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Through multiomics-based metabolic subtyping in intrahepatic cholangiocarcinoma, we identified a subgroup with the worst prognosis that demonstrates significant enrichment in both cyclooxygenase\/arachidonic acid (COX\/AA) metabolism and KRAS mutations. Mechanistically, KRAS mutation\u2013mediated NF-\u03baB pathway activation upregulates CXCL5 expression, thereby recruiting CXCR2+ polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) into the TME. Concurrently, KRAS mutation drives prostaglandin E2 (PGE2) production in tumor cells, and PGE2, in turn, enhances AA uptake and COX-2 expression in PMN-MDSCs, establishing an amplifying loop between tumor cells and PMN-MDSCs that exacerbates PGE2 production. PGE2 accumulation potently suppresses the antitumor activity of CD8+ T cells via the prostaglandin E receptor 4 (EP4). Therapeutic targeting of the COX-2\u2013PGE2\u2013EP4 axis, combined with anti\u2013PD-1 immunotherapy, demonstrates profound synergistic efficacy in both KRAS-mutant murine models and patient-derived tumor fragments harboring KRAS mutations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>This work identifies a PGE2\u2013COX-2 positive feedback loop between tumor cells and PMN-MDSCs that may serve as a therapeutic vulnerability for KRAS-mutant cholangiocarcinoma.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-25-1844","type":"journal-article","created":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T12:31:56Z","timestamp":1775651516000},"page":"1903-1923","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Arachidonic Acid Metabolism in PMN-MDSCs Suppresses Antitumor Capacity of T Cells in\n                    <i>KRAS<\/i>\n                    -Mutant Cholangiocarcinoma"],"prefix":"10.1158","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6457-7026","authenticated-orcid":false,"given":"Jian","family":"Lin","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/032x22645","id-type":"ROR","asserted-by":"publisher"}],"name":"Zhongshan Hospital 1 Center for Tumor Diagnosis and Therapy, Jinshan Hospital; Department of Hepatobiliary Surgery and Transplantation, Liver Cancer Institute and State Key Laboratory of Genetics and Development of Complex Phenotypes, , , Shanghai, China."},{"id":[{"id":"https:\/\/ror.org\/013q1eq08","id-type":"ROR","asserted-by":"publisher"}],"name":"Fudan University 1 Center for Tumor Diagnosis and Therapy, Jinshan Hospital; Department of Hepatobiliary Surgery and Transplantation, Liver Cancer Institute and State Key Laboratory of Genetics and Development of Complex Phenotypes, , , Shanghai, 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