Reprogramming of cancer metabolism via photoresponsive nano-PROTAC enhances pyroptosis-mediated immunotherapy.

Photodynamic therapy (PDT) induces tumor cell pyroptosis, a form of programmed cell death that triggers antitumor immunity. However, high glucose metabolism and hypoxic conditions in the tumor microenvironment (TME) limit PDT efficiency and impair effector cell function. Here, we propose a cancer metabolic reprogramming-enabling photoresponsive nanoproteolysis-targeting chimera (Nano-PROTAC; NanoTAC), derived from the supramolecular self-assembly of drug conjugates that bridge a PROTAC targeting hexokinase II (HK2) and a photosensitizer via a biomarker-cleavable linker. In a triple-negative breast cancer (TNBC) model, NanoTAC initially silences PROTAC activity and accumulates in tumor regions, where it undergoes linker cleavage in response to enzymatic biomarkers. Upon photoirradiation, PDT-induced pyroptotic cell death promotes the release of tumor-associated antigens (TAAs) and damage-associated molecular patterns (DAMPs) to drive the cancer-immunity cycle. Concurrently, targeted protein degradation (TPD) via PROTACs counteracts glucose and oxygen consumption in the TME, ultimately potentiating pyroptosis-mediated photoimmunotherapy. This combination therapy achieves a high rate of complete regression in primary TNBC and confers adaptive immunity to prevent metastasis and recurrence. Our study presents a rationally designed nanomedicine that integrates PDT and PROTACs, shedding light on strategies for more effective cancer immunotherapy.