EIF4A3-induced circEIF2S2 facilitates colorectal cancer growth, metastasis, and immune suppression via the miR-646/UHMK1 Axis.

Circular RNAs (circRNAs) have emerged as critical regulators of colorectal cancer (CRC) progression; however, the biological function of circEIF2S2 remains largely unexplored. In this study, we investigated the expression, functional roles, and regulatory mechanisms of circEIF2S2 in CRC. Bioinformatic analyses and quantitative RT-PCR revealed that circEIF2S2 is significantly upregulated in CRC tissues and cell lines and is associated with unfavorable clinical outcomes. Functional assays demonstrated that circEIF2S2 silencing markedly suppressed CRC cell proliferation, migration, invasion, and immune checkpoint expression, while enhancing CD8 T cell-mediated immune responses in co-culture systems. Mechanistically, circEIF2S2 predominantly localized in the cytoplasm and functioned as a competing endogenous RNA by sponging miR-646, thereby relieving miR-646-mediated repression of UHMK1. In addition, the RNA-binding protein EIF4A3 promoted circEIF2S2 biogenesis through direct interaction with EIF2S2 pre-mRNA. Rescue experiments confirmed that the oncogenic and immunosuppressive effects of circEIF2S2 were partially reversed by miR-646 inhibition or UHMK1 suppression. In vivo, circEIF2S2 depletion significantly inhibited tumor growth and liver metastasis in xenograft models. Collectively, these findings identify the EIF4A3-circEIF2S2-miR-646-UHMK1 axis as an important regulatory pathway involved in CRC progression and tumor-associated immunosuppression.