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As colorectal liver metastases exhibit high levels of CTLA-4 expression, we combined LIGHT overexpression with anti-CTLA-4, leading to complete tumor control. The combination functions by homing tumor-infiltrating lymphocytes, inducing tumor antigen-specific T cells, and reversing T cell exhaustion. Whereas both LIGHT overexpression and anti-CTLA-4 increase tumor-promoting macrophages, the combination eliminates this population. The ability of LIGHT overexpression combined with CTLA-4 inhibition to reverse T cell exhaustion and myeloid cell suppression is supported by analysis of complementary patient cohorts and has strong clinical relevance, especially given that liver metastases contribute to immunotherapy resistance across various cancer types.<\/jats:p>","DOI":"10.1126\/sciadv.adv9161","type":"journal-article","created":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T17:58:48Z","timestamp":1759946328000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":4,"title":["Combination LIGHT overexpression and checkpoint blockade disrupts the tumor immune environment impacting colorectal liver metastases"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6075-489X","authenticated-orcid":true,"given":"Bridget P.","family":"Keenan","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Hematology\/Oncology, University of California, San Francisco, San Francisco, CA 94143, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8615-3467","authenticated-orcid":true,"given":"Guilin","family":"Qiao","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Surgical Oncology, University of California, San Francisco, San Francisco, CA 94143, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-1558-6559","authenticated-orcid":true,"given":"Nicholas","family":"Kunda","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lyonell","family":"Kone","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0102-4341","authenticated-orcid":true,"given":"Sophia M.","family":"Guldberg","sequence":"additional","affiliation":[{"name":"Departments of Otolaryngology-Head and Neck Surgery and Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-3134-9228","authenticated-orcid":true,"given":"Letizia","family":"Todeschini","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Surgical Oncology, University of California, San Francisco, San Francisco, CA 94143, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0657-6938","authenticated-orcid":true,"given":"Prabhakaran","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Microbiology &amp; 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