SLC16A3 as an immunosuppressive Kupffer cell marker predicts poor prognosis in HBV-positive hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) is one of the malignant tumors that currently pose a significant threat to human health, with infection by hepatitis B virus (HBV) being a critical risk factor for the development of HCC. It is critical to identify potential molecular targets affecting HBV-positive HCC patients.

Methods: In this study, we comprehensively utilized single-cell sequencing and external transcriptome sequencing databases to further analyze the mechanism of SLC16A3's influence on liver cancer and its microenvironment under different HBV status. Immunohistochemical staining in our clinical cohort was used to analyze the expression difference and influence of SLC16A3 in HCC. At the same time, we confirmed the direct effects of SLC16A3 on HCC cells with different HBV status through cell line experiments.

Results: Compared with normal tissues, SLC16A3 expression is up-regulated in HBV-positive HCC patients, and the up-regulation amplitude is greater than that in HBV-negative HCC patients, and it is associated with poor prognosis. The validation was performed on several external validation data sets and external validation queues. Multi-omics analysis showed that SLC16A3 expression is related to the specific differentiation of the immune microenvironment, especially Kupfer cells, which can mediate the emergence of the inhibitory immune microenvironment and indirectly lead to poor prognosis. SLC16A3 can directly mediate the proliferation of HBV-positive liver cancer cell lines in vitro.

Conclusion: Our study found that SLC16A3 is closely related to HBV status and liver cancer, and it has a significant marker for the prognosis of HBV-positive liver cancer. SLC16A3 is associated with abnormal metabolic pattern and immune regulation of Kupffer cells, and can directly affect HBV-positive hepatocellular carcinoma cell lines.