Ferroptosis Induction by DGAT1 Inhibition Enhances Cancer Immunotherapy

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. Here, we demonstrate 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 pharmacological inhibition of DGAT1 enhanced ICB therapy efficacy by promoting increased infiltration of cytotoxic T lymphocytes (CTLs). Mechanistically, DGAT1 inhibition reduced lipid droplet (LD) accumulation, triggering elevated lipid peroxidation, mitochondrial dysfunction, and reactive oxygen species (ROS) production. These events culminated in glutathione peroxidase 4 (GPX4) depletion and ferroptosis. Given the availability of clinical-stage DGAT1 inhibitors, our findings provide a strong rationale for repurposing these agents as ferroptosis inducers to enhance cancer immunotherapy. Overall design: To investigate the mechanisms underlying the enhanced antitumor effects of DGAT1 deficiency in combination with immune checkpoint blockade (ICB) therapy, we examined the tumor immune microenvironment (TIME) in DGAT1-deficient tumors. CD45? immune cells were isolated from subcutaneously implanted control and DGAT1-knockout (KO) B16F10 tumors and subjected to single-cell RNA sequencing (scRNA-seq).