Chemiluminescence‐Powered Immunotherapy for Deep Tumors: Promoting PD‐L1 Degradation and Igniting Pyroptosis Through Subcellular Trafficking and Targeting

Abstract

ABSTRACT Organelle‐targeted therapy represents a promising strategy for cancer therapy and immune activation. Here, we present a novel Chemiluminescence‐Powered Immunotherapy (CPIT) platform designed to induce immunogenic pyroptosis and promote PD‐L1 degradation by exploiting two key subcellular organelles—lysosomes and the endoplasmic reticulum (ER). CPIT utilizes a PD‐L1‐targeted delivery vehicle (up to 10.8 %ID/g) to facilitate PD‐L1 degradation within lysosomes (>55% efficiency) and concurrently delivers a dual‐locked chemiluminescence‐resonance energy transfer (CRET) system to the ER for localized pyroptosis. The dual‐locking mechanism ensures tumor‐selective and ER‐confined activation, maximizing oxidative damage and specifically inducing pyroptosis while minimizing off‐target toxicity. In vivo studies demonstrate remarkable tumor selectivity (due to tumor‐specific delivery plus tumor‐selective activation), robust regression of metastatic tumors, and the induction of a durable adaptive immune response. CPIT overcomes the limitation of conventional photodynamic therapy‐driven immunogenic cell death (ICD) strategies, being effective only for superficial tumors. Simultaneously, it lowers the immune activation threshold by promoting PD‐L1 degradation, addressing the challenge of T cell exhaustion common in ICD‐based cancer immunotherapies. This approach holds promise as a transformative approach to treating hard‐to‐reach malignancies and expanding the reach of immunotherapeutic strategies. The modular design of CPIT enables rapid substitution of protein‐specific ligands or alternative chemiluminescent donors, further expanding its potential for diverse cancer immunotherapy applications.