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

Rui Ding1, Yaqing Yuan2, Tongchang Xu2

  • 1Department of Immunology, Key Laboratory of Immune Microenvironment and Disease, The School of Basic Medicine, Nanjing Medical University, Nanjing 211166, Jiangsu Province, China; Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.

Cell Reports
|August 1, 2026
PubMed

Insights

Dendritic cells (DCs) adapt to lactate via the MCT4-lactate axis, a metabolic checkpoint crucial for antitumor immunity. Targeting this axis enhances DC function and STING signaling, offering a novel cancer immunotherapy strategy.

Area of Science:

  • Immunology
  • Metabolic pathways
  • Cancer research

Background:

  • Dendritic cells (DCs) are vital for initiating antitumor immune responses.
  • Lactate accumulation in the tumor microenvironment can impair DC function.
  • Mechanisms of DC adaptation to lactate remain poorly understood.

Purpose of the Study:

  • To elucidate the role of the MCT4-lactate axis in regulating intratumoral DC activity.
  • To investigate the impact of MCT4 on DC-dependent antitumor immunity.
  • To explore the potential of targeting the MCT4-lactate axis for cancer immunotherapy.

Main Methods:

  • Analysis of MCT4 expression in intratumoral DCs.
  • Pharmacological and genetic inhibition of MCT4.
  • Assessment of STING signaling pathway activation.
  • Evaluation of DC-mediated antitumor responses in vitro and in ccRCC patient samples.

Main Results:

  • MCT4 is highly expressed in intratumoral DCs and mediates lactate efflux, enhancing DC function.
  • Inhibition of MCT4 suppresses DC antitumor activity and STING signaling.
  • Loss of MCT4 leads to lactate accumulation, reduced intracellular pH, and impaired cGAS-G3BP1 interaction, hindering dsDNA sensing.
  • 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.
  • MCT4-mediated lactate efflux is essential for sustaining STING signaling and antitumor immunity.
  • Targeting the MCT4-lactate axis is a promising strategy for enhancing cancer immunotherapy.
Keywords:
CP: cancerCP: immunologyMCT4antitumor immunitycGAS-STINGdendritic cellslactate

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