Integrated Multiomics Analysis and Experimental Validation Identify ITPRIPL1 as an Immunoregulatory and Prognostic Biomarker in Gastric Adenocarcinoma

Background Inositol 1,4,5‐trisphosphate receptor‐interacting protein‐like 1 (ITPRIPL1) has been identified as an inhibitory ligand of CD3ε, but its role in stomach adenocarcinoma (STAD) remains unclear. Aims This study aims to elucidate the oncogenic and immunoregulatory roles of ITPRIPL1 in STAD. Materials and Methods Integrative bioinformatic analyses, including transcriptomic and spatial transcriptomic data, were performed to assess ITPRIPL1 expression, prognostic relevance, and immune interactions. Experimental approaches, including proliferation, migration, and invasion assays, were used to validate the functional effects. Results We found that ITPRIPL1 was significantly upregulated in STAD and associated with an unfavorable prognosis. Although enriched in T cell activation pathways, ITPRIPL1‐expressing tumor cells predominantly interacted with regulatory T cells (Tregs) and exhausted T cells (Tex), while showing limited communication with cytotoxic or naïve T cells. Spatial analyses revealed positive correlations between ITPRIPL1 expression and both tumor malignancy and T cell exhaustion signatures, but a negative correlation with CD274 expression. Functional assays confirmed the role of ITPRIPL1 in promoting tumor cell proliferation, migration, and invasion. Discussion Collectively, ITPRIPL1 promotes STAD progression by increasing tumor aggressiveness and fostering interactions with immunosuppressive T cell subsets. Conclusion These findings suggest that ITPRIPL1 is a potential prognostic marker and immunosuppressive target in STAD.