Carbon ion irradiation at a clinically used dose rewires super-enhancers to drive necroptosis and systemic immunity.

Abstract

Radiotherapy augments immunotherapy, yet conventional 2 Gy x-ray fractions largely induce apoptosis, whereas robust immunogenic cell death (ICD) is more commonly associated with higher-dose irradiation regimens. Here, we reveal a dose-independent, high-LET-specific paradigm: a physical dose of 2 Gy of carbon ions provokes antitumor immunity. Carbon ions redirect death wiring to MLKL-dependent necroptosis and trigger an NF-κB-driven inflammatory cascade (IL1A/B, CXCL1/2/3), surpassing 8 Gy x-rays in immunogenicity despite lower direct tumor cell-killing capacity. Multi-omics analyses identify clustered DNA damage-driven super-enhancer remodeling as an epigenetic switch that suppresses cIAP1/2-caspase-8-mediated apoptosis while licensing inflammatory necroptosis. Pharmacologic inhibition of MLKL abolishes these responses to carbon ion radiotherapy (CIRT). In vivo, 2 Gy CIRT drives abscopal response with increased CD8⁺ T cell infiltration and function. Together, these findings establish CIRT as a feasible, immune-stimulatory radiotherapy converting local exposure into systemic control via super-enhancer-mediated reprogramming of death and inflammation, providing a mechanistic rationale to integrate carbon ions into next-generation radio-immunotherapy.