Jian Lin, Chen Sang, Bin Xiang, X Y Shen, Junmei Zhao, Shengshi Xu, Jiaomeng Pan, Youpei Lin, Liangqing Dong, Qianqian Chu, Guoming Shi, Jian Zhou, Jia Fan, M. Q. Zhang, Qiang Gao
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.