Disulfide bond-rich Nano-Silica for High-Efficiency cancer immunotherapy using synergistic endoplasmic reticulum stress cooperated mitochondrial dysfunction

Abstract

In emerging cancer immunotherapy, the effectiveness of T lymphocytes is primarily hindered by elevated programmed cell death 1 ligand 1 (PD-L1) expression; simultaneously, the shift of tumor-associated macrophages (TAMs) towards tumorigenic M2-type macrophages further abrogates the efficacy of immunotherapy. Accordingly, we rationally designed a glutathione (GSH) responsive disulfide bond-rich nano-silica (DLC-HA) capable of efficient T cells infiltrating and TAMs re-polarization by encapsulating an endoplasmic reticulum (ER)-targeted photodynamic agent p-Ce6 and the glycolysis inhibitor lonidamine (LND), which works together to provoke ER stress and mitochondrial dysfunction. On the one hand, ER stress causes PD-L1 down-expression through ER-associated degradation (ERAD), while also stimulating the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway. Meanwhile, LND alters mitochondrial dysfunction and activates the AMPK energy pathway, enhancing ER stress and facilitating PD-L1 degradation. On the other hand, ER stress upregulates calreticulin (CRT) expression and mitochondrial dysfunction alleviates hypoxia to downregulate TAMs inhibitory receptor CD47, all of which effectively promotes the phagocytosis and re-polarization of TAMs to anti-tumorigenic M1-type. As expected, this nanoplatform approach, not only activates the immune response of T cells but also facilitates the re-polarization of TAMs in vitro and in vivo assays, offering a novel strategy for efficient cancer immunotherapy using ER stress cooperated mitochondrial dysfunction.