Selective induction of mitochondrial fragmentation for cancer immunotherapy via mtDNA-Targeting AIE photosensitizer.

Abstract

Mitochondrial damage in tumor cells has recently emerged as a mechanism of immunogenic cell death, with precise triggers acting as potent antitumor immunostimulants. Here, we developed PyTPAMa, an asymmetric AIE-active photosensitizer that selectively accumulates in mitochondria and binds mitochondrial DNA (mtDNA) and induces mitochondrial fragmentation to trigger strong immunostimulation. Upon light activation, PyTPAMa generates a spatially confined, hybrid Type I/II ROS burst that disrupts the mitochondrial network, causing mitochondrial fragmentation, opening the mitochondrial permeability transition pore, and releasing mtDNA into the cytosol. This activates the NLRP3-GSDMD inflammasome, initiating pyroptosis and orchestrating systemic antitumor immunity. RNA sequencing reveals widespread silencing of mitochondrial genes and reprogramming of the NLRP3 inflammasome and antigen-presentation pathways. As a programmable immune ignition switch, PyTPAMa induces immunogenic cell death in vitro, transforms distant "cold" tumors into immune-infiltrated lesions in vivo, and achieves 96% suppression of bilateral 4T1 tumors without systemic toxicity. This work establishes mitochondrial fragmentation as a programmable immune switch and validates PyTPAMa for fragmentation-driven cancer immunotherapy.