{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T17:40:55Z","timestamp":1793036455318,"version":"4.5.0"},"reference-count":44,"publisher":"BMJ","issue":"10","license":[{"start":{"date-parts":[[2025,11,1]],"date-time":"2025-11-01T00:00:00Z","timestamp":1761955200000},"content-version":"unspecified","delay-in-days":1,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004784","name":"Novartis Foundation for Medical-Biological Research","doi-asserted-by":"crossref","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/501100004784","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100008494","name":"Vontobel-Stiftung","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/501100008494","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100031252","name":"Carigest","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100031252","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100022716","name":"Swiss Cancer Foundation","doi-asserted-by":"publisher","award":["KFS-5944-08-2023"],"award-info":[{"award-number":["KFS-5944-08-2023"]}],"id":[{"id":"10.13039\/501100022716","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Maiores Stiftung","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"DOI":"10.13039\/501100001711","name":"Schweizerischer Nationalfonds zur F\u00f6rderung der Wissenschaftlichen Forschung","doi-asserted-by":"publisher","award":["310030_197823"],"award-info":[{"award-number":["310030_197823"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001711","name":"Schweizerischer Nationalfonds zur F\u00f6rderung der Wissenschaftlichen Forschung","doi-asserted-by":"publisher","award":["310030_201202\/1"],"award-info":[{"award-number":["310030_201202\/1"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001711","name":"Schweizerischer Nationalfonds zur F\u00f6rderung der Wissenschaftlichen Forschung","doi-asserted-by":"publisher","award":["320030-232113"],"award-info":[{"award-number":["320030-232113"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2025,10,18]]},"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Tumor-associated macrophages (TAMs) can switch between immune-activating and cancer-promoting states; yet, the stress pathways that lock them into procancerous states remain obscure. Here we defined the role of transcription factor NRF2 as a mediator of procancerous macrophages.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We combined spatial transcriptomics, single-cell RNA sequencing, three-dimensional (3D) cell culture and in vivo tumor models to explore how NRF2 activation status in tumor-associated macrophages modifies responses to immunotherapy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In MC38 colon tumors, repeated anti-CD40 or radiotherapy created necrosis that split TAMs into peripheral Cxcl9+ and peri-necrotic Spp1+ subsets. Spatial transcriptomics, single-cell RNA sequencing, and Keap1-deficient mice showed that the latter are NRF2-imprinted \u201cstress-TAMs\u201d, with immunosuppressive and tumor-promoting activity. The same NRF2 activation gradient separates pro-inflammatory CXCL9+ and anti-inflammatory SPP1+TAMs across diverse human cancers. NRF2-imprinted TAMs silence IFN-STAT1 programs, lose major histocompatibility complex-II and chemokine expression, fail to expand T cells, drive tumor cell invasion in 3D co-cultures, and foster metastasis. Constitutive hematopoietic NRF2 activation accelerated the growth of therapy-na\u00efve MMTV-PyMT breast tumors and markedly impaired the efficacy of agonistic anti-CD40 antibody therapy in MC38 subcutaneous and lung-metastasis models. Conversely, macrophage-specific Nrf2 deletion restored immunogenic TAMs and potentiated anti-CD40 and anti-programmed cell death protein-1 treatments.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our data pinpoint a previously underappreciated cytoprotective mechanism, which inadvertently sustains immunosuppressive macrophages and confers therapy resistance. These results define stress-induced TAMs as an untapped driver of macrophage-based immune evasion. Inhibiting NRF2 activity alongside standard immunotherapies could restore a pro-inflammatory macrophage\u2013T-cell amplification loop, potentially improving patient responses to T-cell\u2014and macrophage-directed immunotherapies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2025-013063","type":"journal-article","created":{"date-parts":[[2025,11,1]],"date-time":"2025-11-01T05:35:21Z","timestamp":1761975321000},"page":"e013063","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":13,"title":["Stress-NRF2 response axis polarizes tumor macrophages and undermines immunotherapy"],"prefix":"10.1136","volume":"13","author":[{"given":"Dominik J","family":"Schaer","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, University of Zurich, Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2918-6262","authenticated-orcid":false,"given":"Nadja","family":"Schulthess-Lutz","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Zurich, Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Livio","family":"Baselgia","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Zurich, Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kahrisan","family":"Kunasingam","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Zurich, Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rok","family":"Humar","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Zurich, Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerstin","family":"Hansen","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Zurich, Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Eschment","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Zurich, Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4386-6475","authenticated-orcid":false,"given":"Elena","family":"Duerst","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Zurich, Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9659-8278","authenticated-orcid":false,"given":"Florence","family":"Vallelian","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Zurich, Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2025,10,31]]},"reference":[{"key":"2026052722305822000_13.10.e013063.1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1256"},{"key":"2026052722305822000_13.10.e013063.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-022-00620-6"},{"key":"2026052722305822000_13.10.e013063.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2013.02.013"},{"key":"2026052722305822000_13.10.e013063.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2021.03.002"},{"key":"2026052722305822000_13.10.e013063.5","doi-asserted-by":"crossref","DOI":"10.1172\/JCI174528","article-title":"Hemorrhage-activated NRF2 in tumor-associated macrophages drives cancer growth, invasion, and immunotherapy resistance","volume":"134","author":"Schaer","year":"2023","journal-title":"J Clin Invest"},{"key":"2026052722305822000_13.10.e013063.6","doi-asserted-by":"crossref","DOI":"10.1084\/jem.20230420","article-title":"An iron-rich subset of macrophages promotes tumor growth through a Bach1-Ednrb axis","volume":"221","author":"Folkert","year":"2024","journal-title":"J Exp Med"},{"key":"2026052722305822000_13.10.e013063.7","doi-asserted-by":"publisher","DOI":"10.1038\/nature13490"},{"key":"2026052722305822000_13.10.e013063.8","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1997.6943"},{"key":"2026052722305822000_13.10.e013063.9","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-025-01145-0"},{"key":"2026052722305822000_13.10.e013063.10","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-031-62731-6_8"},{"key":"2026052722305822000_13.10.e013063.11","doi-asserted-by":"crossref","DOI":"10.1038\/ncomms11624","article-title":"Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription","volume":"7","author":"Kobayashi","year":"2016","journal-title":"Nat Commun"},{"key":"2026052722305822000_13.10.e013063.12","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-022-00932-1"},{"key":"2026052722305822000_13.10.e013063.13","doi-asserted-by":"publisher","DOI":"10.1172\/JCI25790"},{"key":"2026052722305822000_13.10.e013063.14","doi-asserted-by":"publisher","DOI":"10.1172\/JCI137282"},{"key":"2026052722305822000_13.10.e013063.15","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2022015596"},{"key":"2026052722305822000_13.10.e013063.16","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-021-00921-5"},{"key":"2026052722305822000_13.10.e013063.17","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2022.08.005"},{"key":"2026052722305822000_13.10.e013063.18","doi-asserted-by":"publisher","DOI":"10.1126\/science.1198443"},{"key":"2026052722305822000_13.10.e013063.19","doi-asserted-by":"publisher","DOI":"10.1126\/science.ade2292"},{"key":"2026052722305822000_13.10.e013063.20","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.08.009"},{"key":"2026052722305822000_13.10.e013063.21","doi-asserted-by":"crossref","first-page":"155747","DOI":"10.1016\/j.metabol.2023.155747","article-title":"The role of ROS in tumor infiltrating immune cells and cancer immunotherapy","volume":"151","author":"Shah","year":"2024","journal-title":"Metab Clin Exp"},{"key":"2026052722305822000_13.10.e013063.22","doi-asserted-by":"publisher","DOI":"10.1002\/hep.32184"},{"key":"2026052722305822000_13.10.e013063.23","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2018017574"},{"key":"2026052722305822000_13.10.e013063.24","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1038\/s43018-020-00121-4","article-title":"Multimodal Mapping of the Tumor and Peripheral Blood Immune Landscape in Human Pancreatic Cancer","volume":"1","author":"Steele","year":"2020","journal-title":"Nat Cancer"},{"key":"2026052722305822000_13.10.e013063.25","doi-asserted-by":"crossref","DOI":"10.1126\/sciimmunol.abl7482","article-title":"A common framework of monocyte-derived macrophage activation","volume":"7","author":"Sanin","year":"2022","journal-title":"Sci Immunol"},{"key":"2026052722305822000_13.10.e013063.26","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2018.12.001"},{"key":"2026052722305822000_13.10.e013063.27","doi-asserted-by":"crossref","DOI":"10.1080\/2162402X.2016.1268310","article-title":"Immunosurveillance and immunoediting in MMTV-PyMT-induced mammary oncogenesis","volume":"6","author":"Gross","year":"2017","journal-title":"Oncoimmunology"},{"key":"2026052722305822000_13.10.e013063.28","doi-asserted-by":"crossref","DOI":"10.1136\/jitc-2022-005718","article-title":"Antibody-induced erythrophagocyte reprogramming of Kupffer cells prevents anti-CD40 cancer immunotherapy-associated liver toxicity","volume":"11","author":"Pfefferl\u00e9","year":"2023","journal-title":"J Immunother Cancer"},{"key":"2026052722305822000_13.10.e013063.29","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-med-062518-045435"},{"key":"2026052722305822000_13.10.e013063.30","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2022.940674","article-title":"Next Generation CD40 Agonistic Antibodies for Cancer Immunotherapy","volume":"13","author":"Salomon","year":"2022","journal-title":"Front Immunol"},{"key":"2026052722305822000_13.10.e013063.31","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2019.05.004"},{"key":"2026052722305822000_13.10.e013063.32","doi-asserted-by":"publisher","DOI":"10.1172\/jci123360"},{"key":"2026052722305822000_13.10.e013063.33","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2022.12.007"},{"key":"2026052722305822000_13.10.e013063.34","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2024.10.014"},{"key":"2026052722305822000_13.10.e013063.35","doi-asserted-by":"crossref","DOI":"10.1136\/jitc-2020-001341","article-title":"Tumor-associated macrophages: potential therapeutic strategies and future prospects in cancer","volume":"9","author":"Li","year":"2021","journal-title":"J Immunother Cancer"},{"key":"2026052722305822000_13.10.e013063.36","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2024.04.011"},{"key":"2026052722305822000_13.10.e013063.37","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2013.11.007"},{"key":"2026052722305822000_13.10.e013063.38","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01591-09"},{"key":"2026052722305822000_13.10.e013063.39","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201102-0271OC"},{"key":"2026052722305822000_13.10.e013063.40","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2011-0144OC"},{"key":"2026052722305822000_13.10.e013063.41","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2021.680855","article-title":"Acute Hemolysis and Heme Suppress Anti-CD40 Antibody-Induced Necro-Inflammatory Liver Disease","volume":"12","author":"Pfefferl\u00e9","year":"2021","journal-title":"Front Immunol"},{"key":"2026052722305822000_13.10.e013063.42","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pbio.3000410","article-title":"The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research","volume":"18","author":"Percie du Sert","year":"2020","journal-title":"PLoS Biol"},{"key":"2026052722305822000_13.10.e013063.43","unstructured":"Schaer DJ , Schulthess-Lutz N , Baselgia L , et al . A stress-NRF2 response axis polarises tumor macrophages and undermines immunotherapy - sequencing data accession number GSE290434 (Gene Expression Omnibus). n.d. Available: https:\/\/www.ncbi.nlm.nih.gov\/geo\/"},{"key":"2026052722305822000_13.10.e013063.44","unstructured":"Schaer DJ , Schulthess-Lutz N , Baselgia L , et al . A stress-NRF2 response axis polarises tumor macrophages and undermines immunotherapy - Analysis code at GitHub, Available: https:\/\/github.com\/primelab-zurich\/A-stress-response-axis-in-TAMs-dictates-phenotype-heterogeneity-and-immunotherapy-evasion"}],"container-title":["Journal for ImmunoTherapy of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jitc-2025-013063","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T05:31:37Z","timestamp":1779946297000},"score":1,"resource":{"primary":{"URL":"https:\/\/jitc.bmj.com\/lookup\/doi\/10.1136\/jitc-2025-013063"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,31]]},"references-count":44,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2025,10,31]]},"published-print":{"date-parts":[[2025,11]]}},"alternative-id":["10.1136\/jitc-2025-013063"],"URL":"https:\/\/doi.org\/10.1136\/jitc-2025-013063","relation":{},"ISSN":["2051-1426"],"issn-type":[{"value":"2051-1426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,31]]}}}