Photoactivatable Nanozyme-Integrated Microneedles Orchestrate a Self-Amplifying Immunogenic Cell Death-STING Signaling Circuit for Tumor Immune Rewiring.

Abstract

Solid tumors characterized by intrinsically low immunogenicity and a profoundly immunosuppressive microenvironment remain largely refractory to current cancer immunotherapies. Here, a photoactivatable nanozyme-integrated microneedle platform (HTHPH MNs) is developed to enable spatiotemporally controlled immunomodulation via a self-cascaded immunogenic cell death (ICD)-stimulator of interferon genes (STING) amplification circuit. Hollow mesoporous Prussian blue (HMPB) nanozymes coloaded with hydroxyurea (HU) and thapsigargin (TG) are embedded within a poly(γ-glutamic acid) microneedle matrix, allowing localized and minimally invasive intratumoral delivery. Upon near-infrared irradiation, the nanozymes simultaneously induce mild hyperthermia and catalyze endogenous hydrogen peroxide into highly reactive hydroxyl radicals, suppressing heat shock protein-mediated thermotolerance and triggering robust ICD. HU inhibits DNA replication and repair, promoting cytosolic double-stranded DNA accumulation and activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, while TG induces endoplasmic reticulum Ca²⁺ depletion to relieve stromal interaction molecule 1 (STIM1)-mediated inhibition of STING trafficking, thereby amplifying type I interferon signaling. This trimodal self-amplifying immune cascade enhances tumor immunogenicity, remodels the tumor immune microenvironment, and elicits potent local and systemic T cell-mediated antitumor responses. Collectively, this work establishes a nanozyme-microneedle-integrated strategy for the precise orchestration of innate and adaptive antitumor immunity.