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

Area of Science:

• Immunology
• Metabolic pathways
• Cancer research

Background:

• Dendritic cells (DCs) are vital for anti-tumor immunity.
• Lactate accumulation in tumors can impair DC function.
• Mechanisms of DC adaptation to lactate remain unclear.

Purpose of the Study:

• To investigate the role of the MCT4-lactate axis in regulating intratumoral DC activity.
• To elucidate the molecular mechanisms by which DCs adapt to lactate.
• To explore the therapeutic potential of targeting the MCT4-lactate axis in cancer immunotherapy.

Main Methods:

• Analysis of MCT4 expression in intratumoral DCs.
• Pharmacological and genetic inhibition of MCT4.
• Assessment of STING signaling and G3BP1-cGAS interaction.
• Evaluation of DC-dependent anti-tumor responses in vitro and in ccRCC patient samples.

Main Results:

• MCT4 is highly expressed in intratumoral DCs and mediates lactate efflux, boosting DC function.
• Inhibition of MCT4 suppresses DC anti-tumor activity and STING signaling.
• Loss of MCT4 leads to lactate accumulation, reduced intracellular pH, and impaired cGAS-STING pathway activation.
• The MCT4-lactate axis supports STING-dependent DC activity in ccRCC patient samples.

Conclusions:

• The MCT4-lactate axis acts as an intrinsic metabolic checkpoint for intratumoral DC function.
• Targeting the MCT4-lactate axis can enhance DC-mediated anti-tumor immunity.
• This axis represents a promising strategy for cancer immunotherapy.