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

ABSTRACT 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.