Letter to the editor: Disrupted BRCA1‐PALB2 interaction induces tumor immunosuppression and T‐lymphocyte infiltration in HCC through cGAS‐STING pathway

To the editor, We followed with interest in the report by Hui et al. that DNA damage caused by a defective breast cancer (BRCA) pathway induces tumor immunosuppression and T‐lymphocyte infiltration in HCC through the cyclic GMP‐AMP synthase (cGAS) and stimulator of interferon genes (STING) pathway, providing new insight into the interaction between tumor cells and the tumor microenvironment that may help improve anti‐PD1 (programmed death 1) therapy for HCC response.1 In recent years, anti‐PD1 therapy is facing great challenges in HCC because of the complex tumor immune microenvironment (TIME). We appreciate the investigators’ work on the research of TIME remodeling and proposing new treatments for the future. However, after reading this article, we want to highlight some key issues in this study. First, it is known that, on one hand, activation of cGAS‐STING can repolarize tumor‐promoting M2‐type macrophages into M1‐type macrophages; on the other hand, it can induce interferon production to promote dendritic cell (DC) maturation, which mediates CD8+ T‐cell activation to provide tumor regression.2 The investigators elucidated activation of the cGAS‐STING signaling pathway in M1 macrophages and exhibited dramatic immune microenvironment remodeling. However, they did not mention the DCs that are important to HCC anti‐PD1 treatment. This may illustrate a new mechanism of DC maturation caused by DNA damage. Second, in this research, the investigators analyzed the colocalization of CD11c (M1 macrophage marker) in tumor tissues using multiplex immunofluorescence (IF). It is known that CD11c is a commonly used marker of DCs and macrophages. CD11c can be used as a marker of M1 macrophages only in human tissues. When CD11c is used in mouse tissues, it can only label DCs.3 Multiplex IF is not sufficient to prove that cGAS‐STING signaling is activated in the M1 macrophages of Palb2MUT HCC tumors. Therefore, flow cytometry combined with multiple IF will be more rigorous in the study of tumor immune remodeling. Finally, further clinical studies with more samples will serve to elucidate results in HCC.