The role of Sine Oculis Homeobox Homolog 2 in colon Cancer: Insights into prognosis, immune regulation, and therapeutic implications

Colon cancer (CC) remains a significant global health burden, and the search for novel prognostic biomarkers and therapeutic targets is crucial. This study comprehensively analyzed the role of SIX2 (Sine Oculis Homeobox Homolog 2) in CC. Utilizing data from TCGA, GTEx, and CCLE databases, differential expression of SIX2 was observed in multiple cancers, with significant upregulation in many tumors compared to normal tissues. In CC, SIX2's differential expression was notable. Cox regression analysis revealed its prognostic significance, with overexpression associated with poor survival outcomes. SIX2 was strongly associated with gene alterations and correlated with key signaling pathways like WNT and TGF-β. In the tumor microenvironment, SIX2 was related to immune cell infiltration and immune-related molecules. Notably, in CC, it was associated with immunosuppressive cells and checkpoint molecules. Additionally, ABT737 was found to sensitize tumor immunotherapy in the context of SIX2. Animal experiments demonstrated that ABT737 effectively restricted the growth of CC in mice, and its combination with antiPD-1 immunotherapy was more effective. It could reduce the infiltration of CD163+ tumor-associated macrophages but without significantly increasing the infiltration of CD8⁺ T cells. Our findings suggest that SIX2 is a potential key player in CC, offering insights into future research and the development of targeted therapies.