Targeting CD276 inhibits gastric cancer progression and synergizes with anti-PD-1 therapy to enhance T-cell immunity

CD276 is broadly overexpressed in solid tumors and represents an emerging therapeutic target, yet its functional contribution to gastric cancer progression and immunotherapy resistance remains unclear. This study integrated transcriptomic analysis, in vitro functional assays, mechanistic dissection, and immune co-culture systems to investigate how CD276 drives malignancy and immune evasion, and whether its inhibition enhances anti-PD-1 efficacy. Using TCGA data, we confirmed significant CD276 upregulation in gastric cancer. CD276 knockdown in AGS and MKN-28 cells suppressed proliferation, colony formation, and migration, with RNA-seq and Western blot revealing reduced p38/MEK phosphorylation in the MAPK pathway. In co-cultures with PBMC-derived T cells, CD276 inhibition increased GzmB + CD8 + T cells and decreased exhaustion-associated PD-1 + Tim-3 + populations, effects potentiated by PD-1 blockade. In vivo, anti-CD276 plus anti-PD-1 combination therapy exerted the strongest tumor suppression and increased intratumoral CD45 + and CD3 + CD8 + T cell infiltration, indicating enhanced antitumor immunity. Public database analyses further linked high CD276 expression to infiltration of Tregs and M2 macrophages, whereas low CD276 correlated with naïve/effector T cells, monocytic DCs, and favorable responses to PD-1/CTLA-4 blockade. Notably, CD276 upregulation was observed in immunotherapy-resistant cases. CD276 promotes gastric cancer, with concurrent associations with cell-intrinsic MAPK signaling and microenvironmental immune suppression. Targeting CD276 exerts dual anti-tumor effects and synergizes with PD-1 blockade, positioning it as a candidate strategy to overcome immune checkpoint resistance.