KIF20A drives epithelial cell proliferation and migration in gastric adenocarcinoma, facilitating macrophage M2 polarization and subsequent immune evasion

Gastric adenocarcinoma is a major clinical challenge due to its aggressive progression and immunosuppressive microenvironment. Here, we identify KIF20A, a mitotic kinesin, is identified as a central oncogenic driver that promotes tumor cell proliferation, migration, and immune evasion. Through integrated bulk and single-cell transcriptomic analyses of gastric adenocarcinoma tissues ( n  = 13 patients), we demonstrate that KIF20A overexpression was shown to correlate with poor prognosis ( P  < 0.001) and drives cell cycle dysregulation via CDC45/ORC1-mediated G2/M checkpoint bypass. Mechanistically, KIF20A+ epithelial cells exhibited enriched activation of RUNX2-dependent migratory programs (AUCell score: 0.23 vs. 0.15 in KIF20A− cells, P  < 0.001) and suppressed intrinsic apoptosis through BCL2 upregulation. Single-cell trajectory analysis revealed that KIF20A+ cells orchestrate macrophage M2 polarization via SPP1-CD44 signaling, fostering an immunosuppressive niche. Pharmacologically, the multi-kinase inhibitor Sorafenib suppresses KIF20A expression (IC₅₀ = 10 μM) and induced mitochondrial dysfunction, as evidenced by glutathione depletion (ΔGSH = −59%, P  < 0.01) and ROS accumulation (ΔMDA = +45%, P  < 0.001). Functional assays confirmed sorafenib's dose-dependent inhibition of proliferation (CCK-8: 38.5% reduction at 10 μM) and migration (Transwell: 70% suppression at 10 μM), mediated through G2/M arrest (flow cytometry: G2/M population Δ = +10.6%, P  < 0.01). Molecular docking identified a high-affinity interaction between sorafenib and KIF20A (binding energy: −6.11 kcal/mol), suggesting direct targeting. The current study unveiled KIF20A as a dual regulator of tumor-intrinsic malignancy and immune evasion, positioning sorafenib as a promising therapeutic agent to disrupt KIF20A-driven pathways in gastric adenocarcinoma.