Friend or Foe? The Dual Role of Ferroptosis in Tumor Immunity and Immunotherapy.

Abstract

Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, plays a context-dependent dual role in tumor immunity and immunotherapy. On one hand, it can act as an immunogenic cell death mechanism, releasing damage-associated molecular patterns that activate dendritic cells and promote T cell priming. On the other hand, ferroptosis may suppress antitumor immunity by triggering death or dysfunction in key immune cells, including T lymphocytes, dendritic cells, and macrophages. This review synthesizes current insights into the molecular determinants of ferroptosis sensitivity within the tumor microenvironment. It examines how immune cells can induce ferroptosis in cancer cells, and how tumors evolve resistance through upregulation of proteins like GPX4 and FSP1 or metabolic rewiring. The interplay between ferroptosis and immunity offers promising therapeutic avenues, such as combining ferroptosis inducers with immune checkpoint inhibitors or employing nanotechnology for targeted delivery. However, the net immunogenic outcome depends on temporal, cellular, and microenvironmental factors. Future strategies must aim to selectively induce immunogenic ferroptosis in tumors while preserving immune cell function, leveraging biomarkers and microenvironment modulation to optimize combination therapies in cancer immunotherapy.