Immunotherapy Inhibits Tumor Cholesterol Synthesis via the IFNγ–IRF1–SREBF2 Axis

Tumor cells employ metabolic mechanisms to limit antitumor immunity and promote resistance to immunotherapy. However, how immunotherapy modulates tumor metabolism remains unclear. In this study, we demonstrated that anti-PD-1 treatment regulated cholesterol biosynthesis in cancer cells through the effector cytokine IFNγ. Mechanistically, IFNγ-induced IRF1 transcriptionally suppresses the expression of SREBF2, a master regulator of cholesterol synthesis. Reduced cholesterol content inhibited tumor growth and sensitized tumor cells to statins, drugs that can lower cholesterol. Overall, our study reveals that IFNγ-mediated inhibition of cholesterol biosynthesis in tumor cells is an important antitumor mechanism of immunotherapy.