Background <p>HOMER family proteins are extensively expressed across human tissues, exhibiting aberrant expression patterns that are specific to tissues and diseases. HOMER1 has been linked to neurodevelopmental disorders, HOMER2 to hearing loss, and HOMER3 has been implicated in oncogenic processes across various malignancies [1, 2]. Homer Scaffold Protein 3 (HOMER3), a scaffold protein comprising 361 amino acids, is encoded on human chromosome 19p13.11. However, its role across different cancers remains inadequately characterized. This study aims to comprehensively evaluate the expression landscape, prognostic significance, drug sensitivity associations, and immune-related features of HOMER3 across diverse cancer types, with a particular focus on colorectal cancer (CRC), to support its potential as a prognostic biomarker and therapeutic target in CRC.</p> Methods <p>Transcriptomic and clinical data for 33 cancer types, encompassing both tumor and normal tissue samples, were obtained from public databases, including TCGA and CCLE. Differential expression of HOMER3, prognostic relevance, immune-related characteristics, and correlations with drug sensitivity were systematically assessed between tumor tissues and adjacent non-tumor counterparts. The differential expression pattern and clinical significance of HOMER3 were further validated in CRC specimens.</p> Results <p>HOMER3 expression is significantly elevated in multiple malignancies and correlates with poor prognosis, with the most pronounced increase observed in CRC. Furthermore, HOMER3 is significantly associated with immune cell infiltration, as well as with drug sensitivity and tumor-associated pathways across various cancer types.</p> Conclusion <p>Integrated pan-cancer analyses suggest that HOMER3 may serve as a prognostic biomarker in multiple cancer types. In CRC, HOMER3 presents as a promising candidate for prognostic assessment and therapeutic targeting.</p>