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Homeobox (HOX) genes are essential regulators of embryonic development and cellular differentiation under physiological conditions. Among this gene family, HOXA10 has emerged as a pivotal factor in gastrointestinal (GI) cancers, influencing tumor growth, metastasis, disease progression, and resistance to therapy. HOXA10 functions as a transcription factor and plays key roles not only in embryogenesis but also in immunomodulation. HOXA10 and its transcriptional targets play a crucial role in cancer development, promoting cell growth, invasion, migration, metastasis, and resistance to cell death. Recent studies have explored the influence of HOXA10 on the tumor immune microenvironment, particularly its role in modulating immune cell recruitment and signaling pathways that enable tumor immune evasion. Our recent research identified a HOXA10-regulated five-gene signature that distinguishes long-term from short-term survivors of pancreatic cancer, with HOXA10 expression correlating with increased regulatory T cell (T_reg) infiltration. HOXA10 impacts genes and pathways involving macrophages, Tregs, and other immune cells, potentially creating an immunosuppressive niche that promotes metastasis and diminishes the effectiveness of immunotherapies. In this review, we examine the diverse functions of HOXA10 in GI cancers, offering a comprehensive comparison with other HOX family proteins to elucidate their overlapping and distinct roles in malignancy. Our goal is to provide a thorough overview of how HOXA10 contributes to tumor development and its microenvironment. We highlight its critical role in facilitating cancer progression and metastasis, supported by data from cell lines, patient tumor samples, and clinical studies. Recognizing existing gaps in the understanding of HOXA10's role in cancer, we also explore potential strategies to target this gene, with an emphasis on synergistic approaches that combine HOXA10 inhibition and immunotherapy. Ultimately, these insights aim to identify vulnerabilities within GI cancers that could be exploited through novel therapeutic agents and combination treatments, paving the way for improved clinical outcomes.