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

ABSTRACT 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.