Mild photothermal treatment sensitized immune checkpoint blockade therapy based on ATP-exhausted nanoenzymes

•ATP-exhausted nanozymes are constructed for mild photothermal therapy.•The therapeutic mechanism relies on oxidative damage to mitochondria.•Nitric oxide impairs mitochondria protective autophagy caused by external stimuli.•Mild photothermal therapy can sensitized immune checkpoint blockade therapy. Despite the clinical success of immune checkpoint blockade (ICB) therapies, overcoming immunologically “cold” tumors remains challenging. Photothermal therapy (PTT) has been proven to boost the immunogenicity of the tumor for facilitating ICB therapy. Further, improving the immunosuppressive “cold” tumor microenvironment (TME) by safer mild PTT (mPTT) with low temperature is more preferable for clinical applications. Herein, a hollow structured Mo-doped Cu9S5 (CuMo) nanozyme loaded with GSH-responsive nitric oxide (NO) donors (sodium nitroprusside, SNP), abbreviated as CuMo-SNP, are constructed for boosting immune response by mPTT. The CuMo-SNP possess photothermal and glutathione oxidase/peroxidase-like enzymatic activities, which lead to reactive oxygen species (ROS) generation and enhance intracellular oxidative stress towards mitochondria. Meanwhile, the continuously generated NO by GSH-responsive SNP impairs mitochondria protective autophagy to recover the ROS-induced oxidative damage for mitochondria, leading to effectively block of ATP production. The limited ATP level can restrain the synthesis of intracellular heat stress induced heat shock proteins (HSPs), thus achieving enhanced therapeutic effect of mPTT upon 1064 nm laser irradiation. After combined with immune checkpoint inhibitor anti-PD-L1 (αPD-L1) antibody, ATP-exhausted CuMo-SNP mediated mPTT can intensify the recruitment of tumor-infiltrating lymphocytes to reprogram the “cold” TME, sensitizing the tumor to ICB therapy.