Mitochondria-associated ER stress evokes immunogenic cell death through the ROS-PERK-eIF2? pathway under PTT/CDT combined therapy

Chemodynamic therapy (CDT) can effectively induce immunogenic cell death (ICD) in tumours and is thus a promising strategy for boosting the efficacy of immunotherapy. However, the mechanism by which CDT enhances ICD and lowers ICD efficiency is unknown and this restricts its clinical application. In this study, a second near-infrared (NIR-II) window irradiation-triggered hydrogen peroxide (H 2 O 2 ) selfsupplying nanocomposite ((Cu 2 Se-CaO 2 )@LA) was constructed. The modified lauric acid was melted by the heat energy of the NIR-II irradiation, to expose the CaO 2 nanoparticles, and they then reacted with water to produce H 2 O 2 and Ca 2 + . H 2 O 2 was then converted to hydroxyl radicals by the photothermalenhanced CDT process of the Cu 2 Se nanocubes. Notably, the CDT and Ca 2 + overload was found to induce sequential damage to the mitochondria and endoplasmic reticulum (ER), which upregulated the PERKmediated eIF2 alpha phosphorylation pathway and caused subsequent ICD. NIR-II irradiation of the (Cu 2 SeCaO 2 )@LA also increased reactive oxygen species (ROS) formation and this was sufficient to increase dendritic cell maturation, attracting cytotoxic T lymphocytes, and suppressing tumour growth in vivo. Overall, we demonstrated that an enhanced CDT strategy under NIR-II exposure and H 2 O 2 self-supply can induce extensive ICD by inducing mitochondria-associated ER stress, which represents a highly effective and promising strategy for ICD amplification and tumour immunotherapy.