Sequential treatment with PARPi and WEE1i enhances antitumor immune responses in preclinical models of ovarian cancer

作者：Xiaofei Jiao, Jiahao Liu, Yijie Wu, Qing Peter Wild Zhong, Li Zhu, Linghui Wang, Huayi Li, Minghua Xiang, Xuejiao Zhao, Guang‐Nian Zhao, Gordon B. Mills, Ding Ma, Qinglei Gao, Yong Fang · 发表于：Science Translational Medicine · 年份：2025 · DOI：10.1126/scitranslmed.adu6989 · 被引用次数：11 · 研究领域：PARP inhibition in cancer therapy、Immune Cell Function and Interaction、CRISPR and Genetic Engineering

The antitumor activity demonstrated by DNA damage response inhibitors (DDRis) can be partially attributed to their capacity to enhance immune responses. However, the toxicity of DDRis to lymphocytes, particularly when a DDRi is combined with other treatments targeting cell cycle checkpoint kinases, indicates a need for the development of different DDRi treatment schedules. Here, we systematically assessed changes to the tumor immune microenvironment (TIME) in response to DDRis across various treatment timelines in ovarian cancer. Using single-cell analysis, we found that the sequential treatment with an inhibitor of poly(ADP-ribose) polymerase (PARPi), followed by an inhibitor of the cell cycle checkpoint kinase WEE1 (WEE1i), resulted in more effective cancer eradication and stronger antitumor immune responses in vivo, compared with mono- and concurrent therapy. Both sequential and concurrent treatment schedules could induce lethal DNA damage and activate the cGAS-STING pathway in cancer cells, but T cell viability was greater under sequential treatment. Proteomic analysis showed that T cells more quickly recovered from DNA damage after DDRi treatment compared with cancer cells. Both immune checkpoint therapy and CAR T cells were more effective when combined with sequential treatment compared with monotherapy treatment in a syngeneic high-grade serous ovarian cancer mouse model and in a treatment-resistant ovarian cancer patient-derived xenograft model. Our study demonstrated...