year":"2017","unstructured":"Habiel, D. M. et al. Divergent roles for clusterin in lung injury and repair. Sci Rep. 7, 15444 (2017).","journal-title":"Sci Rep."},{"key":"2607_CR25","doi-asserted-by":"publisher","first-page":"3625","DOI":"10.1016\/j.celrep.2018.03.010","volume":"22","author":"T Xie","year":"2018","unstructured":"Xie, T. et al. Single-cell deconvolution of fibroblast heterogeneity in mouse pulmonary fibrosis. Cell Rep. 22, 3625\u20133640 (2018).","journal-title":"Cell Rep."},{"key":"2607_CR26","doi-asserted-by":"publisher","first-page":"2285","DOI":"10.1007\/s00432-019-02989-x","volume":"145","author":"J Hotzel","year":"2019","unstructured":"Hotzel, J. et al. Protein expression of close homologue of L1 (CHL1) is a marker for overall survival in non-small cell lung cancer (NSCLC). J. Cancer Res. Clin. Oncol. 145, 2285\u20132292 (2019).","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"2607_CR27","doi-asserted-by":"publisher","DOI":"10.1016\/j.critrevonc.2024.104554","volume":"205","author":"L Liguori","year":"2025","unstructured":"Liguori, L. et al. KRAS mutations in advanced non-small cell lung cancer: from biology to novel therapeutic strategies. Crit. Rev. Oncol. Hematol. 205, 104554 (2025).","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"2607_CR28","doi-asserted-by":"publisher","first-page":"976","DOI":"10.3389\/fimmu.2020.00976","volume":"11","author":"N Karin","year":"2020","unstructured":"Karin, N. CXCR3 ligands in cancer and autoimmunity, chemoattraction of effector T cells, and beyond. Front. Immunol. 11, 976 (2020).","journal-title":"Front. Immunol."},{"key":"2607_CR29","doi-asserted-by":"publisher","first-page":"502","DOI":"10.1016\/j.immuni.2012.11.012","volume":"38","author":"W Kastenmuller","year":"2013","unstructured":"Kastenmuller, W. et al. Peripheral prepositioning and local CXCL9 chemokine-mediated guidance orchestrate rapid memory CD8+ T cell responses in the lymph node. Immunity 38, 502\u2013513 (2013).","journal-title":"Immunity"},{"key":"2607_CR30","doi-asserted-by":"publisher","first-page":"1014","DOI":"10.1016\/j.immuni.2018.04.006","volume":"48","author":"LB Rodda","year":"2018","unstructured":"Rodda, L. B. et al. Single-cell RNA sequencing of lymph node stromal cells reveals niche-associated heterogeneity. Immunity 48, 1014\u20131028 (2018).","journal-title":"Immunity"},{"key":"2607_CR31","doi-asserted-by":"publisher","first-page":"1091","DOI":"10.1016\/j.immuni.2012.08.016","volume":"37","author":"JR Groom","year":"2012","unstructured":"Groom, J. R. et al. CXCR3 chemokine receptor-ligand interactions in the lymph node optimize CD4+ T helper 1 cell differentiation. Immunity 37, 1091\u20131103 (2012).","journal-title":"Immunity"},{"key":"2607_CR32","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1186\/s12865-020-00396-3","volume":"22","author":"W Xiu","year":"2021","unstructured":"Xiu, W. & Luo, J. CXCL9 secreted by tumor-associated dendritic cells up-regulates PD-L1 expression in bladder cancer cells by activating the CXCR3 signaling. BMC Immunol. 22, 3 (2021).","journal-title":"BMC Immunol."},{"key":"2607_CR33","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms13277","volume":"7","author":"IC Hirako","year":"2016","unstructured":"Hirako, I. C. et al. Splenic differentiation and emergence of CCR5+CXCL9+CXCL10+ monocyte-derived dendritic cells in the brain during cerebral malaria. Nat. Commun. 7, 13277 (2016).","journal-title":"Nat. Commun."},{"key":"2607_CR34","doi-asserted-by":"publisher","first-page":"670","DOI":"10.1016\/j.cell.2016.11.037","volume":"168","author":"AW Lambert","year":"2017","unstructured":"Lambert, A. W., Pattabiraman, D. R. & Weinberg, R. A. Emerging biological principles of metastasis. Cell 168, 670\u2013691 (2017).","journal-title":"Cell"},{"key":"2607_CR35","doi-asserted-by":"publisher","first-page":"30219","DOI":"10.1074\/jbc.M403595200","volume":"279","author":"RA Colvin","year":"2004","unstructured":"Colvin, R. A., Campanella, G. S., Sun, J. & Luster, A. D. Intracellular domains of CXCR3 that mediate CXCL9, CXCL10, and CXCL11 function. J. Biol. Chem. 279, 30219\u201330227 (2004).","journal-title":"J. Biol. Chem."},{"key":"2607_CR36","doi-asserted-by":"publisher","first-page":"875","DOI":"10.1084\/jem.187.6.875","volume":"187","author":"F Sallusto","year":"1998","unstructured":"Sallusto, F., Lenig, D., Mackay, C. R. & Lanzavecchia, A. Flexible programs of chemokine receptor expression on human polarized T helper 1 and 2 lymphocytes. J. Exp. Med. 187, 875\u2013883 (1998).","journal-title":"J. Exp. Med."},{"key":"2607_CR37","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1038\/ni.1731","volume":"10","author":"MA Koch","year":"2009","unstructured":"Koch, M. A. et al. The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nat. Immunol. 10, 595\u2013602 (2009).","journal-title":"Nat. Immunol."},{"key":"2607_CR38","doi-asserted-by":"publisher","first-page":"1933","DOI":"10.1681\/ASN.2015020203","volume":"27","author":"H-J Paust","year":"2016","unstructured":"Paust, H.-J. et al. CXCR3+ regulatory T cells control TH1 responses in crescentic GN. J. Am. Soc. Nephrol. 27, 1933\u20131942 (2016).","journal-title":"J. Am. Soc. Nephrol."},{"key":"2607_CR39","doi-asserted-by":"publisher","first-page":"14103","DOI":"10.1073\/pnas.1616710113","volume":"113","author":"TG Tan","year":"2016","unstructured":"Tan, T. G., Mathis, D. & Benoist, C. Singular role for T-BET+CXCR3+ regulatory T cells in protection from autoimmune diabetes. Proc. Natl Acad. Sci. USA 113, 14103\u201314108 (2016).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2607_CR40","doi-asserted-by":"publisher","first-page":"1498","DOI":"10.1016\/j.immuni.2019.04.010","volume":"50","author":"MT Chow","year":"2019","unstructured":"Chow, M. T. et al. Intratumoral activity of the CXCR3 chemokine system is required for the efficacy of anti-PD-1 therapy. Immunity 50, 1498\u20131512 (2019).","journal-title":"Immunity"},{"key":"2607_CR41","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1038\/ni904","volume":"4","author":"JD Fontenot","year":"2003","unstructured":"Fontenot, J. D., Gavin, M. A. & Rudensky, A. Y. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat. Immunol. 4, 330\u2013336 (2003).","journal-title":"Nat. Immunol."},{"key":"2607_CR42","doi-asserted-by":"publisher","first-page":"1613","DOI":"10.1016\/j.immuni.2023.06.003","volume":"56","author":"MA Moreno Ayala","year":"2023","unstructured":"Moreno Ayala, M. A. et al. CXCR3 expression in regulatory T cells drives interactions with type I dendritic cells in tumors to restrict CD8+ T cell antitumor immunity. Immunity 56, 1613\u20131630.e5 (2023).","journal-title":"Immunity"},{"key":"2607_CR43","doi-asserted-by":"publisher","first-page":"386","DOI":"10.1016\/j.immuni.2023.01.010","volume":"56","author":"M Zagorulya","year":"2023","unstructured":"Zagorulya, M. et al. Tissue-specific abundance of interferon-gamma drives regulatory T cells to restrain DC1-mediated priming of cytotoxic T cells against lung cancer. Immunity 56, 386\u2013405 (2023).","journal-title":"Immunity"},{"key":"2607_CR44","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1158\/1078-0432.CCR-19-1868","volume":"26","author":"IG House","year":"2020","unstructured":"House, I. G. et al. Macrophage-derived CXCL9 and CXCL10 are required for antitumor immune responses following immune checkpoint blockade. Clin. Cancer Res. 26, 487\u2013504 (2020).","journal-title":"Clin. Cancer Res."},{"key":"2607_CR45","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.107873","volume":"32","author":"Y Qu","year":"2020","unstructured":"Qu, Y. et al. Baseline frequency of inflammatory Cxcl9-expressing tumor-associated macrophages predicts response to avelumab treatment. Cell Rep. 32, 107873 (2020).","journal-title":"Cell Rep."},{"key":"2607_CR46","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-024-02177-7","volume":"23","author":"YF Ren","year":"2024","unstructured":"Ren, Y. F. et al. Single-cell RNA sequencing reveals immune microenvironment niche transitions during the invasive and metastatic processes of ground-glass nodules and part-solid nodules in lung adenocarcinoma. Mol. Cancer 23, 263 (2024).","journal-title":"Mol. Cancer"},{"key":"2607_CR47","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.109523","volume":"36","author":"H Prizant","year":"2021","unstructured":"Prizant, H. et al. CXCL10+ peripheral activation niches couple preferred sites of Th1 entry with optimal APC encounter. Cell Rep. 36, 109523 (2021).","journal-title":"Cell Rep."},{"key":"2607_CR48","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.ceb.2015.05.003","volume":"36","author":"J Lian","year":"2015","unstructured":"Lian, J. & Luster, A. D. Chemokine-guided cell positioning in the lymph node orchestrates the generation of adaptive immune responses. Curr. Opin. Cell Biol. 36, 1\u20136 (2015).","journal-title":"Curr. Opin. Cell Biol."},{"key":"2607_CR49","doi-asserted-by":"publisher","first-page":"1503","DOI":"10.1016\/j.ccell.2022.10.008","volume":"40","author":"S Salcher","year":"2022","unstructured":"Salcher, S. et al. High-resolution single-cell atlas reveals diversity and plasticity of tissue-resident neutrophils in non-small cell lung cancer. Cancer Cell 40, 1503\u20131520 (2022).","journal-title":"Cancer Cell"},{"key":"2607_CR50","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-15647-5","volume":"11","author":"T Tsukui","year":"2020","unstructured":"Tsukui, T. et al. Collagen-producing lung cell atlas identifies multiple subsets with distinct localization and relevance to fibrosis. Nat. Commun. 11, 1920 (2020).","journal-title":"Nat. Commun."},{"key":"2607_CR51","doi-asserted-by":"publisher","first-page":"619","DOI":"10.1038\/s41586-020-2922-4","volume":"587","author":"KJ Travaglini","year":"2020","unstructured":"Travaglini, K. J. et al. A molecular cell atlas of the human lung from single-cell RNA sequencing. Nature 587, 619\u2013625 (2020).","journal-title":"Nature"},{"key":"2607_CR52","doi-asserted-by":"publisher","first-page":"1482","DOI":"10.1016\/j.jtho.2016.05.025","volume":"11","author":"Y Shintani","year":"2016","unstructured":"Shintani, Y. et al. IL-6 secreted from cancer-associated fibroblasts mediates chemoresistance in NSCLC by increasing epithelial-mesenchymal transition signaling. J. Thorac. Oncol. 11, 1482\u20131492 (2016).","journal-title":"J. Thorac. Oncol."},{"key":"2607_CR53","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-15188-x","volume":"11","author":"M Pein","year":"2020","unstructured":"Pein, M. et al. Metastasis-initiating cells induce and exploit a fibroblast niche to fuel malignant colonization of the lungs. Nat. Commun. 11, 1494 (2020).","journal-title":"Nat. Commun."},{"key":"2607_CR54","doi-asserted-by":"publisher","first-page":"430","DOI":"10.1016\/j.cell.2024.10.042","volume":"188","author":"L Onder","year":"2025","unstructured":"Onder, L. et al. Fibroblastic reticular cells generate protective intratumoral T cell environments in lung cancer. Cell 188, 430\u2013446 (2025).","journal-title":"Cell"},{"key":"2607_CR55","doi-asserted-by":"publisher","first-page":"886","DOI":"10.1016\/j.ajpath.2019.12.007","volume":"190","author":"X Zhao","year":"2020","unstructured":"Zhao, X. et al. Diminished CD68+ cancer-associated fibroblast subset induces regulatory T-cell (Treg) infiltration and predicts poor prognosis of oral squamous cell carcinoma patients. Am. J. Pathol. 190, 886\u2013899 (2020).","journal-title":"Am. J. Pathol."},{"key":"2607_CR56","doi-asserted-by":"publisher","first-page":"4531","DOI":"10.1158\/1078-0432.CCR-20-0328","volume":"26","author":"D Zamarin","year":"2020","unstructured":"Zamarin, D. et al. Mogamulizumab in combination with durvalumab or tremelimumab in patients with advanced solid tumors: a phase I study. Clin. Cancer Res. 26, 4531\u20134541 (2020).","journal-title":"Clin. Cancer Res."},{"key":"2607_CR57","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1007\/s10238-024-01362-8","volume":"24","author":"HG Roider","year":"2024","unstructured":"Roider, H. G. et al. Selective depletion of tumor-infiltrating regulatory T cells with BAY 3375968, a novel Fc-optimized anti-CCR8 antibody. Clin. Exp. Med. 24, 122 (2024).","journal-title":"Clin. Exp. Med."},{"key":"2607_CR58","doi-asserted-by":"crossref","unstructured":"van Lieshout, M. N. M. Spatial Point Patterns: Methodology and Applications with R Vol. 72 (CRC, 2016).","DOI":"10.1111\/biom.12533"},{"key":"2607_CR59","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-017-1382-0","volume":"19","author":"FA Wolf","year":"2018","unstructured":"Wolf, F. A., Angerer, P. & Theis, F. J. SCANPY: large-scale single-cell gene expression data analysis. Genome Biol. 19, 15 (2018).","journal-title":"Genome Biol."},{"key":"2607_CR60","doi-asserted-by":"publisher","first-page":"661","DOI":"10.1038\/s41587-021-01139-4","volume":"40","author":"V Kleshchevnikov","year":"2022","unstructured":"Kleshchevnikov, V. et al. Cell2location maps fine-grained cell types in spatial transcriptomics. Nat. Biotechnol. 40, 661\u2013671 (2022).","journal-title":"Nat. Biotechnol."},{"key":"2607_CR61","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1038\/s41587-024-02173-8","volume":"43","author":"S He","year":"2025","unstructured":"He, S. et al. Starfysh integrates spatial transcriptomic and histologic data to reveal heterogeneous tumor-immune hubs. Nat. Biotechnol. 43, 223\u2013235 (2025).","journal-title":"Nat. Biotechnol."},{"key":"2607_CR62","doi-asserted-by":"publisher","first-page":"1843","DOI":"10.1101\/gr.271288.120","volume":"31","author":"BF Miller","year":"2021","unstructured":"Miller, B. F., Bambah-Mukku, D., Dulac, C., Zhuang, X. & Fan, J. Characterizing spatial gene expression heterogeneity in spatially resolved single-cell transcriptomic data with nonuniform cellular densities. Genome Res. 31, 1843\u20131855 (2021).","journal-title":"Genome Res."},{"key":"2607_CR63","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1038\/s41592-021-01358-2","volume":"19","author":"G Palla","year":"2022","unstructured":"Palla, G. et al. Squidpy: a scalable framework for spatial omics analysis. Nat. Methods 19, 171\u2013178 (2022).","journal-title":"Nat. Methods"},{"key":"2607_CR64","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1007\/978-1-0716-0327-7_16","volume":"2120","author":"G Sturm","year":"2020","unstructured":"Sturm, G., Finotello, F. & List, M. Immunedeconv: an R package for unified access to computational methods for estimating immune cell fractions from bulk RNA-sequencing data. Methods Mol. Biol. 2120, 223\u2013232 (2020).","journal-title":"Methods Mol. Biol."},{"key":"2607_CR65","doi-asserted-by":"publisher","first-page":"6238","DOI":"10.1158\/0008-5472.CAN-18-3560","volume":"79","author":"A Jim\u00e9nez-S\u00e1nchez","year":"2019","unstructured":"Jim\u00e9nez-S\u00e1nchez, A., Cast, O. & Miller, M. L. Comprehensive benchmarking and integration of tumor microenvironment cell estimation methods. Cancer Res. 79, 6238\u20136246 (2019).","journal-title":"Cancer Res."}],"updated-by":[{"DOI":"10.1038\/s41590-026-02680-7","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T00:00:00Z","timestamp":1788998400000}}],"container-title":["Nature Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41590-026-02607-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41590-026-02607-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41590-026-02607-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T07:03:22Z","timestamp":1789110202000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41590-026-02607-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,11]]},"references-count":65,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2026,9]]}},"alternative-id":["2607"],"URL":"https:\/\/doi.org\/10.1038\/s41590-026-02607-2","relation":{},"ISSN":["1529-2908","1529-2916"],"issn-type":[{"value":"1529-2908","type":"print"},{"value":"1529-2916","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,11]]},"assertion":[{"value":"21 July 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 July 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 August 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 September 2026","order":5,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Correction","order":6,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"A Correction to this paper has been published:","order":7,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"https:\/\/doi.org\/10.1038\/s41590-026-02680-7","URL":"https:\/\/doi.org\/10.1038\/s41590-026-02680-7","order":8,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"A.S. reports institutional grants or contracts from Boehringer Ingelheim and Genentech; consulting fees from Genentech, Gilead, AbbVie, Memorial Sloan Kettering and Bronx Lebanon; and travel support from the International Association for the Study of Lung Cancer and the College of American Pathologists. A.S. holds patents for a device for cell blocks and a Major Pathological Calculator Tool, and holds stock in Link Biosystems. The other authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}]}}