Pan-cancer multi-omics profiling of OAS3 reveals its immunological and prognostic associations across human cancers.

Background: The enzyme 2'-5'-oligoadenylate synthetase 3 (OAS3) plays a well-established role in antiviral immunity, but its involvement in cancer biology remains poorly understood. This study aimed to comprehensively investigate the expression patterns, mutation characteristics, prognostic significance, functional roles, and therapeutic potential of OAS3 across multiple cancer types. Methods: Utilizing multi-omics data from public cancer databases, we analyzed OAS3 expression patterns, survival correlations, immune interactions, pathway enrichment, genomic associations, mutation profiles, and functional validation of OAS3 knockdown in THP-1 cells for apoptosis assays. Results: OAS3 expression was significantly upregulated in 32 cancer types, highlighting its context-dependent roles as an oncogene. The expression patterns of OAS3 were found to be stage-specific and cancer-specific across multiple tumor types. Survival analysis revealed that high OAS3 expression was significantly associated with unfavorable prognosis in several cancers. Further analyses demonstrated that OAS3 expression was correlated with immune-related genes, immune checkpoints, tumor stemness, and immune cell infiltration across multiple tumor types. Moreover, gene set enrichment profiling revealed significant involvement of OAS3 in interferon response and immune regulation, with prominent enrichment in Janus kinase-signal transducer and activator of transcription (JAK-STAT) and Notch signaling pathways. Mutation analysis highlighted high mutation frequencies of OAS3 in several cancer types, especially in endometrial cancer and melanoma. Comprehensive molecular profiling further identified significant associations between OAS3 expression levels and key genomic features (tumor mutation burden, homologous recombination deficiency and RNA modification-related proteins). Besides, OAS3's expression was associated with key processes such as cell cycle regulation and immune evasion, further underscoring its potential as a therapeutic target in lung and breast cancers. Finally, we found that OAS3 was observably related with some mutation types (CEBPA, FLT3 internal tandem duplication, NRAS, and EVI1 expression) in patients with acute myeloid leukemia (LAML). Functional validation through RNA interference demonstrated that OAS3 knockdown significantly induced apoptosis in THP-1 cells. Conclusion: This study demonstrates that OAS3 acts as a pivotal modulator in the complex network of cancer progression, highlighting its dual role in both tumorigenesis and immune response regulation.