From a single phenolic precursor to an all-in-one therapeutic cascade: Spatially programmed photoenzymatic immunotherapy and deep-tumor metabolic reprogramming to engineer robust in situ vaccination

In situ vaccination, while promising for tumor immunotherapy, is fundamentally challenged by the inability to spatiotemporally coordinate immunogenic killing in vascularized regions with immunometabolism reprogramming in hypoxic depths without exacerbating immunosuppression. Here, we report an in situ nanovaccine platform comprising a cascade-unlocking nanoassembly derived from a single bioactive precursor (caffeic acid, CA), designed to overcome these barriers. This platform is engineered through a copper-catalyzed polymerization-assembly process, which bypasses the cumbersome integration of multiple pre-synthesized functional components. Specifically, Cu 2+ -driven co-assembly of CA monomers with semiquinone-rich oligomer nanoparticles yields a Cu 2+ -quenched system. Upon tumor accumulation, elevated glutathione triggers disassembly and reduces Cu 2+ to Cu + , restoring electron transfer and photoenzymatic activity in stabilized semiquinone radicals (lasting over 8 weeks). The released oligomeric units penetrate hypoxic regions, inducing immunogenic tumor killing and repolarizing M2-like macrophages via hypoxia-tolerant photoenzymatic catalysis. Concurrently, Cu + ions and CA monomers are disseminated in deeper tumor cores, disrupting mitochondrial metabolism, activating AMPK, and promoting PD-L1 degradation. By coordinating periphery-focused catalytic immunoactivation with core-targeted metabolic–immune reprogramming, this system amplifies T cell activation (9.3-fold) and suppresses both primary and metastatic (98.9%) tumors. This all-in-one nanoplatform enables spatiotemporally programmed in situ vaccination, disrupting immunosuppressive niches and initiating self-reinforcing antitumor immunity across heterogeneous tumors.