Lysosome-Anchoring Activation Design of Type I Photosensitizer Evokes Pyroptosis and Antitumor Immunity

Abstract

Pyroptosis, an inflammatory form of programmed cell death, has attracted growing attention as a promising pathway for cancer immunotherapy. However, few molecular design strategies with near-infrared (NIR) photoactivated pyroptosis inducers have been developed. Herein, a lysosome-targeted NIR type I photoinduced superoxide radical (O 2 −• ) generator (ENBS) that can evoke pyroptosis and antitumor immunity was presented here for the first time. In this work, ENBS not only selectively accumulates in lysosomes and disrupts the integrity of lysosomes but also induces gasdermin D (GSDMD) mediated pyroptosis. As a result, it finally promotes the maturation of dendritic cells (DCs), achieving T-cell-mediated immune activation in vivo. To the best of our knowledge, this is the first example of an NIR photoactivated superoxide radical pyroptosis generator-based immunotherapy system through the caspase-1/GSDMD pathway, anticipated to provide valuable guidelines for pyroptosismediated cancer immunotherapy.