A Photon‐Driven Unimolecular Immunostimulant for Self‐Amplified Pyroptosis and cGAS‐STING Pathway by Destroying the Pyroptosis Checkpoint

Abstract

AbstractImmunotherapy is a groundbreaking approach for clinically treating tumors, but its effectiveness is hindered by the tumor's immunosuppressive environment and lack of immune cell infiltration, enabling tumors to evade the immune system. Although the activation of both innate and adaptive immunities is a promising strategy to counteract this bottleneck, their synergy remains challenging. Therefore, we developed Bio‐Cy, an unprecedented organic unimolecular photosensitive immunostimulant, which stimulates self‐amplifying pyroptosis and cGAS‐STING pathways by disrupting pyroptosis checkpoints to enhance adaptive and innate immunity activation. Mechanistic studies have shown that Bio‐Cy can target cancer cells and be transported to lysosomes via endocytosis, generating reactive oxygen species through a Type I photodynamic mechanism to destroy cancer cells, even under hypoxic conditions. Interestingly, this lysosomal disruption not only activates the caspase‐3/GSDME‐dependent pyroptosis of adaptive immunity through mitochondrial damage by releasing Ca2+, but also enhances the cGAS‐STING innate immune pathway by releasing mitochondrial DNA. More importantly, the initial lysosomal damage impairs protective cellular autophagy, destroying the pyroptosis checkpoint and thus preventing the clearance of damaged mitochondria and amplifying immune responses, ultimately boosting immunotherapy. This strategy effectively treats primary tumors and inhibits metastatic growth, offering a new paradigm for photoimmunotherapy.