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 (W6+), 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.