Ferroptosis in the tumor microenvironment: perspectives for immunotherapy

Different immune cells in the TME display distinct sensitivities to ferroptosis. Ferroptosis is a metabolic vulnerability of activated CD8+ T cells, while inhibition of ferroptosis can promote the survival and antitumor effects of CD8+ T cells in tumors. In tumors with different immunophenotypes, ferroptosis inducers might have distinct impacts on cancer immunity, which may determine the efficacy of immune checkpoint inhibitor immunotherapy. Targeting ferroptosis, which provokes lipid peroxidation in cancer cells, presents potentially new avenues for anticancer therapy. Recent studies have begun to explore how immune cells in the tumor microenvironment (TME) respond and adapt to lethal lipid peroxides (LPOs). A better understanding of this process in the TME is likely to uncover another side of ferroptosis in cancer immunity and promote the development of ferroptosis-targeted therapy. This Opinion article overviews the main metabolic processes in ferroptosis, summarizes the emerging roles of ferroptosis not only in immune cells in the TME but also in the crosstalk between tumor cells and immune cells, and presents a perspective on the targeting of ferroptosis in cancer immunotherapy. Targeting ferroptosis, which provokes lipid peroxidation in cancer cells, presents potentially new avenues for anticancer therapy. Recent studies have begun to explore how immune cells in the tumor microenvironment (TME) respond and adapt to lethal lipid peroxides (LPOs). A better understanding of this process in the TME is likely to uncover another side of ferroptosis in cancer immunity and promote the development of ferroptosis-targeted therapy. This Opinion article overviews the main metabolic processes in ferroptosis, summarizes the emerging roles of ferroptosis not only in immune cells in the TME but also in the crosstalk between tumor cells and immune cells, and presents a perspective on the targeting of ferroptosis in cancer immunotherapy. a PL hydroperoxide, generated by the dioxygenation of AA in phosphatidylethanolamine (PE). one of the most abundant but at the same time the PUFA most susceptible to lipid peroxidation in human cells. critical mediators of antitumor immunity; activated on the detection of tumor-specific antigens. a scavenger receptor that functions as a translocase, binding long-chain fatty acids and facilitating their transport into cells. also known as alarmins; molecules released by stressed cells undergoing necrosis that function as ‘find-me’ (attractant), ‘eat-me’ (engulfment), or ‘danger’ (activation) signals for the recruitment and activation of effector immune cells and exacerbate the inflammatory response. the major enzyme against ferroptosis that detoxifies LPOs, even when they are inserted into membranes. a tripeptide antioxidant that serves as a cofactor for GPX4 to reduce LPOs. monoclonal antibodies that target inhibitory immune checkpoints [e.g., PD-1, cytotoxic lymphocyte antigen 4 (CTLA-4)] to reactivate tumor-specific CD8+ T cells with functional defects due to the presence of immune checkpoint signaling. produces NO, an important inflammatory and tumoricidal mediator in macrophages. enzymes that catalyze the dioxygenation of free and esterified PUFAs to generate various lipid hydroperoxides. a major oxidative metabolite of AA through the action of the COX pathway and a well-known immunosuppressive factor. comprises the heterodimers SLC7A11 and SLC3A2 responsible for importing extracellular cystine in exchange for intracellular glutamate. one of the most abundant immune cells in the TME. TAMs can polarize into the antitumor M1 phenotype and the tumor-promoting M2 phenotype in response to different stimuli. a complex biological network whose diverse components, including tumor cells, mesenchymal cells, immune cells, and the surrounding matrix, influence the hallmarks and fates of tumor cells. the endoplasmic reticulum (ER) stress response transcription factor that activates unfolded protein response (UPR) target genes via direct binding to the UPR element.