Enhancement of ferroptosis in escape variant tumor cells by IFN-γ derived from antigen-specific T cells controls tumor with heterogeneity.

Authors

Daisuke Ehara, Kiyoshi Yasui, Mitsuhiro Yoneda, Daisuke Muraoka, Situo Deng, Pengyu Miao, Chenxu Jiang, Huimin Sun, Sachiko Okamoto, Yasunori Amaishi, Hiroyuki Murota, Hiroaki Ikeda

Published in

Cancer immunology research. Jul 03, 2026. Epub Jul 03, 2026.

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 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.

PMID:
42397036
Bibliographic data and abstract were imported from PubMed on 03 Jul 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.