A CHMP2B‐Targeting Photodynamic Degrader Synergizes With GSK‐3 Inhibition to Unleash Pyroptosis‐Driven Antitumor Immunity

ABSTRACT Conventional cancer therapies rarely induce robust antitumor immunity, as they typically trigger non‐immunogenic cell death and fail to counteract intrinsic immune resistance mechanisms. In this work, we develop a charged multivesicular body protein 2B (CHMP2B)‐targeting photodynamic degrader (Chat‐PDD) that both activates and amplifies pyroptosis‐mediated antitumor immunity. Chat‐PDD is assembled from a CHMP2B‐targeting chimeric peptide (Chat‐CHP), composed of a CHMP2B‐binding sequence, the photosensitizer protoporphyrin IX (PpIX), and a membrane‐anchoring palmitic acid moiety, and is co‐formulated with the glycogen synthase kinase‐3 (GSK‐3) inhibitor elraglusib (Elr). Chat‐PDD selectively accumulates on tumor cell membranes and localizes to CHMP2B. Upon photoactivation, membrane‐confined photodynamic therapy disrupts the plasma membrane, facilitates CHMP2B degradation, and directly triggers pyroptotic cell death. Concurrently, GSK‐3 inhibition enhances granzyme B secretion to potentiate T cell cytotoxicity. Notably, photodynamic degradation of CHMP2B impairs endosomal sorting complex required for transport III (ESCRT‐III)‐dependent membrane repair, thereby amplifying the release of damage‐associated molecular pattern (DAMP) and reinforcing granzyme B‐mediated killing. By inducing pyroptosis and blocking the membrane repair pathway, Chat‐PDD elicits systemic antitumor immunity and effectively suppresses metastatic progression. This work presents a sophisticated strategy to reprogram tumor cell death pathways and overcome their inherent resistance to immune activation.