Radiotherapy (RT) is routinely used in cancer treatment, but expansion of its clinical indications remains challenging. The mechanism underlying the radiation-induced bystander effect (RIBE) is not understood and not therapeutically exploited. We suggest that the RIBE is predominantly mediated by irradiated tumor cell–released microparticles (RT-MPs), which induce broad antitumor effects and cause immunogenic death mainly through ferroptosis. Using a mouse model of malignant pleural effusion (MPE), we demonstrated that RT-MPs polarized microenvironmental M2 tumor-associated macrophages (M2-TAMs) to M1-TAMs and modulated antitumor interactions between TAMs and tumor cells. Following internalization of RT-MPs, TAMs displayed increased programmed cell death ligand 1 (PD-L1) expression, enhancing follow-up combined anti–PD-1 therapy that confers an ablative effect against MPE and cisplatin-resistant MPE mouse models. Immunological memory effects were induced.

放射疗法（RT）通常用于癌症治疗，但是扩大其临床适应症仍然具有挑战性。辐射诱导的旁观者效应（RIBE）的潜在机制尚不清楚，也未进行治疗性利用。我们建议RIBE主要由辐射的肿瘤细胞释放微粒（RT-MPs）介导，该微粒可引起广泛的抗肿瘤作用并主要通过肥大症引起免疫原性死亡。使用恶性胸腔积液（MPE）的小鼠模型，我们证明RT-MPs将微环境M2肿瘤相关巨噬细胞（M2-TAMs）极化为M1-TAMs，并调节TAM和肿瘤细胞之间的抗肿瘤相互作用。在RT-MP内在化之后，TAM显示出增加的程序性细胞死亡配体1（PD-L1）表达，加强后续联合抗PD-1治疗，可赋予MPE和顺铂耐药MPE小鼠模型以消融作用。诱导了免疫记忆作用。