PARP inhibitors accumulate B7-H3 on fibroblasts via blocking autophagic flux to potentiate immune evasion in ovarian cancer

PARP inhibitors accumulate B7-H3 on fibroblasts via blocking autophagic flux to potentiate immune evasion in ovarian cancer

Besides targeting tumor cells via canonical synthetic lethality, poly(ADP-ribose) polymerase inhibitors (PARPis) can remodel tumor immune microenvironment (TIME), which then affects PARPis’ anti-tumor capabilities. However, exact function of PARPis on TIME remains insufficiently explored. Here, by l...

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Main Authors: Tian Fang, Yu Xia, Ying Li, Sen Xu, Huayi Li, Siyuan Wang, Pu Huang, Yiyu Qian, Ping Jin, Ning Jin, Cheng Xu, Zhen Wang, Xiaoming Xiong, Mengjie Wang, Dongchen Zhou, Ya Wang, Xiaoting Li, Tao Xu, Qi Zhang, Dan Liu, Yong Fang, Guang-Nian Zhao, Qinglei Gao
Format: Article
Language:English
Published: Taylor & Francis Group 2025-12-01
Series:OncoImmunology
Subjects:
Autophagy
B7-H3
cancer-associated fibroblast
ovarian cancer
PARP inhibitor
Online Access:https://www.tandfonline.com/doi/10.1080/2162402X.2025.2516294
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Summary:Besides targeting tumor cells via canonical synthetic lethality, poly(ADP-ribose) polymerase inhibitors (PARPis) can remodel tumor immune microenvironment (TIME), which then affects PARPis’ anti-tumor capabilities. However, exact function of PARPis on TIME remains insufficiently explored. Here, by leveraging paired samples during neoadjuvant PARPi Niraparib treatment derived from a prospective clinical trial, we discovered that the expression of immune checkpoint ligand B7-H3 was induced by PARPis in cancer-associated fibroblasts (CAFs) of ovarian cancer. Depletion of B7-H3 in CAFs by using host cd276 (coding B7-H3) knockout mice or B7-H3 deficient fibroblast cells both boosted T cell functions and enhanced the anti-tumor capacities of PARPis in immunocompetent mouse models. Besides, increased B7-H3 on CAFs also attenuated the anti-tumor potentials of T cells in co-culture system. Mechanistically, PARPis blocked autophagic flux by inhibiting PIP4K2A expression, a critical regulator of autophagosome and lysosome fusion, and therefore dampening the lysosomal degradation of B7-H3. Importantly, neutralizing B7-H3 antibodies had synergistic effects with PARPis and achieved superior therapeutic efficacy than PARPis plus PD-1 blockade in a syngeneic mouse ovarian cancer model. Collectively, this study revealed an autophagy-mediated pathway by which PARPis contribute to immune evasion via enhanced B7-H3 accumulation on CAFs, highlighting the complexity of the regulation of PARPis on TIME and the potential application of combining PARPis with B7-H3 blockade in the treatment of ovarian cancer.
ISSN:2162-402X

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