Abstract This study aimed to investigate the safety and efficacy of radiotherapy combined with poly ADP-ribose polymerase (PARP) inhibitors and immune checkpoint inhibitors in small cell lung cancer (SCLC). Tumor-bearing xenograft mouse model was used to examine the safety and anti-tumor effects of radiotherapy plus niraparib and PD-1 antibodies. SCLC cell lines were used to explore the underlying mechanisms in this combination. PARP inhibitor suppressed SCLC cell proliferation, induced cell apoptosis, and increased cell cycle arrest at G2/M phase. Niraparib treatment augmented radiation-induced double-strand DNA breaks, which subsequently activated the cGAS/STING pathway to increase the expression levels of CXCL10, CCL5 and PD-L1 in SCLC cells. Moreover, the combination of radiation, niraparib and PD-1 antibodies significantly inhibited SCLC tumor growth and prolonged the survival of immunocompetent C57BL/6 mice. The induced CCL5 and CXCL10 activated CD8+ T cells in vivo. Our study indicated that niraparib combined with radiation promoted immune checkpoint inhibitor functions via inducing PD-L1 expression, and activated CD8+ T cells via increasing CXCL10 and CCL5 levels through cGAS/STING pathway. The combination treatment of PARP inhibitors, radiotherapy and immunotherapy were safe in vivo, effectively suppressed SCLC tumor progression, increased survival and decreased the adverse events via lowering the dose of individual treatment. Citation Format: Nannan Zhang, Yanping Gao, Zihang Zeng, Yuan Luo, Xueping Jiang, Jianguo Zhang, Jiali Li, Zhengrong Huang, Yan Gong, Conghua Xie. Poly ADP-ribose polymerase inhibitor promotes the immunoradiotherapeutical efficacy in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1394.