Arachidonic Acid Metabolism in PMN-MDSCs Suppresses Antitumor Capacity of T cells in KRAS-Mutant Cholangiocarcinoma.

Metabolic reprogramming within the tumor microenvironment impairs antitumor immunity and compromises the efficacy of immunotherapy. Through multi-omics-based metabolic subtyping in intrahepatic cholangiocarcinoma (iCCA), 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-mediated NF-κB pathway activation upregulates CXCL5 expression, thereby recruiting CXCR2+ polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) into the tumor microenvironment. Concurrently, KRAS mutation drives prostaglandin E2 (PGE2) production in tumor cells, and PGE2 in turn enhances arachidonic acid 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 prostaglandin E receptor 4 (EP4). Therapeutic targeting of the COX-2-PGE2-EP4 axis, combined with anti-PD-1 immunotherapy, demonstrates profound synergistic efficacy in both KRAS-mutant murine models and patient-derived tumor fragments harboring KRAS mutations.