A pH and glucose dual-responsive nanocatalyst system for targeted tumor therapy, microenvironment reprogramming, and synergistic immune checkpoint blockade.

Immune checkpoint blockade (ICB) therapy often yields limited clinical efficacy due to immunosuppressive characteristics of the tumor microenvironment. Typical unfavorable factors include hypoxia, excessive accumulation of glutathione (GSH), and infiltration of M2-type tumor-associated macrophages. Single ICB treatment rarely achieves simultaneous in situ tumor eradication and systemic antitumor immune activation. This study develops a pH and glucose dual-responsive layered nanocarrier named BGHCCC to address the above challenges. The nanoplatform synergistically combines oxygen supplementation, starvation therapy, copper-amplified chemodynamic therapy (CDT), and calcium overload effects. Such combinatorial effects remodel the tumor microenvironment and improve tumor sensitivity to ICB therapy. Hollow calcium peroxide (HMCaO₂) serves as the core substrate for the in-situ immobilization of copper-doped resveratrol-derived carbon dots (CuRCDs). The final BGHCCC nanosystem is fabricated through noncovalent self-assembly of binary bovine serum albumin and glucose oxidase (BSA/GOx) protein complexes on the surface of HMCaO₂@CuRCDs. Comprehensive material characterizations confirm the tumor microenvironment-responsive controllable dissociation behavior of BGHCCC. Systematic assessments of in vitro catalytic performance, cellular biological functions, and in vivo antitumor efficacy are further conducted using tumor-bearing mouse models. Experimental results reveal that BGHCCC can consume intratumoral glucose, deplete intracellular GSH, and relieve hypoxic conditions through oxygen release. It also promotes the generation of hydroxyl radicals to activate cascaded biochemical reactions. These bioactive behaviors effectively induce tumor immunogenic cell death. In addition, BGHCCC can modulate the HIF-1α/PD-L1 signaling axis and regulate the phenotypic transformation of tumor-associated macrophages. This nanoplatform favors the polarization of macrophages from the immunosuppressive M2 phenotype to the antitumor M1 phenotype. In vivo experiments suggest that the combination of BGHCCC and αPD-L1 exhibits favorable biosafety and potent inhibitory effects on solid tumor growth. This combinatorial treatment increases the intratumoral infiltration of CD8+ effector T cells and triggers robust systemic antitumor immune responses. This study integrates multiple antitumor pathways into a single dual-responsive nanosystem and develops a synergistic therapeutic strategy to reverse tumor immunosuppression. It provides a feasible design reference for the development of combinatorial immunotherapeutic nanoplatforms with potential clinical translation value.