Hepatocellular carcinoma (HCC) is one of the most common and lethal cancers worldwide, accounting for a significant portion of cancer-related deaths. Its aggressive nature, late diagnosis, and resistance to conventional therapies contribute to poor clinical outcomes. Immune evasion, a hallmark of cancer progression, plays a pivotal role in HCC, allowing tumor cells to escape immune surveillance and establish a favorable microenvironment for growth and metastasis. Human Leukocyte Antigen (HLA) Class I molecules are critical components of the immune system that mediate tumor-immune interactions by presenting tumor-derived antigens to cytotoxic T lymphocytes (CTLs). Disruptions in HLA expression or allele-specific variations can impair antigen presentation, reducing immune recognition and facilitating tumor immune escape. Despite this central role, the specific impact of HLA Class I alleles on HCC progression, prognosis, and therapeutic response remains underexplored. A deeper understanding of the relationship between HLA-I alleles and HCC could reveal novel immunogenomic biomarkers for both prognosis and therapeutic intervention. To address this knowledge gap, we conducted a comprehensive analysis of HLA Class I alleles in HCC patients using data from The Cancer Genome Atlas (TCGA). Our dataset comprised ۸,۹۹۸ samples, including patients with HCC and a pan-cancer cohort. We investigated allele frequency disparities across these groups to identify HLA-I alleles with potential prognostic significance. Statistical analyses were performed using Fisher's exact test to determine the significance of allele frequency differences, providing insights into their association with HCC development and clinical outcomes. Several HLA Class I alleles were identified as significantly associated with an increased risk of HCC, including A۱۱:۰۱, A۳۳:۰۳, B۴۶:۰۱, C۰۱:۰۲, C۰۷:۰۶, and C۰۸:۰۱. These alleles demonstrated higher frequencies in HCC patients compared to the pan-cancer cohort, suggesting their role in disease susceptibility. Notably, HLA-B*۵۱:۰۱ exhibited a significant correlation with improved survival outcomes (Log HR -۰.۷۶۹, p-value ۰.۰۳۵), highlighting its potential as a prognostic biomarker. However, the prognostic relevance of other identified alleles remains unclear and requires further validation through detailed survival analyses. This study highlights the importance of HLA Class I alleles in HCC, revealing their association with disease risk and survival outcomes. These findings suggest that specific HLA-I alleles may serve as valuable immunogenomic biomarkers for prognosis, paving the way for tailored therapeutic strategies, including personalized immunotherapy approaches. Future studies are warranted to further elucidate the functional mechanisms underlying these associations and their clinical utility
