The following is the summary of “Sex Differences in Genomic Features of Hepatitis B–Associated Hepatocellular Carcinoma With Distinct Antitumor Immunity” published in the January 2023 issue of Cellular and Molecular Gastroenterology and Hepatology by Xu, et al.

In people infected with the hepatitis B virus (HBV), aflatoxin exposure raises the risk of developing hepatocellular carcinoma (HCC), especially in men. Therefore, researchers looked into whether or not the HCC genome and antitumor immunity vary by gender. As a result of HBV infection and aflatoxin exposure, 101 HCC patient samples (47 males, 54 females) from Qidong were sequenced using whole-genome, whole-exome, and RNA sequencing. In addition, analyses of the effects of androgen on the expression of genes involved in aflatoxin metabolism and factors involved in nonhomologous DNA end joining (NHEJ) were performed in HBV-positive HCC cell lines and then repeated in syngeneic with tumors.

Both the genomic landscape and the transcriptional dysfunction pathways of Qidong HCC were different in males and females. Males displayed a signature of up-regulated type I interferon signaling/response and repressed antitumor immunity, as evidenced by their increased expression of aflatoxin metabolism-related genes like AHR and CYP1A1 and decreased expression of NHEJ factors like XRCC4, LIG4, and MRE11. When HBV-positive cells were treated with aflatoxin B1, adding 2 nmol/L testosterone to the culture medium significantly increased the expression of aflatoxin metabolism-related genes while simultaneously decreasing NHEJ factors, leading to increased nuclear DNA leakage into the cytosol and subsequent activation of cGAS-STING.

Daily oral gavage administration of tamoxifen suppressed NHEJ factor expression and activated cGAS-STING in tumors in syngeneic tumor-bearing, leading to enhanced T-cell infiltration and a more potent anti-programmed cell death protein 1 treatment response. In addition, DNA repair was inhibited by androgen signaling when exposed to genotoxic stress. As a result of the change, more nuclear DNA leaked into the cytosol, activating the cGAS-STING pathway, which led to greater T-cell infiltration into the tumor mass and enhanced anti-programmed cell death protein 1 immunotherapy in HCCs.