PTPN1 synergistically promotes hepatocellular carcinoma progression by inhibiting the expression of STAT5 in CD8+ T cells and enhancing the activity of the PI3K-AKT pathway.

Protein tyrosine phosphatases (PTPs) are pivotal in cellular signal transduction. Recent studies have identified protein tyrosine phosphatase, non-receptor type 1 (PTPN1), as a novel immune checkpoint. However, its effects and underlying mechanisms in hepatocellular carcinoma (HCC) remain underexplored. This study aims to elucidate the impact of PTPN1 on the prognosis of HCC patients, the tumor microenvironment (TME), and the biological behavior of HCC cells, with the goal of assessing its clinical potential in HCC. Expression profiles and clinical data for liver cancer patients were obtained from the TCGA database, while single-cell RNA sequencing data were sourced from the GEO database. Corresponding cell function assays were conducted for further validation. PTPN1 mRNA expression was significantly elevated in liver cancer, with higher levels correlating with increased malignancy. Cox analysis found PTPN1 as an influencing factor for prognosis of HCC patients. Gene function and pathway analyses revealed that PTPN1 is implicated in immune-related pathways associated with cancer and hematopoiesis. Notably, PTPN1 expression was found to suppress infiltration of CD8+ T cells. Further investigations using single-cell RNA sequencing and experimental assays demonstrated that silencing PTPN1 in T cell populations enhanced JAK2 and STAT5 expression in CD8+ T cells, as well as their proliferation. Additionally, PTPN1 overexpression in liver cancer cells promoted cell proliferation and invasion through activation of the PI3K-AKT signaling pathway. PTPN1 may inhibit T cell proliferation via the JAK2-STAT5 axis while simultaneously advancing liver cancer progression by activating the PI3K-AKT pathway in cancer cells. These findings suggest that PTPN1 could serve as a promising target for immunotherapy in liver cancer.