Photothermal therapy triggering organelle stress and metabolic reprogramming to potentiate antitumor immunity

Metabolic reprogramming is a hallmark of malignant tumors, providing tumor cells with energy and promoting immune escape through changes in glucose, lipid, and amino acid metabolism. Photothermal therapy (PTT) not only eliminates tumor cells through localized hyperthermia but also disrupts metabolic networks. However, the mechanisms by which PTT-induced metabolic perturbation engages antitumor immunity remain a considerable challenge. This review proposes that PTT interferes with tumor metabolism through organelle stress and synergizes with exogenous drugs to enhance metabolic perturbation, thereby eliciting a potent antitumor immune response. We first detail how hyperthermia and ROS induced by PTT damage organelles, leading to organelle stress, including mitochondrial depolarization, endoplasmic reticulum (ER) proteotoxicity, cytosolic enzyme denaturation, and nucleolar stress. Critically, stressed organelles release immunogenic signals, activating the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway to trigger innate immune recognition, and regulating the functions of CD8⁺ T cells and macrophages through metabolites in the tumor microenvironment (TME). We also discuss how tumor cells activate adaptive responses, such as heat shock protein (HSP) upregulation and metabolic switching, to resist sublethal thermal stress, and evaluate synergistic strategies designed to amplify organelle stress and overcome thermotolerance. Finally, we focus on the latest advancements in overcoming tumor heterogeneity and advancing the clinical translation of targeted organelle PTT nanoplatforms. It is expected to elucidate the mechanism by which organelle stress in PTT causes metabolic perturbation, the tumor adaptive response, and its impact on tumor immunity, providing innovative ideas and references for the development of metabolic and tumor combined treatment strategies based on PTT.