Circ_0027446: a novel biomarker and therapeutic target to combat colorectal cancer and enhance immune response.

Circ_0027446 has been reported to promote malignant behaviors, including proliferation, invasion, metastasis, epithelial-mesenchymal transition, and glycolytic metabolism, in several cancers; however, its expression and biological significance in colorectal cancer (CRC) remain unclear. circ_0027446 expression was first analyzed in the GSE197991 dataset and then verified in 72 paired CRC tissues and CRC cell lines. Its association with clinicopathological features was further examined in the clinical cohort. Cell proliferation, apoptosis, invasion, PD-L1 expression, and CD8⁺ T-cell responses were evaluated by CCK-8, flow cytometry, Transwell, western blotting, co-culture, and ELISA. The interactions among circ_0027446, miR-6882-3p, and HOXB9 were assessed by RNA pull-down and dual-luciferase reporter assays. Rescue experiments based on miR-6882-3p inhibition and HOXB9 overexpression were performed, and a xenograft model followed by H&E staining, TUNEL staining, and IHC analysis was used for further validation. circ_0027446 was upregulated in CRC. Higher circ_0027446 expression was associated with larger tumor size, lymph node metastasis, advanced TNM stage, and shorter overall survival. Knockdown of circ_0027446 reduced CRC cell proliferation and invasion and increased apoptosis. It also decreased PD-L1 expression and was accompanied by increased CD8⁺ T-cell viability and higher levels of IFN-γ, IL-2, and TNF-α in the co-culture system. Mechanistically, circ_0027446 interacted with miR-6882-3p, whereas miR-6882-3p negatively regulated HOXB9. Inhibition of miR-6882-3p or HOXB9 overexpression partly reversed the effects of circ_0027446 knockdown on malignant activities, PD-L1 expression, and IFN-γ secretion. In vivo, circ_0027446 knockdown suppressed tumor growth, increased apoptosis, reduced HOXB9 and PD-L1 expression, and increased IFN-γ staining. circ_0027446 was upregulated in CRC and may contribute to tumor progression and immune escape-related changes, at least partly through the miR-6882-3p/HOXB9 axis. Therefore, circ_0027446 may be involved in CRC progression and merits further study.