Augmenting cGAS/STING-mediated innate immunity by copper-based nanoplatform for synergistic cancer immunotherapy via inducing irreversible DNA damage.

Activation of cGAS/STING signaling pathway has emerged as an attractive therapeutic strategy to enhance cancer immunotherapy efficacy. Actually, endogenous damaged double-stranded DNA (dsDNA) can intrinsically activate this pathway, but tumor resistance often arises through extensive DNA repair mechanisms. To overcome this challenge, we firstly developed ataxia telangiectasia mutated inhibitor (ATMi) loaded hollow-structured CuS nanoparticles with in situ surface growth of platinum nanoparticles (Pt-NPs; chemo-prodrugs), termed as HCuS@Pt@ATMi (HCuSPtA). Upon cellular internalization, the HCuS NPs mediate photothermal/photodynamic therapy (PTT/PDT), combined with ROS-activated Pt-NPs exert chemotherapeutic effects, synergistically inducing dsDNA damage in both nuclear and mitochondrial genomes. Crucially, the released ATMi disrupts DNA repair system through prohibiting the cell cycle checkpoint activation, leading to the accumulation of damaged dsDNA. These irreversible damaged dsDNA fragments not only activate the cGAS/STING pathway, but also serve as immunogenic damage-associated molecular patterns (DAMPs), promoting dendritic cell cross-presentation upon extracellular release. In vivo studies confirmed significant cytotoxic T lymphocyte infiltration and superior anti-tumor efficacy. By inducing dysfunctional DNA repair system to achieve irreversible dsDNA damage, this work provides a novel approach to augment cGAS/STING-mediated innate immunity, advancing combinatorial strategies for cancer immunotherapy.