A Metabolic Nanoplatform Potentiates Triple-Negative Breast Cancer Radiosensitivity via Disrupting Carbonic Anhydrase IX/Pentose Phosphate Pathway Crosstalk

Abstract Radiotherapy resistance in tumors driven by metabolic adaptations within acidic microenvironments involves the upregulation of both carbonic anhydrase IX (CA IX) and the pentose phosphate pathway (PPP) as well as the functional crosstalk between them. To overcome this, we developed a polyvinylpyrrolidone (PVP)-modified gadolinium acetazolamide (PGA) nanoradiosensitizer. PGA simultaneously inhibits CA IX to trigger intracellular acidification and tumor cell acidosis, suppresses PPP through regulation of glucose-6-phosphate dehydrogenase (G6PD), and depletes key radioresistance-sustaining metabolites, such as NADPH, lipids, and nucleotide precursors. In addition, the high-Z element Gd endows PGA with potent radiosensitizing properties by enhancing X-ray absorption and DNA damage. In orthotopic and metastatic triple-negative breast cancer (TNBC) mouse models, PGA combined with radiotherapy markedly improves the therapeutic efficacy. Mechanistically, this metabolic reprogramming amplifies radiation-induced apoptosis and immunogenic cell death (ICD) while inhibiting metastasis-associated matrix metalloproteinases (MMPs) and the epithelial-mesenchymal transition (EMT) process. Consequently, PGA effectively overcomes radioresistance and suppresses TNBC lung metastasis through the coordinated disruption of tumor metabolism and remodeling of the tumor immune microenvironment. This work advances the frontier of metabolism-targeted nanomedicine for precision cancer therapy, offering a promising strategy to combat radiotherapy resistance in aggressive breast cancer.