A Metal-Phenolic Nanocoordinator Launches Radiotherapeutic Cancer Pyroptosis Through an Epigenetic Mechanism

Radiotherapy, although clinically effective in immunoactivation, still cannot radio-functionalize tumor as a potent immunogenetic center. Given that newly found pyroptosis efficiently releases immunogenic damage-associated molecular patterns, initiating radiotherapeutic pyroptosis may turn a vision of radiotherapy-induced immunity into reality. However, a precondition is that the absent gasdermin E (GSDME), which essentiates in caspase-3-mediated pyroptosis, can be well translated in cancer cells. Here, an epigenetic strategy to launch cancer pyroptosis in radiotherapy is introduced. The nanocoordinator (PWE) is constructed via a metal-phenolic coordination between polyphenolic DNA methyltransferase inhibitor (epigallocatechin-3-gallate, EGCG), high-Z radiosensitizer (W6+), and polyphenol-modified block copolymer. While recovering GSDME expression by EGCG, PWE cleaves GSDME into fragmented GSDME N-terminal (pyroptotic key protein) via radiotherapeutic caspase-3. To examine anti-tumor immune activities, PWE amplifies immunological effects of traditional radiotherapy and decreases radiotherapy-upregulated regulatory T cells, providing new insight into tumor radiotherapy.