2026/07/03 by Daisuke Ehara, Kiyoshi Yasui, Mitsuhiro Yoneda +9 · 1 voice
Immunology and Microbiology · Medicine · #Cancer Immunotherapy and Biomarkers #Ferroptosis and cancer prognosis #Immune cells in cancer
paper · doi:10.1158/2326-6066.cir-25-0175
openalex publication_date 2026/07/03 · openalex created_date 2026/07/04 · openalex updated_date 2026/07/04
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 IFN-γ 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 TCR-T cells eradicates a heterogeneous tumor model consisting of human melanoma cells and their β2 microglobulin knockout counterparts. In NOG 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.