Disrupted BRCA1‐PALB2 interaction induces tumor immunosuppression and T‐lymphocyte infiltration in HCC through cGAS‐STING pathway

Background and Aims: BRCA1 (BRCA1 DNA repair associated) and PALB2 (partner and localizer of BRCA2) interact with each other to promote homologous recombination and DNA double‐strand breaks repair. The disruption of this interaction has been reported to play a role in tumorigenesis. However, its precise function in HCC remains poorly understood. Approach and Results: We demonstrated that mice with disrupted BRCA1‐PALB2 interaction were more susceptible to HCC than wild‐type mice. HCC tumors arising from these mice showed plenty of T‐lymphocyte infiltration and a better response to programmed cell death 1 (PD‐1) antibody treatment. Mechanistically, disruption of the BRCA1‐PALB2 interaction causes persistent high level of DNA damage in HCC cells, leading to activation of the cyclic GMP‐AMP synthase (cGAS)–stimulator of interferon genes (STING) signaling pathway in both malignant hepatocytes and M1 macrophages in the tumor microenvironment. The activated cGAS‐STING pathway induces programmed cell death 1 ligand 1 expression via the STING–interferon regulatory factor 3 (IRF3)–signal transducer and activator of transcription 1 pathway, causing immunosuppression to facilitate tumorigenesis and tumor progression. Meanwhile, M1 macrophages with an activated cGAS‐STING pathway could recruit T lymphocytes through the STING‐IRF3 pathway, leading to T‐lymphocyte infiltration in tumors. After normalizing immune responses by PD‐1 antibody treatment, the infiltrating T lymphocytes attack tumor cells rapidly and effectively. Conclusions: This study reveals that persistent DNA damage caused by a defective BRCA pathway induces tumor immunosuppression and T‐lymphocyte infiltration in HCC through the cGAS‐STING pathway, providing insight into tumor immune microenvironment remodeling that may help improve HCC response to PD‐1 antibody treatment.