Ferroptosis triggers anti-tumor immunity via promoting chaperone-mediated autophagic degradation of SHP2

Ferroptosis, a form of regulated cell death characterized by iron-dependent lipid peroxidation, plays a significant role in various physiological and pathological processes, including cancer. However, the connection between ferroptosis and anti-tumor immunity remains incompletely understood. Our investigation demonstrates that ferroptosis inducers like RSL3 can enhance the efficacy of anti-PD-1 therapy by activating the STAT1 signaling pathway. Mechanistically, RSL3 activates the tyrosine phosphatase SHP2 in cancer cells and facilitates its degradation through chaperone-mediated autophagy mediated by the KFERQ motif from residues 530 to 534. This enhances cancer cells’ sensitivity to IFN-γ, leading to increased phosphorylation and nuclear translocation of STAT1 and higher expression of major histocompatibility complex class I (MHC I). Consequently, this heightened sensitivity correlates with increased susceptibility to T cell-mediated cytotoxicity. In vivo studies showed that RSL3 treatment reduced SHP2 expression within tumor tissues and bolstered anti-tumor immunotherapy by promoting increased T cell infiltration and function. The combination of RSL3 and anti-PD-1 antibody demonstrates superior therapeutic efficacy in controlling tumor growth compared to monotherapy. Our study not only elucidates a previously unrecognized link between ferroptosis and anti-tumor immunity but also presents a rationale for combining ferroptosis inducers with immune checkpoint inhibitors in cancer treatment.