{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T06:16:25Z","timestamp":1793427385875,"version":"4.5.0"},"reference-count":36,"publisher":"National Academy of Sciences","issue":"33","license":[{"start":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T00:00:00Z","timestamp":1786320000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,8,18]]},"abstract":"<jats:p>\n                    Immunotherapy resistance remains a major barrier to achieving sustained patient improvement in non\u2013small cell lung cancer (NSCLCs). Here, through integrating CODEX, metabolomics, CyTOF, ATAC-seq, and single-cell spatial transcriptomics from NSCLC tumors, we uncover an unrecognized role of ALDH9A1 in promoting resistance to anti-PD-1 therapy. In immunocompetent, but not immunocompromised mouse models, loss of ALDH9A1 markedly restrains tumor growth. This effect is accompanied by increased maturation of tertiary lymphoid structures and reduced accumulation of protumorigenic MDSCs within tumor immune microenvironment. Mechanistically, ALDH9A1-driven carnitine production elevates acetyl-CoA levels, remodels chromatin accessibility, and activates Il1b superenhancers in tumor cells, thereby promoting MDSC polarization and CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell exhaustion. In vivo, genetic or pharmacological inhibition of ALDH9A1, or antibody-mediated IL-1\u03b2 neutralization, suppresses tumor progression and restores sensitivity to anti-PD-1 therapy. IL-1\u03b2 further activates NF-\u03baB and upregulates ALDH9A1, establishing a feedback ALDH9A1-IL-1\u03b2 loop. Importantly, the ALDH9A1\/IL-1\u03b2 axis is frequently hyperactivated in NSCLC patients and correlates with inferior responses to anti-PD-1 immunotherapy. Together, this study reveals a previously unappreciated NSCLC-specific immunoregulatory pathway and identifies ALDH9A1 as a promising therapeutic target for improving immunotherapy efficacy.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2535328123","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T19:09:16Z","timestamp":1786388956000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":2,"title":["Single-cell multiomics identifies an ALDH9A1\u2013carnitine signaling axis driving resistance of NSCLC to immunotherapy"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6126-3176","authenticated-orcid":false,"given":"Hailei","family":"Du","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0220qvk04","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Thoracic Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-7165-3465","authenticated-orcid":false,"given":"Tong","family":"Lang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/042g3qa69","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Respiratory and Critical Care Medicine, Weifang Second People\u2019s Hospital","place":["Weifang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-6145-5137","authenticated-orcid":false,"given":"Xiaoxue","family":"Zha","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04c4dkn09","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Intensive Care Medicine, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China","place":["Hefei, China"]},{"name":"Department of Intensive Care Medicine, Anhui Provincial Cancer Hospital","place":["Hefei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5226-1139","authenticated-orcid":false,"given":"Chao","family":"Qu","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/034haf133","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Interventional Therapy, The First Hospital of Jilin University","place":["Changchun, China"]},{"id":[{"id":"https:\/\/ror.org\/034haf133","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Public Laboratory Platform, The First Hospital of Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0150-4433","authenticated-orcid":false,"given":"Ling","family":"Chen","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0220qvk04","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Respiratory and Critical Care Medicine Ruijin Hospital, North, Shanghai Jiaotong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-7032-0893","authenticated-orcid":false,"given":"Shihua","family":"Yao","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02bjs0p66","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Thoracic Surgery, Navy Military Medical University Affiliated Changhai Hospital","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2253-4180","authenticated-orcid":false,"given":"Xing","family":"Feng","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03v76x132","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Immunobiology and Yale Stem Cell Center, Yale University School of Medicine","place":["New Haven"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0660-1695","authenticated-orcid":false,"given":"Zhaohui","family":"Jin","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/011ashp19","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pharmacy, West China Hospital, Sichuan University","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,8,10]]},"reference":[{"key":"e_1_3_4_1_2","first-page":"1","article-title":"Treatment of NSCLC after chemoimmunotherapy\u2014Are we making headway?","author":"Reck M.","year":"2025","unstructured":"M. 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Du Data from \u201cSingle-cell multiomics identifies an ALDH9A1-carnitine signaling axis driving resistance of NSCLC to immunotherapy.\u201d Gene Expression Omnibus (GEO). https:\/\/www.ncbi.nlm.nih.gov\/bioproject\/PRJNA1377217. Deposited 24 July 2026."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2535328123","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T19:10:30Z","timestamp":1786389030000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2535328123"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,10]]},"references-count":36,"journal-issue":{"issue":"33","published-print":{"date-parts":[[2026,8,18]]}},"alternative-id":["10.1073\/pnas.2535328123"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2535328123","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,10]]},"assertion":[{"value":"2025-12-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-10","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-10","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2535328123"}}