Irradiated Tumor Cell‐Derived Microparticles Activate Systemic Anti‐Tumor Immunity via the STING/NLRP3/GSDMD Axis in Neutrophils

Radiotherapy is known to trigger immunogenic cell death and activate local anti-tumor immune responses. However, its systemic immunomodulatory effects remain poorly understood. Here, we discovered that irradiated tumor cell-derived microparticles (RT-MPs) are released into the circulation and subsequently taken up by neutrophils in the spleen. The mitochondrial DNA contained within RT-MPs promotes the hyperactivation of neutrophils, leading to the secretion of interleukin-1beta (IL-1β) via the STING/NLRP3/GSDMD axis. IL-1β, in turn, enhances the antigen-presenting capacity of dendritic cells (DCs), which facilitates the formation of cytotoxic T lymphocytes (CTLs) in the spleen. These CTLs then contribute to the destruction of distant, non-irradiated tumors. Our findings provide valuable insights into the mechanisms by which radiotherapy can directly modulate systemic anti-tumor immunity, highlighting the potential for leveraging these effects to improve the efficacy of cancer treatment.