Metabolic–epigenetic rewiring driven by MCT4-mediated lactate export contributes to resistance to PD-1 blockade in NSCLC

Abstract

Resistance to PD-1 blockade remains a major obstacle in non-small cell lung cancer (NSCLC) treatment. To understand the molecular mechanisms underlying immunotherapy resistance, we performed integrative transcriptomic and proteomic analyses of clinical tumor samples from immunotherapy responders and nonresponders. Tumors from nonresponders exhibited increased glycolytic activity and expression of the lactate transporter MCT4, which correlated with reduced CD8⁺ T-cell infiltration and unfavorable clinical outcomes. In highly glycolytic NSCLC cell models, MCT4 deficiency not only restored CD8⁺ T-cell proliferation and effector function but also induced tumor-intrinsic mitochondrial stress, characterized by increased reactive oxygen species levels, reduced ATP production, and loss of mitochondrial membrane potential, ultimately leading to G2/M cell cycle arrest. Mechanistically, MCT4 deficiency activated the EHMT2/H3K9me3 axis, resulting in the transcriptional repression of genes that govern cell cycle progression. Importantly, pharmacological inhibition of MCT4 produced comparable effects. Collectively, these findings indicate that the lactate transporter MCT4 suppresses antitumor immunity and that targeting MCT4 represents a promising strategy to overcome immunotherapy resistance in patients with highly glycolytic NSCLC.