Cancer-Associated Fibroblasts and Prostaglandin E2 Signaling in Gastric Cancer: Immunometabolic Mechanisms and Implications for Immunotherapy Resistance

Cancer-associated fibroblasts (CAFs) and prostaglandin E2 (PGE2) signaling have each been implicated in resistance to immune checkpoint inhibitors (ICIs) in gastric cancer. CAFs are associated with immune exclusion, whereas PGE2 can suppress CD8+ T-cell responses through prostaglandin E receptors 2 and 4 (EP2 and EP4) and alter dendritic-cell and myeloid-cell function. Whether PGE2 produced by CAFs directly contributes to ICI resistance in gastric cancer, however, remains unclear. To distinguish association from functional involvement, we synthesize the available literature into a conceptual continuum describing the possible contribution of PGE2 to CAF-associated immunotherapy resistance. At the Model A end, PGE2 may accompany CAF activation or local inflammation, whereas other CAF-associated mechanisms, including extracellular matrix remodeling, lactate, and CXCL12 signaling, may account for much of the resistance phenotype. At the Model B end, PGE2 may make an identifiable functional contribution to resistance beyond these alternative mechanisms, although the cellular source of the relevant PGE2 remains unresolved. These models represent interpretive endpoints derived from the available evidence rather than experimentally validated resistance subtypes or an established CAF-derived PGE2 pathway. Clinical findings with the EP4 antagonist ONO-4578 support the therapeutic potential of receptor blockade but do not identify the cellular source of PGE2 involved. Key unresolved questions concern the cellular sources of PGE2, its relationship with immune exclusion, and whether PGE2-related markers improve the prediction of ICI response beyond established indicators.