Ferroptosis and immunotherapy: Breaking barriers in cancer treatment resistance

Cancer treatment has been revolutionized by immunotherapy; however, its efficacy is often hindered by intrinsic or acquired resistance mechanisms within the tumor microenvironment. Ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, has recently emerged as a potent strategy to overcome these therapeutic barriers. This review explores the dynamic interplay between ferroptosis and immune responses, highlighting how ferroptosis modulates macrophage polarization, T cell activity, and cytokine signaling to reshape the immunosuppressive tumor milieu. The induction of ferroptosis enhances tumor immunogenicity, facilitates T cell infiltration, and sensitizes resistant cancer cells to immune checkpoint inhibitors, CAR T-cell therapy, and monoclonal antibodies. Additionally, targeting ferroptosis pathways disrupts immune escape mechanisms mediated by regulatory T cells and myeloid-derived suppressor cells, further augmenting immunotherapeutic outcomes. By dissecting the molecular and metabolic underpinnings of ferroptosis and its integration with immune strategies, this article underscores its potential to overcome cancer immunotherapy resistance and pave the way for innovative combinatorial treatments.