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

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.