Claudin18.2 and the PD-1/PD-L1 axis in gastric cancer: mechanistic insights and implications for combination immunotherapy.

introductionClaudin18.2 is a highly specific therapeutic target selectively expressed in gastric cancer cells. Emerging evidence suggests that Claudin18.2 positivity may be associated with an immunosuppressive tumor microenvironment and suboptimal responses to PD-1/PD-L1 blockade. However, the underlying mechanisms and therapeutic implications remain incompletely understood.

methodsThis article is a narrative review with a structured search. Relevant studies published up to 30 September 2025 were identified through searches of PubMed, Embase, Web of Science, Cochrane Library, and Scopus. Predefined inclusion and exclusion criteria were applied to select studies that addressed the relationship among Claudin18.2 expression, tumor immune microenvironment characteristics, immune checkpoint regulation, and immunotherapy outcomes in gastric cancer.

resultsClaudin18.2-positive gastric cancer presents a distinct immunosuppressive microenvironment, characterized by reduced NK cell infiltration, altered macrophage and neutrophil composition, dysregulated cytokine signaling, and increased infiltration of CD8 + and CD4 + T cells with evidence of functional impairment or exhaustion within the tumor core. Mechanistically, Claudin18.2 modulates immune checkpoint pathways by upregulating PD-1 through the PKC/ERK-MAPK pathway. Claudin18.2-targeted therapy may also indirectly regulate PD-L1 expression through immune activation and the JAK/STAT signaling pathway. Importantly, immune activation induced by Claudin18.2-targeted antibodies, CAR-T cells, bispecific antibodies, and ADCs (Antibody-Drug Conjugates) may partially reverse immune suppression and enhance sensitivity to PD-1/PD-L1 inhibition, although direct evidence remains limited.

conclusionThis review suggests that Claudin18.2 may serve as a key regulator of immune dysfunction rather than immune exclusion in gastric cancer, providing a potential biological rationale for combinatorial strategies integrating Claudin18.2-targeted therapies with immune checkpoint inhibition. Given the heterogeneity of available studies and the indirect nature of some evidence, these insights should be interpreted as exploratory; they may nonetheless help guide patient stratification and inform the rational design of future combination immunotherapy trials in Claudin18.2-positive gastric cancer.