DGAT1 Inhibition Induces Ferroptosis and Enhances Cancer Immunotherapy Efficacy

Area of Science:

• Oncology
• Cell Death Mechanisms
• Immunotherapy

Background:

• Ferroptosis, a cell death pathway driven by lipid peroxidation, shows promise in cancer therapy.
• Clinically viable ferroptosis inducers are lacking, hindering therapeutic application.
• Diacylglycerol O-acyltransferase 1 (DGAT1) is a potential target for modulating cell death pathways.

Purpose of the Study:

• To investigate the role of DGAT1 inhibition in inducing ferroptosis.
• To evaluate the impact of DGAT1 inhibition on the efficacy of immune checkpoint blockade (ICB) therapy.
• To elucidate the molecular mechanisms by which DGAT1 inhibition affects cancer cells and immunotherapy.

Main Methods:

• Inhibition of DGAT1 using genetic and pharmacological approaches in cancer cell lines and murine models.
• Assessment of ferroptosis markers, including lipid peroxidation, mitochondrial dysfunction, and reactive oxygen species (ROS) production.
• Evaluation of ICB therapy efficacy, including tumor growth, immune cell infiltration (cytotoxic T lymphocytes - CTLs), and patient data analysis.

Main Results:

• DGAT1 inhibition induced a ferroptosis-like phenotype in cancer cells.
• Low DGAT1 expression in human cancer cohorts correlated with better prognosis and increased ferroptosis gene signatures.
• DGAT1 inhibition enhanced ICB therapy efficacy in murine models by increasing CTL infiltration.
• Mechanistically, DGAT1 inhibition reduced lipid droplet accumulation, leading to increased lipid peroxidation, mitochondrial dysfunction, ROS production, and subsequent GPX4 depletion and ferroptosis.

Conclusions:

• DGAT1 inhibition is a viable strategy to induce ferroptosis in cancer cells.
• Repurposing clinical-stage DGAT1 inhibitors could enhance cancer immunotherapy responses.
• Targeting DGAT1 offers a novel therapeutic approach for improving cancer treatment outcomes, particularly in combination with ICB therapy.