Adora2b-induced cAMP upregulates PD-1 on CD8+ T cells; PD-1 signaling recruits SHP-2 to inhibit ERK, forming a “double brake” with Adora2b (32, 96).Consistent with the role of Adora2b in regulating immune cell function via adenosine-cAMP signaling (as observed in pancreatic cancer models, where Adora2b activation in CD8+ T cells suppresses cytotoxicity through cAMP-mediated pathways) (97), in GC CD8+ T cells, Adora2b-induced cAMP/PKA signaling may converge with PD-1-mediated immunosuppression. Here, ADORA2B is linked to familial pancreatic carcinoma.