Tumor cell ferroptosis in antitumor immunity and immunotherapy efficacy

Cancer immunotherapy, particularly immune checkpoint blockade (ICB), has represented a major advancement for the treatment of various cancers. Though ICB has been an effective tool in the clinical management of patients, a significant subset of individuals do not respond clinically. This observation has motivated deeper investigations into the mechanisms of efficacy versus resistance to ICB. Of these, tumor cell-intrinsic mechanisms, such as the activation of immune regulatory oncogene pathways or immune selection for antigen-loss variants, have been a promising focus of study. Recent evidence has emerged that ferroptosis, a tumor cell-intrinsic cell death pathway, plays an important role in CD8⁺ T cell-mediated tumor cell killing, and that some resistant tumors have lost sensitivity to this process. Ferroptosis is an iron-dependent mechanism of cell death that is mediated by the peroxidation of lipids. Tumor cell-intrinsic regulators govern ferroptosis sensitivity and, in turn, can influence the success of immune-mediated tumor control. Here, we discuss the growing understanding of regulation of ferroptosis and examine the complex interplay between tumor cell-intrinsic ferroptosis pathways and the host immune response, with an emphasis on how ferroptosis might be leveraged to potentiate immunotherapy efficacy.