PARP inhibitor plus radiotherapy reshapes an inflamed tumor microenvironment that sensitizes small cell lung cancer to the anti-PD-1 immunotherapy

Small cell lung cancer (SCLC) is a highly malignant tumor with extremely poor prognosis. The treatment strategy is very limited, and patient outcomes remain dismal with the 5-year survival rate being mere 3-6%. Thus, novel therapeutic strategies for SCLC patients are urgently needed. In this study, we found that the triple-therapy of poly (ADP-ribose) polymerase (PARP) inhibitor, radiotherapy (RT) and anti-PD-1 treatment significantly inhibited tumor growth and prolonged survival in the syngeneic SCLC models in immunocompetent C57BL/6 mice. Mechanistically, we demonstrated that the combination of PARP inhibitor niraparib and RT reshaped an inflamed tumor microenvironment, including activation of the cGAS/STING immune response pathway, induction of immunogenic cell death, and upregulation of PD-L1 on tumor cells. Furthermore, this triple-therapy substantially augmented CD8(+) T cell infiltration and activation, and enhanced anti-tumor effects as revealed by increased median survival time and reduced tumor volume without additional myelosuppression or hepatic injury. Together, our studies demonstrated that PARP inhibitor combined with RT potentiated anti-tumor immunity and enhanced the efficacy of anti-PD-1 immunotherapy in preclinical study, which provided a promising therapeutic strategy for SCLC patients in clinic.

Automated summary

The combination of PARP inhibitor, radiotherapy, and anti-PD-1 treatment significantly inhibits tumor growth and prolongs survival in syngeneic SCLC models in mice. This combination therapy reshapes the tumor microenvironment, induces immunogenic cell death, and upregulates PD-L1 expression on tumor cells. It also enhances CD8(+) T cell infiltration and activation, leading to improved anti-tumor effects.