G0S2 Promotes PD-L1 Expression in Monocytes and Influences the Efficacy of PD-1 Inhibitors in Hepatocellular Carcinoma

<b>Background:</b> Hepatocellular carcinoma (HCC) is a prevalent and highly lethal form of liver cancer, with limited effective treatment options, particularly in the advanced stages. Immunotherapy using PD-1 inhibitors has emerged as a promising treatment modality, yet a substantial proportion of patients exhibit resistance or fail to respond to such therapies. This study aimed to elucidate the role of G0/G1 Switch 2 (G0S2) in regulating PD-L1 expression in monocytes within the HCC tumor microenvironment and to investigate its impact on the efficacy of PD-1 inhibitors. <b>Methods:</b> Gene expression data among HCC patients treated with PD-1 inhibitors were obtained from the HCC single-cell sequencing database; immunohistochemistry was performed to detect G0S2 expression in liver cancer tissues and adjacent non-tumorous tissues of HCC patients; flow cytometry was utilized to analyze the expression of G0S2, PD-L1, CD206, and CD14 in PBMCs from HCC patients; and CD8⁺T cell proliferation and IFN-γ secretion were used to evaluate the impact of G0S2 knockdown. <b>Results:</b> Utilizing single-cell sequencing data from HCC patients, we identified that G0S2 expression was significantly elevated in the non-responders (NR) compared to responders (R) to PD-1 inhibitor therapy. The immunohistochemical analysis confirmed higher levels of G0S2 in HCC tumor tissues and adjacent non-tumorous tissues, while the flow cytometry revealed the increased expression of G0S2, PD-L1, and CD206 in peripheral blood mononuclear cells (PBMCs) from NR patients compared to R patients and healthy controls. The functional experiments involving the knockdown of G0S2 in the THP-1 monocyte cell line resulted in a significant reduction in PD-L1 expression and a concomitant increase in CD8⁺T cell proliferation and IFN-γ production. <b>Conclusions:</b> These findings indicate that G0S2 facilitates the upregulation of PD-L1 in monocytes, thereby suppressing T cell activity and contributing to resistance against PD-1 inhibitors in HCC. The high expression of G0S2 in peripheral blood monocytes offers a non-invasive and easily detectable biomarker for predicting the efficacy of PD-1 inhibitor therapy. Consequently, targeting G0S2 may enhance the responsiveness to immunotherapy in HCC patients, providing a new avenue for optimizing treatment strategies and improving patient outcomes.