Targeting DGKα/PA axis inhibits tumor immune evasion and augments sensitivity to immunotherapy in gastrointestinal cancers.

Immune checkpoint inhibitors (ICIs) have shown promising antitumor efficacy in certain types of solid tumors. However, the efficacy of ICIs remains unsatisfactory owing to the dysregulation of signaling pathways in local tumor tissues. Here, we reveal that diacylglycerol kinase α (DGKα)-derived phosphatidic acid (PA) directly binds to nuclear factor-κB (NF-κB) and enhances the transcriptional activity of NF-κB to increase the expression of programmed cell death 1-ligand 1 (PD-L1) and facilitate the immune evasion of tumor cells and orchestrate immune microenvironment. Inhibition of DGKα activity decreases the intratumoral PD-L1 level and induces cytotoxic T lymphocytes (CTLs) infiltration and resultantly enhances the antitumor efficacy of ICIs. Plasma PA can function as a biomarker to evaluate the efficacy of ICIs in gastrointestinal cancers. Overall, our results identify the DGKα/PA axis as a metabolic driver of immune evasion and CTLs exclusion, representing a promising target to enhance ICIs' efficacy in gastrointestinal cancer treatments.