MPC-mediated lactate production drives histone lactylation in dendritic cells to affect tumor progression and immunotherapy

Lactate is an abundant oncometabolite in the tumor microenvironment (TME). Lactate driven by metabolic reprogramming leads to acidic microenvironment formation to promote the immune evasion of tumor cells and reduce the effectiveness of immunotherapy for patients with tumors. The expression of mitochondrial pyruvate carrier (MPC) is crucial for pyruvate metabolism, and its dysregulation can lead to the formation of an acidic microenvironment caused by excessive lactic acid. However, the impact of MPC on tumor metabolic processes and biological behavior, as well as how lactate impacts immunosuppression, remains unclear. Here, we found that MPC1 and MPC2, two subunits of MPC, were downregulated in patients with colorectal cancer (CRC). Co-overexpression of MPC1 and MPC2 decreased lactate levels and inhibited cell proliferation, migration and invasion in vitro and tumor growth in vivo in the setting of CRC. Knockdown of MPC1 or MPC2 increased lactate levels and promoted the proliferation, migration and invasion of CRC cells. Mechanistically, the accumulation of lactate promotes the elevation of histone lactylation levels, and MPC regulates the expression of CD33, a marker of dendritic cell (DC) maturation, via histone lactylation, decreasing CD8⁺ T cell functions. In addition, the overexpression of MPC increased the therapeutic effect of the anti-PD-1 antibody. Our findings reveal that MPC downregulation-mediated lactate production impacts DC maturation via histone lactylation-dependent transcriptional regulation to impair CD8⁺ T cell responses, suggesting that targeting MPC could enhance immunotherapy efficacy by modulating the TME.