Biomimetic Organic Nanozyme as Tumor Vaccines for Targeted Suppression of Ammonia-Induced T Lymphocyte Death to Augment Breast Cancer Immunotherapy.

Ammonia-induced T lymphocyte death (AITD) offers a new perspective on immune regulation after the activation of CD8+ T cells. However, the use of a single AITD inhibitor is constrained by multiple factors in the immunosuppressive tumor microenvironment and requires combination strategies to achieve breakthroughs. Herein, a rationally designed organic nanozyme (IR-IHpd) is presented, integrating anthocyanin-based near-infrared photodynamic therapy (NIR-PDT) and Hemin-derived peroxidase (POD)-like catalytic activity. Under 780 nm laser irradiation, it generates ROS through Type I/II photodynamic mechanisms while catalyzing H2O2 into cytotoxic ·OH, establishing an uninterrupted ROS generation. Co-encapsulated with CB-839 in DSPE-Hyd-PEG and coated with dendritic cell (DC) membranes to form a biomimetic system (DMIC), this system targets both tumors and T cells. After intravenous administration, the DMIC nanozyme system efficiently accumulates in tumor tissues, tumor-draining lymph nodes, and spleens, where NIR irradiation induces tumor immunogenic cell death while promoting DCs maturation and T cell activation. The DMIC also functions as a tumor vaccine, capable of directly activating T cells and preventing tumor occurrence. Furthermore, the released CB-839 reduces intracellular ammonia levels in T cells, thereby enhancing anti-tumor immunity. This pioneering work achieves targeted AITD inhibition for the first time, integrating NIR-PDT, metabolic modulation, and immune activation to advance nanozyme-based immunotherapy.