MCT4-mediated lactate efflux promotes STING-dependent dendritic cell antitumor immunity.

The mechanisms by which DCs evolutionarily adapt to lactate accumulation to maintain their functions remain largely elusive. Here, our study highlights the MCT4-lactate axis as an intrinsic metabolic checkpoint governing intratumoral DC activity. Intratumoral lactate supplementation impedes DC-dependent antitumor activity. Additionally, we observe that MCT4 is highly expressed in intratumoral DCs and mediates lactate efflux to boost DC function. Pharmacological or genetic inhibition of MCT4 suppresses DC antitumor responses. Mechanistically, MCT4-controlled lactate efflux sustains STING signaling and STING-dependent antitumor immunity. Loss of MCT4 in DCs augments lactate accumulation, subsequently reducing intracellular pH and disrupting the interaction between G3BP1 and cGAS, ultimately leading to impaired dsDNA sensing by cGAS. Importantly, the MCT4-lactate axis supports STING-dependent DC activity in ccRCC patient samples. Our findings uncover how intratumoral DCs adapt to lactate and suggest that targeting the MCT4-lactate axis represents a promising cancer immunotherapy strategy.