Abstract
Colorectal cancer (CRC) remains a major cause of cancer-related mortality worldwide. While immune checkpoint blockade (ICB) has transformed cancer therapy, its clinical benefit in CRC is often limited by an immune-excluded tumor microenvironment (TME). MicroRNA-21-5p (miR-21-5p) is a well-established oncomiR in CRC; however, its role in immune resistance remains incompletely elucidated. In this study, we explored the potential immunoregulatory role of miR-21-5p in CRC by integrating transcriptomic profiling of TCGA-COAD and TCGA-READ cohorts with experimental validation of its target PTEN in CRC cell models. MiR-21-5p was markedly upregulated in tumors compared with adjacent normal tissues and was associated with reduced infiltration of CD8(+) T cells and dendritic cells. Functional assays confirmed that miR-21-5p directly targets PTEN; transcriptomic correlations further suggested potential links to PI3K/AKT activation and alterations in JAK-STAT and Th17-associated signaling. Elevated miR-21-5p was associated with transcriptomic signatures indicative of altered Th1/Th2 balance, reduced IgA-related immune responses, and features of an immune-excluded TME. Therapeutically, the inhibition of miR-21-5p has been reported in previous studies to restore PTEN and modulate signaling pathways. However, our study did not evaluate immune reactivation or checkpoint-blockade efficacy; thus, such therapeutic implications remain hypothetical. Collectively, these findings suggest that the miR-21-PTEN-PI3K/AKT axis may contribute to shaping immune-related features in CRC. These findings provide a rationale for future studies investigating whether targeting miR-21-5p could enhance antitumor immunity or improve immunotherapy response in CRC.