Photoactivated Self‐Assembled Nanomicelles Integrating Mitophagy Inhibition to Enhance Pyroptosis for Cancer Immunotherapy

Abstract

Multimodal therapy often demonstrates superior therapeutic effects compared to monotherapy. Phototherapy is a promising approach for cancer treatment, as it can induce tumor pyroptosis and activate antitumor immune responses. However, mitochondrial oxidative stress during pyroptosis frequently stimulates protective autophagy in tumor cells, thereby seriously impeding the progress of pyroptosis. Therefore, developing a therapeutic approach that enhances pyroptosis through inhibiting autophagy is critical for improving tumor treatment efficacy. In this study, a photoactivated mitochondrial‐targeting self‐assembled nanomicelle ( 3M@C ) that integrates an aggregation‐induced emission photosensitizer and the autophagy inhibitor chloroquine is designed. 3M@C can generate both type I and type II reactive oxygen species and heat under light exposure, inducing mitochondrial dysfunction and triggering pyroptosis, thereby achieving photodynamic synergistic photothermal therapy. Meanwhile, 3M@C can inhibit mitophagy, further enhance pyroptosis effects, and activate antitumor immune responses. In vivo experiments demonstrate that this synergistic therapeutic strategy exhibits excellent biosafety and significant antitumor efficacy, effectively suppressing tumor growth. In addition, this method of photoactivated self‐assembled nanomicelles integrates mitophagy inhibition to enhance pyroptosis, providing a promising strategy for novel tumor photoimmunotherapy.