Enhancement of Ferroptosis in Escape Variant Tumor Cells by IFNγ Derived from Antigen-Specific T Cells Controls Tumor with Heterogeneity

Abstract Tumor masses often exhibit heterogeneity, including escape variant clones that lack antigen-presenting machinery and/or tumor antigens, which poses a major challenge to immunotherapy. Ferroptosis, a form of regulated cell death driven by iron-dependent lipid peroxidation, has been shown to effectively induce cell death in various tumor cells. Recent studies have reported that IFNγ suppresses the expression of system Xc−, thereby enhancing the induction of ferroptosis. Based on this, we hypothesized that combining immunotherapy with ferroptosis inducers could enhance antitumor effects against both antigen-positive and antigen-negative tumor cells. We found that combining RSL3, a ferroptosis inducer, with MART-1–specific T-cell receptor–engineered T cells eradicates a heterogeneous tumor model consisting of human melanoma cells and their β2-microglobulin knockout counterparts. In NOD.Cg-PrkdcscidIl2rgtm1Sug/ShiJic mice, this combination therapy demonstrates a significant antitumor effect against tumors with heterogeneity. These findings suggest that integrating ferroptosis inducers with immunotherapy could overcome the limitations imposed by escape-variant tumor clones, offering a promising strategy for cancer treatment.