Abstract
BACKGROUND: Tendomodulin (TNMD) is pivotal in various malignancies, including colorectal cancer (CRC). However, its comprehensive impact across cancers, particularly its immunomodulatory function in CRC, remains underexplored. This study explored the role of TNMD in CRC by focusing on its immunomodulatory functions through comprehensive molecular and clinical analyses. METHODS: Multiple bioinformatics databases and analytical tools were utilized for the TNMD in pan-cancer analysis. To validate the role of TNMD in CRC, we performed experiments, including immunofluorescence (IF), immunohistochemistry (IHC), real-time quantitative reverse transcription PCR (qPCR), western blotting, and cell migration assays. RESULTS: TNMD expression and gene mutation vary across cancers and offer high diagnostic value. Survival analysis found that TNMD is associated with prognosis in multiple cancers. Notably, in patients with high microsatellite instability (MSI-H) CRC, TNMD expression correlated positively with various immune cells, particularly natural killer (NK) cells, whereas it was inversely correlated with regulatory T cells (Tregs). Crucially, in patients with microsatellite stability (MSS) CRC, high TNMD expression was associated with better immunotherapy outcomes, indicating its potential as a biomarker for patient stratification and tailored treatment approaches. Furthermore, single-cell sequencing data revealed stronger interactions between TNMD-positive tumor cells and fibroblasts or macrophages in the tumor microenvironment. Finally, TNMD was overexpressed in CRC tumor tissues and cell lines, thereby promoting invasion and metastasis. CONCLUSIONS: Our findings reveal a critical immunomodulatory role of TNMD in CRC, particularly in influencing tumor-immune interactions. Beyond its potential diagnostic and prognostic biomarker, TNMD promotes CRC metastasis and invasion, thus emerging as a promising therapeutic target. These findings highlight TNMD's significance in CRC and potentially other malignancies.