AbstractBackgroundHepatocellular carcinoma (HCC) is widely recognized as a globally prevalent malignancy. Immunotherapy is a promising therapy for HCC patients. Increasing evidence suggests that lncRNAs are involved in HCC progression and immunotherapy.AimThe study reveals the mechanistic role of long non‐coding RNA (lncRNA) FOXD1‐AS1 in regulating migration, invasion, circulating tumor cells (CTCs), epithelial‐mesenchymal transition (EMT), and immune escape in HCC in vitro.MethodsThis study employed real‐time PCR (RT‐qPCR) to measure FOXD1‐AS1, miR‐615‐3p, and programmed death‐ligand 1 (PD‐L1). The interactions of FOXD1‐AS1, miR‐615‐3p, and PD‐L1 were validated via dual‐luciferase reporter gene and ribonucleoprotein immunoprecipitation (RIP) assay. In vivo experimentation involves BALB/c mice and BALB/c nude mice to investigate the impact of HCC metastasis.ResultsThe upregulation of lncRNA FOXD1‐AS1 in malignant tissues significantly correlates with poor prognosis. The investigation was implemented on the impact of lncRNA FOXD1‐AS1 on the migratory, invasive, and EMT of HCC cells. It has been observed that the lncRNA FOXD1‐AS1 significantly influences the generation and metastasis of MCTC in vivo analysis. In mechanistic analysis, lncRNA FOXD1‐AS1 enhanced immune escape in HCC via upregulation of PD‐L1, which acted as a ceRNA by sequestering miR‐615‐3p. Additionally, lncRNA FOXD1‐AS1 was found to modulate the EMT of CTCs through the activation of the PI3K/AKT pathway.ConclusionThis study presents compelling evidence supporting the role of lncRNA FOXD1‐AS1 as a miRNA sponge that sequesters miR‐655‐3p and protects PD‐L1 from suppression.