{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T20:32:07Z","timestamp":1791232327685,"version":"4.1.0"},"reference-count":65,"publisher":"BMJ","issue":"7","license":[{"start":{"date-parts":[[2025,7,15]],"date-time":"2025-07-15T00:00:00Z","timestamp":1752537600000},"content-version":"unspecified","delay-in-days":14,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"T-Star Center","award":["NSTC 113-2634-F-039-001"],"award-info":[{"award-number":["NSTC 113-2634-F-039-001"]}]},{"name":"Tianjin Health Research Project","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"name":"Tianjin Key Medical Discipline (Specialty) Construction Project","award":["TJYXZDXK-061B"],"award-info":[{"award-number":["TJYXZDXK-061B"]}]},{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology in Taiwan","doi-asserted-by":"crossref","award":["112-2639-B-039-001-ASP"],"award-info":[{"award-number":["112-2639-B-039-001-ASP"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81972186"],"award-info":[{"award-number":["81972186"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82172687"],"award-info":[{"award-number":["82172687"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82373361"],"award-info":[{"award-number":["82373361"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006606","name":"Natural Science Foundation of Tianjin","doi-asserted-by":"crossref","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/501100006606","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2025,6,17]]},"published-print":{"date-parts":[[2025,7]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Despite the remarkable clinical outcomes of epidermal growth factor receptor (EGFR)-targeted therapies in patients with lung cancer, therapeutic resistance eventually develops. This study elucidates the role of galectin-9 (Gal-9), a TIM-3 immune checkpoint ligand, in facilitating tumor immune escape during EGFR tyrosine kinase inhibitor (TKI) therapy, and evaluates the therapeutic potential of combined EGFR-TKI and Gal-9 blockade in preclinical models.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>EGFR-TKI-mediated Gal-9 regulation was systematically investigated through multianalysis including RNA-seq transcriptomics, quantitative reverse transcription-PCR, immunoblotting, ELISA, flow cytometry, and immunohistochemical validation across human and murine lung\/colorectal cancer cell lines, murine tumor tissues, and paired patient tumor tissues\/serum samples. Therapeutic efficacy was evaluated in two syngeneic murine models, with comprehensive immune monitoring of tumor microenvironment (TME), tumor-draining lymph nodes (tdLNs), and splenic compartments. Mechanistic investigations employed CD8<jats:sup>+<\/jats:sup> T-cell\/macrophage depletion strategies (anti-CD8\u03b1 monoclonal antibodies (mAbs)\/PLX-3397), type I interferon (IFN-I) pathway inhibition (anti-IFNAR1 mAbs), and lymph node retention approaches (FTY720 administration).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>EGFR-TKI treatment significantly induced Gal-9 expression in both tumor cells and host immune cells, particularly myeloid cells. Clinical validation revealed elevated Gal-9 levels in EGFR-TKI-treated patient with lung cancer tumor tissues and serums, correlating with reduced progression-free survival. Mechanistically, EGFR-TKIs triggered DNA damage-potentiated cytosolic double-stranded DNA accumulation and activated tumor-intrinsic STING-IFN-I innate immune pathway that transcriptionally regulated Gal-9 expression. Notably, Gal-9-neutralizing antibodies synergized with EGFR-TKI to markedly inhibit tumor growth in two syngeneic mouse models, including the poorly immunogenic LLC lung tumor model unresponsive to programmed cell death protein-1\/programmed death-ligand 1 blockade. The combination therapy remodeled myeloid landscapes toward antigen-presenting phenotypes, promoted dendritic cell accumulation in the tdLN and enhanced CD8<jats:sup>+<\/jats:sup> T response in the TME. Depleting CD8<jats:sup>+<\/jats:sup> T cells or macrophages\/monocytes abrogated the therapeutic benefits. Blocking the IFN-I pathway attenuated Gal-9 expression and enhanced the antitumor immunity of afatinib in the LLC tumor model.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>These findings identify Gal-9 upregulation as a key mechanism mediating immune evasion and limiting EGFR-TKI efficacy, providing a promising combinational therapeutic strategy of EGFR-TKI and Gal-9 blockade for the treatment of EGFR-driven cancers.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2024-010926","type":"journal-article","created":{"date-parts":[[2025,7,15]],"date-time":"2025-07-15T11:50:31Z","timestamp":1752580231000},"page":"e010926","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":16,"title":["Anti-galectin-9 therapy synergizes with EGFR inhibition to reprogram the tumor microenvironment and overcome immune evasion"],"prefix":"10.1136","volume":"13","clinical-trial-number":[{"clinical-trial-number":"nct03785249","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct02450656","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04666688","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-6402-6511","authenticated-orcid":false,"given":"Dongli","family":"Linghu","sequence":"first","affiliation":[{"name":"Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaming","family":"Song","sequence":"additional","affiliation":[{"name":"Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China"},{"name":"Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liyan","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Tianjin Medical University General Hospital, Tianjin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengjie","family":"Liu","sequence":"additional","affiliation":[{"name":"Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boning","family":"Liu","sequence":"additional","affiliation":[{"name":"Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riyao","family":"Yang","sequence":"additional","affiliation":[{"name":"AHMC Dermatology and Research Center, Arcadia, California, USA"},{"name":"Department of Molecular and Cellular Oncology, The University of Texas M. 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