Piezocatalytic nanotransducers rewire tumor immunometabolism via in situ peroxynitrite generation

The dense extracellular matrix (ECM) and stromal cells in breast cancer constitute a formidable physical and immunosuppressive barrier that facilitates immune evasion and tumor progression. Within this desmoplastic microenvironment, cancer-associated fibroblasts (CAFs) overexpress indoleamine 2,3-dioxygenase-1 (IDO-1), an enzyme that activates the tryptophan-kynurenine metabolic pathway to induce T cell exhaustion and immune tolerance. Consequently, modulating tryptophan metabolism in CAFs represents a promising strategy to potentiate antitumor immunotherapy. Herein, we develop a CAF-targeted nanomedicine system based on dasatinib-loaded Nb₂GeTe₄ (NGT) nanosheets for ultrasound-mediated immunometabolic modulation. Under low-intensity ultrasound, NGT exhibits efficient piezocatalytic charge separation, efficiently separating electron-hole pairs to trigger the generation of superoxide anions (·O₂^-). These reactive species rapidly react with intracellular nitric oxide to form peroxynitrite (ONOO^-), which induces site-specific tyrosine nitration of IDO-1. This process irreversibly inactivates IDO-1, thereby disrupting the tryptophan-kynurenine immunosuppressive axis. Simultaneously, the controlled release of dasatinib inhibits CAF-mediated fibrosis, dismantling the stromal barrier, reducing tumor stiffness and facilitating the infiltration of cytotoxic T lymphocytes. This study establishes a precise piezocatalysis-driven strategy for reprogramming the tumor microenvironment in desmoplastic malignancies, providing a promising avenue for the development of two-dimensional nanomaterials in cancer immunotherapy.