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The distinct landscape of tumor immune microenvironment in homologous recombination deficient cancers

Qiuyang Xu,Yuanjia Wen,Taiyua Huang,Huayi Li,Xingzhe Liu,Shen-nan Shi,Wenjian Gong,Gordon B. Mills,Ding Ma,Qing-cui Gao,Yong Fang

Published 2025 in Biomarker Research

ABSTRACT

Homologous recombination deficiency (HRD) is a common characteristic of human cancers, which occurs most frequently in ovarian and breast cancers. The unique genetic vulnerabilities, coupled with the synthetic lethality effect of Poly-(ADP-ribose) polymerase (PARP) inhibitors (PARPi), provide a promising opportunity for targeting HRD cancers. However, only a few HRD patients benefit from PARPi monotherapy, and it is therefore imperative to explore effective combination therapies for HRD tumors. Growing evidence has underscored the distinct tumor microenvironment (TME) landscape of HRD cancers. Immune activation and immune suppression co-exist in a dynamic balance during the development of HRD cancers. At the late stage, however, negative immune regulation predominates, resulting in the formation of an immunosuppressive microenvironment. This intricate network reprograms cancer biology in multiple aspects and serves as a potential target for cancer treatment. In this review, we briefly outline the current HRD tests and genetic characteristics of HRD cancers, focusing on breast, ovarian, pancreatic, and prostate cancers. We then summarize the interactions and crosstalk between immune cells and cancer cells, as well as various signaling pathways within the TME of HRD cancers. Additionally, we highlight recent advances in combining PARP inhibitors with immunotherapies in preclinical models and clinical trials of HRD cancers. This review provides valuable insights and perspectives into the distinct landscape of TME in HRD cancers, and offers a rationale for expanding the application of this combined therapeutic approach to a broader range of HRD cancers.

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