Improved Immunotherapy for Gastric Cancer by Nanocomposites with Capability of Triggering Dual-Damage of Nuclear/Mitochondrial DNA and Cgas/Sting-Mediated Innate Immunity

Immune checkpoint inhibitors-based cancer immunotherapy is yielding great clinical benefit, but its efficacy is limited in gastric cancer (GC) by the lack of T-cell infiltration in the tumor microenvironment. Notably, activating the DNA-sensitive cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS/STING) signaling pathway could trigger innate immunity and the recruitment of tumor-infiltrating lymphocytes. Herein, we constructed co-loaded platinum nanoparticles (Pt-NPs; chemo-prodrugs) and IR820 (photosensitizer) into hollow mesoporous organosilica nanoparticles (termed as HMON@IR820/Pt-NPs). The HMON@IR820/Pt-NPs exhibit appropriate size distribution, good biocompatibility, and generate reactive oxygen species under mild near infrared irradiation (0.7 W cm -2 ). Importantly, HMON@IR820/Pt-NPs efficiently enter GC cells and release loaded drugs. Pt-NPs can trigger H 2 O 2 decomposition to O 2 , enhancing photodynamic efficiency. Furthermore, IR820 could enter into mitochondria, then induce mitochondria oxidative stress disorder, resulting in the releasing of oxidative mtDNA. Meanwhile, this oxidative process also allowed for oxidation of Pt(0) to cytotoxic Pt(II), resulting in the dysfunction of nDNA. Dual-damage to nDNA and mitoDNA activates the c-GAS/STING pathway, stimulating innate immunity, including a primary anti-tumor effect and recruitment of CD8 + T cells, enhancing cross-presentation inside dendritic cells, and sustaining lethality in distant tumors. In summary, HMON@IR820/Pt-NPs have the potential to improve immunotherapy efficacy in GC.