Cascade-Catalytic MnO2 Nanoreactor Amplifies Oxidative Stress and Activates cGAS–STING Pathway To Remodel the Immunosuppressive Microenvironment of Triple-Negative Breast Cancer

Abstract Triple-negative breast cancer (TNBC) is characterized by a highly immunosuppressive tumor microenvironment, which severely limits the therapeutic efficacy of current immunotherapies. To address this challenge, we developed a hyaluronic acid-modified tumor-targeted MnO2 nanoreactor (HMGR@HA) for the codelivery of GOx and 20(S)-ginsenoside Rg3 (Rg3), thereby integrating metabolic interference with cascade catalytic therapy and endogenous immune activation. In this system, GOx continuously catalyzed the oxidation of glucose to generate H2O2, which was subsequently converted by MnO2 into highly cytotoxic reactive oxygen species (ROS) while simultaneously producing oxygen. This process established a self-reinforcing catalytic cycle that effectively circumvented the intrinsic limitation of insufficient endogenous H2O2 within the tumor microenvironment. The resulting amplified oxidative stress, in synergy with the chemotherapeutic effect of Rg3, induced profound mitochondrial dysfunction and triggered the cytosolic release of mtDNA. As a potent endogenous danger signal, cytosolic mtDNA robustly activated the cGAS-STING signaling axis, thereby converting localized oxidative damage into strong innate immune activation. In addition, HMGR@HA induced immunogenic cell death (ICD), promoted dendritic cells (DCs) maturation, enhanced infiltration of CD4+ and CD8+ effector T cells, and significantly depleted regulatory T cells (Tregs), collectively leading to extensive remodeling of the tumor immune microenvironment. Ultimately, this self-amplifying catalytic platform effectively drives the transition from localized tumor eradication to systemic antitumor immunity, offering a highly efficient therapeutic strategy for TNBC immunotherapy.