UCHL1 Expression in Colorectal Cancer: Clinicopathological Significance, Prognostic Value, and Implications for Immunotherapy Response

Background/Objectives: Ubiquitin C-terminal hydrolase L1 (UCHL1) exhibits context-dependent roles in various cancers, but its clinical significance and biological functions specifically in colorectal cancer (CRC) remain incompletely understood. Methods: We systematically evaluated UCHL1 expression, clinicopathological associations, prognostic value, and immunological role in CRC using multiple public databases (TCGA, GTEx, UALCAN, GEPIA2, GSCA, and ENCORI) combined with immunohistochemical validation on a tissue microarray containing 80 paired CRC and adjacent normal tissues. Functional enrichment was assessed using ssGSEA, and immune cell infiltration was analyzed using the immunedeconv R package. The immunotherapy response was evaluated using the TIDE algorithm. Results: UCHL1 mRNA and protein levels were significantly downregulated in CRC tissues compared with normal tissues. Paradoxically, high UCHL1 expression was significantly associated with advanced T stage, N stage, TNM stage, and poor overall and disease-free survival. ssGSEA revealed positive associations with multiple aspects of oncogenic pathways, including tumor inflammation signature, tumor proliferation signature, epithelial–mesenchymal transition markers, extracellular matrix-related genes, angiogenesis, apoptosis, and G2M checkpoint regulation. Notably, UCHL1 expression was positively correlated with computationally estimated infiltration of macrophages, CD4+ T cells, and CD8+ T cells, and with elevated expression of immune checkpoint genes, as well as higher TIDE scores. These correlative findings suggest a potential association with immunotherapy-related pathways that warrants further investigation. Conclusions: UCHL1 is downregulated in CRC, but its elevated expression is associated with aggressive disease and poor prognosis. It is implicated in multiple oncogenic pathways and may contribute to an immunosuppressive tumor microenvironment, suggesting its potential as a candidate prognostic biomarker that warrants further functional investigation.