PDK3 drives colorectal carcinogenesis and immune evasion and is a therapeutic target for boosting immunotherapy.

Pyruvate Dehydrogenase Kinase 3 (PDK3) has emerged as a significant player in various cancer types, yet its specific impact on cancers including colon cancer remains ambiguous. Through pan-cancer analysis using TCGA data, we found that the expression of and the composition of the immune microenvironment for different tumors were highly heterogeneous across tumors. is highly expressed in colorectal cancer and may promote tumor proliferation by activating PI3K-AKT signaling. In addition, we found that was able to inhibit tumor antigen presentation signals to suppress immune killing. High expression predicts less CD8 T cell infiltration and effector function. Moreover, inhibition of expression bolstered CD8 T cell-mediated cytotoxicity CD8 T cell infiltration and activation in vivo. Notably, was found to facilitate STAT1 activation and elevate programmed death-ligand 1 (PD-L1) expression in colon cancer cells. Importantly, inhibition combination with PD-1 blockade significantly activates the infiltrated CD8 T cells to suppress tumor growth and improves the survival benefit in several murine tumor models. In summary, these findings underscore PDK3's role in fueling colon cancer growth by orchestrating PI3K-AKT signaling and PD-L1 expression and dampening CD8 T cell function.