Targeting the SELP/PSGL1 axis reprograms M2 macrophages and enhances anti-PD-1 efficacy in gastric cancer

Immune evasion and an immunosuppressive tumor microenvironment contribute to the poor prognosis of gastric cancer (GC), but the mechanisms governing tumor-associated macrophage (TAM) polarization remain unclear. Here we identify P-selectin (SELP) as a key driver of GC progression and immune suppression. SELP was markedly upregulated in GC and correlated with advanced stage, increased M2 macrophage infiltration, and poor survival. Mechanistically, SELP engaged PSGL1 on TAMs to activate PI3K/AKT/mTOR signaling, which enhanced glycolysis and lactate production. Lactate in turn induced MYB, thereby promoting SELP transcription and establishing a feed-forward circuit that sustained M2-like polarization. Therapeutically, genetic or pharmacological targeting of SELP reprogrammed TAMs towards a pro-inflammatory state, increased intratumoural CD8⁺ T-cell infiltration, and inhibited tumor growth. Moreover, SELP inhibition with KF38789 potentiated the antitumour efficacy of PD-1 blockade in syngeneic GC models. Together, these findings define a SELP/PSGL1-PI3K/AKT/mTOR-lactate-MYB signaling axis that promotes macrophage-mediated immune evasion in GC and highlight SELP as a potential therapeutic target for improving immunotherapy response.