DGAT1 Inhibition Induces Ferroptosis and Enhances Cancer Immunotherapy Efficacy.

Ferroptosis, a form of regulated cell death driven by lipid peroxidation, has emerged as a promising mechanism in cancer therapy. However, the lack of clinically viable ferroptosis inducers has precluded its therapeutic evaluation in patients. In this study, we demonstrated that inhibition of diacylglycerol O-acyltransferase 1 (DGAT1) induces a ferroptosis-like phenotype in cancer cells and enhances the efficacy of immune checkpoint blockade (ICB) therapy. In human cancer cohorts, low DGAT1 expression correlated with improved prognosis and elevated ferroptosis-associated gene signatures. In murine models, both genetic knockout and pharmacologic inhibition of DGAT1 enhanced ICB therapy efficacy by promoting increased infiltration of cytotoxic T lymphocytes. Mechanistically, DGAT1 inhibition reduced lipid droplet accumulation, triggering elevated lipid peroxidation, mitochondrial dysfunction, and reactive oxygen species production. These events culminated in glutathione peroxidase 4 depletion and ferroptosis. Given the availability of clinical-stage DGAT1 inhibitors, these findings provide a strong rationale for repurposing these agents as ferroptosis inducers to improve responses to cancer immunotherapy. SIGNIFICANCE: DGAT1 inhibition promotes ferroptosis by reducing lipid droplet accumulation, increasing lipid peroxidation, and inducing mitochondrial dysfunction, ultimately enhancing sensitivity to immune checkpoint blockade and offering a promising strategy for improving cancer treatment.