Carbon Ion Radiotherapy Induces Necroptosis and Super-Enhancer Reprogramming to Enhance Antitumor Immunity
Carbon ion radiotherapy (CIRT) exhibits superior physical and biological properties compared to conventional X-rays, yet its mechanisms in regulating cell death and tumor immunogenicity remain unclear. Here, we show that low-dose (2 Gy) carbon ions, unlike high-dose X-rays (8 Gy), specifically trigger necroptosis via MLKL phosphorylation and activate NF-kB-driven inflammation, as confirmed by transcriptomics, western blot, and NSA inhibitor assays. Furthermore, carbon-ion-induced super-enhancer (SE) reprogramming upregulates necroptosis- and inflammation-related genes, linking chromatin remodeling to cell fate determination. Mechanistically, CIRT redistributes SEs to amplify cIAP1/2 mediated apoptosis suppression while enhancing NF-kB-dependent inflammatory responses. In vivo, carbon-ion-irradiated tumors display potent abscopal effects, completely suppressing secondary tumor growth. Our findings reveal a novel mechanism by which CIRT orchestrates SE reprogramming and necroptosis to boost antitumor immunity, offering new strategies for combinatorial radio-immunotherapy.