Immunotherapy can improve survival in a variety of cancers by modulating the interaction between tumors and the tumor immune microenvironment (TIME). V-set and transmembrane domain containing 2 like (VSTM2L) regulates interleukin (IL)-4 signaling pathway-which involves immune-related factors-and has been linked to some cancers. However, the expression profile and prognostic significance of VSTM2L in different cancers as well as its relationship to the TIME are not known. This study investigated the pan-cancer expression profile, prognostic value, and immunologic relevance of VSTM2L. VSTM2L expression in different cancers was analyzed using the Cancer Cell Line Encyclopedia (CCLE), Human Protein Atlas (HPA), Tumor Immune Estimation Resource (TIMER), The Cancer Genome Atlas (TCGA), and Genotype-Tissue Expression (GTEx) portal. We examined the association between VSTM2L expression and clinical outcomes by Kaplan-Meier and Cox regression analyses using TCGA and Kaplan-Meier Plotter, and the results were validated in a Gene Expression Omnibus cohort. The correlations between VSTM2L expression and immune cell infiltration, immunomodulators, tumor mutation burden (TMB), microsatellite instability (MSI), and immune and stromal scores across cancers were analyzed using TCGA, TIMER, and Tumor-Immune System Interactions and Drugbank databases (TISIDB). The results showed that VSTM2L expression varied across cancers and its aberrant expression was associated with clinical outcomes: upregulation of VSTM2L was positively associated with advanced stage and reduced overall survival (OS), disease-specific survival (DSS), progression-free interval (PFI), and disease-free interval (DFI) in stomach adenocarcinoma (STAD); and its upregulation was associated with early-stage disease and improved OS, DSS, PFI, and DFI in kidney renal papillary cell carcinoma (KIRP). VSTM2L expression level was correlated with immune cell infiltration, expression of immunomodulators, TMB, MSI, and immune and stromal scores in multiple cancers. In conclusion, VSTM2L has prognostic value in various cancers and can predict both poor (STAD) and good (KIRP) outcomes. The relationship between VSTM2L expression and immune markers suggests a role in modulating the TIME.

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