Firing up “cold” tumors: Ferroptosis causes immune activation by improving T cell infiltration
Xinru Li, Yawen Li, Halahati Tuerxun, Yixin Zhao, Yixin Zhao, Xingyu Liu, Yuguang Zhao, Yuguang Zhao
Abstract
Immune checkpoint blocking (ICB), a tumor treatment based on the mechanism of T-cell activation, has shown high efficacy in clinical trials, but not all patients benefit from it. Immune checkpoint inhibitors (ICIs) do not respond to cold tumors that lack effective T-cell infiltration but respond well to hot tumors with sufficient T-cell infiltration. How to convert an unresponsive cold tumor into a responsive hot tumor is an important topic in cancer immunotherapy. Ferroptosis, a newly discovered immunogenic cell death (ICD) form, has great potential in cancer therapy. In the process of deeply understanding the mechanism of cold tumor formation, it was found that ferroptosis showed a powerful immune-activating effect by improving T-cell infiltration, and the combination of ICB therapy significantly enhanced the anti-tumor efficacy. This paper reviews the complex relationship between T cells and ferroptosis, as well as summarizes the various mechanisms by which ferroptosis enhances T cell infiltration: reactivation of T cells and reversal of immunosuppressive tumor microenvironment (TME), as well as recent advances of ICI in combination with targeted ferroptosis therapies, which provides guidance for better improving the ICB efficacy of cold tumors. • Defects in the cancer-immune cycle lead to the formation of a cold tumor immunophenotype. • Immunogenic ferroptosis promotes T cell priming. • Targeting immunosuppressive cells ferroptosis in the tumor microenvironment improves T cell infiltration. • Recently, many new drugs targeting ferroptosis have been developed, and their combination with ICIs has shown strong anti-tumor efficacy, reflecting the great potential of ferroptosis in ICB therapy.