MCT1-mediated histone lactylation modulates lung cancer cell sensitivity to T-cell–mediated killing by influencing mitochondrial dysfunction.

e20051 Background: Histone lactylation, a newly identified epigenetic modification, has been extensively implicated in the initiation and progression of tumors. However, the precise role of histone lactylation in modulating tumor cell responses to T cell-mediated cytotoxicity remains insufficiently explored. Methods: To elucidate the adaptive changes tumor cells undergo in response to T cell-induced cytotoxicity within the tumor microenvironment (TME), we performed a comprehensive, genome-wide CRISPR-Cas9 screen. This approach facilitated the identification of genetic alterations in lung cancer cells co-cultured with cytotoxic T lymphocytes (CTLs) that promote their evasion of T cell-mediated destruction. Complementary RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) analyses were employed to investigate the molecular mechanisms by which tumor cells modulate their response to T cell-mediated killing, particularly following the deletion of the monocarboxylate transporter 1 (MCT1). Results: MCT1 deletion significantly heightened the cancer-cell susceptibility to CTL-mediated killing. Furthermore, the loss of MCT1 led to mitochondrial dysfunction within the tumor cells. Mechanistically, MCT1 knockout resulted in a reduction of histone H3K18 lactylation and downregulation of ferridoxin reductase (FDXR), which disrupted mitochondrial homeostasis and precipitated mitochondrial dysfunction. Notably, the combination of MCT1 inhibition with immune checkpoint blockade (ICB) therapy substantially enhanced ICB efficacy, prolonged survival in both lung cancer and malignant pleural effusion (MPE) murine models, and alleviated the immunosuppressive milieu within the TME. Conclusions: Our findings reveal a novel role for lactate metabolism in modulating mitochondrial dysfunction and anti-tumor immunity, with lactylation-mediated regulation of mitochondrial homeostasis serving as a critical mechanism. These results provide new insights into the epigenetic regulation of tumorigenesis and highlight potential immune-metabolic strategies for targeted lactate metabolism therapies in the treatment of lung cancer and MPE.