VCP downstream metabolite glycerol-3-phosphate (G3P) inhibits CD8T cells function in the HCC microenvironment.

CD8T cells within the tumor microenvironment (TME) are often functionally impaired, which limits their ability to mount effective anti-tumor responses. However, the molecular mechanisms behind this dysfunction remain incompletely understood. Here, we identified valosin-containing protein (VCP) as a key regulator of CD8T cells suppression in hepatocellular carcinoma (HCC). Our findings reveal that VCP suppresses the activation, expansion, and cytotoxic capacity of CD8T cells both in vitro and in vivo, significantly contributing to the immunosuppressive nature of the TME. Mechanistically, VCP stabilizes the expression of glycerol-3-phosphate dehydrogenase 1-like protein (GPD1L), leading to the accumulation of glycerol-3-phosphate (G3P), a downstream metabolite of GPD1L. The accumulated G3P diffuses into the TME and directly interacts with SRC-family tyrosine kinase LCK, a critical component of the T-cell receptor (TCR) signaling pathway in CD8T cells. This interaction heightens the phosphorylation of Tyr505, a key inhibitory residue, ultimately reducing LCK activity and impairing downstream TCR signaling. Consequently, CD8T cells lose their functional capacity, diminishing their ability to fight against HCC. Importantly, we demonstrated that targeting VCP in combination with anti-PD1 therapy significantly suppresses HCC tumor growth and restores the anti-tumor function of CD8T cells, suggesting synergistic therapeutic potential. These findings highlight a previously unrecognized mechanism involving VCP and G3P in suppressing T-cell-mediated immunity in the TME, positioning VCP as a promising upstream target for enhancing immunotherapy in HCC.