Induced Ferroptosis Pathway by Regulating Cellular Lipid Peroxidation With Peroxynitrite Generator for Reversing “Cold” Tumors

Abstract Overcoming the resistance of tumor cells to apoptosis and immunosuppression is an important challenge to improve tumor immunotherapy. Non‐apoptotic death mode of ferroptosis has been regarded as a new strategy to enhance tumor immunotherapy against drug‐resistant cancers. The lethal accumulation of lipid peroxides (LPO) determines the progress of ferroptosis. The high susceptibleness of ferroptosis provides an opportunity for combating triple‐negative breast cancer. Reactive nitrogen species (RNS) produced by nitric oxide (NO) and reactive oxygen species (ROS) is more lethal than ROS for tumor cells. Herein, an RNS‐mediated immunotherapy strategy for inducing ferroptosis pathway is proposed by improving LPO accumulation, and constructed a multifunctional liposome (Lipo‐MT‐SNAP) comprised of peroxynitrite (ONOO ⁻ ) generator, tumor targeted group, inhibiting glutathione peroxidase 4 (GPX4), and basic units (dipalmitoyl phosphatidylcholine and cholesterol). The significant enhancement of LPO resulted from the intense oxidative damage of ONOO ⁻ impaired synthesis of GPX4 by depleting glutathione, which further amplified ferroptosis and triggered immunogenic cell death. In vivo, RNS‐mediated photoimmunotherapy can promote polarization of M2 to M1 macrophages and dendritic cells maturation, further infiltrate T cells, regulate the secretion of inflammatory factors, and reprogram the tumor microenvironment. The powerful RNS‐mediated ferroptosis induces strong immunogenicity and effectively inhibit tumor proliferation.