TOPK Inhibition Promotes Anti‐Tumor Immunity Via eIF4F Complex Mediated STAT1 Translation in Gastric Cancer

Immune checkpoint blockade-directed immunotherapy emerges as a revolutionary therapy in gastric cancer (GC). However, the proportion of patients who can benefit from it and its overall efficacy remain limited. Here the aim is to identify key dual-function targets that both inhibit proliferation and suppress immune evasion. Using whole genome-wide CRISPR-Cas9-based screening, the serine/threonine kinase T-lymphokine-activated killer cell-originated protein kinase (TOPK) is identified as a key regulator of PD-L1 in gastric cancer upon IFN-γ stimulation. Mechanical study is performed to explore the role of TOPK in promoting GC malignancy and immune evasion in vitro and vivo. Higher TOPK levels in tumor tissues are observed, correlated with clinical stages, efficacy and survival. Upon IFN-γ stimulation, TOPK phosphorylates eIF4F complex component eIF4A1 to increase its unwinding activity of STAT1 mRNA, enhancing STAT1 translation efficiency. This process leads to adaptive overexpression of PD-L1 and IDO1, resulting in immunometabolic suppression through PD-L1-mediated inhibition, IDO1-induced tryptophan depletion and kynurenine production. TOPK inhibitors reshape tumor immunometabolic microenvironment to trigger anti-tumor immunity in GC. The IFN-γ-TOPK-eIF4F-STAT1-PD-L1/IDO1 axis as a crucial regulator of the tumor immunometabolic microenvironment and provide novel insights into the combination of targeted therapy and immunotherapy for GC treatment.