During cancer immunoediting, cancer cells deregulate cell death executioner mechanisms to escape immunotherapy-induced antitumor immunity. Ferroptosis, a type of regulated necrosis triggered by lipid peroxidation, plays a pivotal role in the anti-tumor activity of T cell-based immunotherapies; however, mechanisms for the modulation of ferroptosis in immune-refractory tumor cells are unclear. In this study, using preclinical models of immune refractory tumors obtained following the course of immunoediting by PD-1 blockade and adoptive T cell therapy (ACT), we find that T cell-based immunotherapy drives the development of ferroptosis resistance of tumor cells. In this process, E2F1 is upregulated by immunotherapy and it in turn binds to the promoter of the HMGCR gene to upregulate HMGCR, thereby contributing to the resistance to ferroptosis. Notably, HMGCR inhibition renders immune-refractory tumor cells susceptible to ACT and PD-1 blockade. Thus, our results reveal a mechanism by which cancer cells modulate ferroptosis to acquire resistance to immunotherapy and implicate the E2F1-HMGCR axis as a central molecular target for controlling ferroptosis resistance of immune-refractory cancer.
© 2025. The Author(s).