PGK1 Suppresses CD8+ T Cell-Mediated Antitumor Immunity Through CCL2/CCR2/Tumor-Associated Macrophages Axis in Hepatocellular Carcinoma.

Patients with advanced hepatocellular carcinoma (HCC) have a poor prognosis and few effective treatments. The highly immunosuppressive tumor microenvironment and multifaceted immune escape mechanisms in HCC profoundly restrict the clinical efficacy of immune checkpoint inhibitors. Phosphoglycerate kinase 1 (PGK1) is established as an oncogenic driver in malignant tumor progression. However, its role in modulating tumor immunity remains elusive. This study found that HCC cell-intrinsic PGK1 contributed to tumor progression through inhibiting CD8+ T cell-mediated antitumor immunity. Then, in vivo and in vitro results demonstrated that tumor-associated macrophages (TAMs) function as critical mediators in PGK1-driven immunosuppression. Furthermore, PGK1 promoted the recruitment and M2 polarization of TAMs through upregulation of C-C motif chemokine ligand 2 (CCL2) expression. Blockade of CCL2 significantly attenuated PGK1-induced infiltration of C-C motif chemokine receptor 2 (CCR2)+ TAMs and inhibited M2 polarization, while reversing the impaired infiltration and function of CD8+ T cells. This work further demonstrated that PGK1 enhanced CCL2 secretion through activating the AKT/GSK3β/β-catenin pathway in HCC cells. In vivo experiments revealed that the combination of PGK1 inhibitor and immunotherapy elicited potent antitumor efficacy. Taken together, this study highlighted PGK1 as a pivotal regulator of tumor immunobiology and provided novel insights into combination immunotherapy for HCC.