Metal-Phenolic Nanomedicines Targeting Fatty Acid Metabolic Reprogramming to Overcome Immunosuppression in Radiometabolic Cancer Therapy.

Radiation therapy (RT) is a prevalent cancer treatment; however, its therapeutic outcomes are frequently impeded by tumor radioresistance, largely attributed to metabolic reprogramming characterized by increased fatty acid uptake and oxidation. To overcome this limitation, we developed polyphenol-metal coordination polymer (PPWQ), a novel nanoradiotherapy sensitizer specifically designed to regulate fatty acid metabolism and improve RT efficacy. These nanoparticles (NPs) utilize a metal-phenolic network (MPN) to integrate tungsten ions (W), quercetin (QR), and a PD-L1-blocking peptide within a PEG-polyphenol scaffold. When exposed to X-rays, PPWQ induces reactive oxygen species (ROS) to cause DNA damage, while QR inhibits CD36 expression, effectively curbing fatty acid uptake and mitigating immune evasion. In a 4T1 tumor-bearing mouse model, PPWQ demonstrated significant enhancement of RT by facilitating dendritic cell activation, boosting memory cytotoxic T lymphocytes, and skewing macrophages toward a pro-immune phenotype. These results underscore the potential of PPWQ to target metabolic vulnerabilities and advance the integration of immunotherapy with radiotherapy.