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Here, we present a novel Chemiluminescence\u2010Powered Immunotherapy (CPIT) platform designed to induce immunogenic pyroptosis and promote PD\u2010L1 degradation by exploiting two key subcellular organelles\u2014lysosomes and the endoplasmic reticulum (ER). CPIT utilizes a PD\u2010L1\u2010targeted delivery vehicle (up to 10.8 %ID\/g) to facilitate PD\u2010L1 degradation within lysosomes (&gt;55% efficiency) and concurrently delivers a dual\u2010locked chemiluminescence\u2010resonance energy transfer (CRET) system to the ER for localized pyroptosis. The dual\u2010locking mechanism ensures tumor\u2010selective and ER\u2010confined activation, maximizing oxidative damage and specifically inducing pyroptosis while minimizing off\u2010target toxicity. In vivo studies demonstrate remarkable tumor selectivity (due to tumor\u2010specific delivery plus tumor\u2010selective activation), robust regression of metastatic tumors, and the induction of a durable adaptive immune response. CPIT overcomes the limitation of conventional photodynamic therapy\u2010driven immunogenic cell death (ICD) strategies, being effective only for superficial tumors. Simultaneously, it lowers the immune activation threshold by promoting PD\u2010L1 degradation, addressing the challenge of T cell exhaustion common in ICD\u2010based cancer immunotherapies. This approach holds promise as a transformative approach to treating hard\u2010to\u2010reach malignancies and expanding the reach of immunotherapeutic strategies. The modular design of CPIT enables rapid substitution of protein\u2010specific ligands or alternative chemiluminescent donors, further expanding its potential for diverse cancer immunotherapy applications.<\/jats:p>","DOI":"10.1002\/adma.202519569","type":"journal-article","created":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T10:10:17Z","timestamp":1768903817000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Chemiluminescence\u2010Powered Immunotherapy for Deep Tumors: Promoting PD\u2010L1 Degradation and Igniting Pyroptosis Through Subcellular Trafficking and Targeting"],"prefix":"10.1002","volume":"38","author":[{"given":"Yahui","family":"Cao","sequence":"first","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy Key Laboratory of Functional Polymer Materials of Ministry of Education Nankai University  Tianjin P. R. 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4688-7551","authenticated-orcid":false,"given":"Changhua","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy Key Laboratory of Functional Polymer Materials of Ministry of Education Nankai University  Tianjin P. R. 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