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Background: Chromosome 5 open reading frame 46 (C5ORF46), also known as antimicrobial peptide with 64 amino acid residues (AP-64) and skin and saliva-secreted protein 1 (SSSP1), belongs to the family of open reading frame genes and encodes a small exosomal protein. C5ORF46 has been implicated in antibacterial activity and associated with patient prognosis in pancreatic cancer, colorectal cancer, and stomach cancer. These findings highlight the importance of C5ORF46 in gastrointestinal (GI) tumor inception and development. However, the prognostic and immunological value of C5ORF46 in human GI tumors remains largely unknown. In this study, we sought to explore the potential value of C5ORF46 in GI tumor prognosis and immunology.Method: RNA sequencing (RNA-seq) was performed on the tumor and tumor-adjacent normal samples we collected to identify potential target genes for GI tumors. Apart from our RNA-seq data, all original data were downloaded from The Cancer Genome Atlas (TCGA) database and integrated via Strawberry Perl (v 5.32.0) and R (v 4.1.1). The differential expression of C5ORF46 was examined with Oncomine, Tumor Immune Estimation Resource (TIMER), Gene Expression Profiling Interactive Analysis (GEPIA), Cancer Cell Line Encyclopedia (CCLE), the Human Protein Atlas (HPA) and TCGA databases. The c-BioPortal database was used to investigate the genomic alterations of C5ORF46. The effect of C5ORF46 on prognosis and clinical phenotypes was explored via bioinformatics analyses on the TCGA and GEPIA databases. We used the bioinformatics analyses based on the TCGA database to analyze tumor mutational burden (TMB), microsatellite instability (MSI), tumor immune cell infiltration, and the correlations between C5ORF46 expression and several immune-related genes. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was carried out via the DAVID website and presented as bubble charts using ShengXinRen online tools. Gene set enrichment analysis (GSEA) was performed using R scripts based on data downloaded from the GSEA website. Immunohistochemistry (IHC) was used to validate the expression of C5ORF46 in GI tumors.Results: The results of our RNA-seq data indicated a critical role for C5ORF46 in colon carcinogenesis. Consistently, we demonstrated that C5ORF46 was highly expressed in tumor tissues compared to normal tissues in human GI tumors. Moreover, a strong correlation was observed between C5ORF46 expression levels and patient prognosis, staging, TMB, MSI, and immune cell infiltration. Further, C5ORF46 presented as an important regulator in the tumor microenvironment (TME) and was active in the regulation of cancer immune functions. C5ORF46 is significantly correlated with genes regulating inflammation and immune responses.Conclusion:C5ORF46 may serve as a biomarker for GI tumor prognosis and immunology. C5ORF46 could be a novel target for GI tumor immunotherapy.