Multimodal Analysis Reveals Immune Suppression Associated With Hepatocellular Carcinoma Related to RBM27 and Constructs a Prognostic Model

Background Hepatocellular carcinoma (HCC) exhibits aggressive progression and therapy resistance due to immunosuppressive microenvironments. RNA‐binding motif protein 27 (RBM27) is implicated in RNA processing, yet its role in HCC immune evasion remains uncharacterized. Methods Multiomics analyses (TCGA/GEO, single‐cell/spatial transcriptomics) were integrated with functional validation (in vitro/vivo). RBM27 expression was assessed in HCC tissues/cell lines. Knockdown models (lentiviral shRNA) evaluated impacts on proliferation, migration, invasion (Transwell/wound healing), and tumor growth (xenografts). Immune profiling (ssGSEA/TIP), metabolic pathways (GSEA/KEGG), and prognostic modeling (Cox/nomogram) were performed. Spatial transcriptomics mapped immune niche alterations. Results Compared with adjacent nontumor tissues, the expression level of RBM27 was markedly overexpressed in HCC tissues. Genomic analysis revealed that this upregulation is driven by copy number variations (CNVs), particularly gene amplification, alongside specific mutational patterns. This abnormal upregulation was closely correlated with advanced clinical stages of the disease, elevated AFP, and poor survival (OS/DSS/PFI; p < 0.05). RBM27 knockdown suppressed HCC proliferation, migration, invasion, and xenograft growth. Mechanistically, RBM27 activated oxidative phosphorylation, driving immunosuppression via CD8+ T cell and NK cell depletion, Treg/Th2 enrichment, and impaired cancer‐immunity cycle steps. Spatial analysis confirmed RBM27 + malignant niches with lymphoid exclusion. A prognostic nomogram (C − index = 0.688) incorporating RBM27 predicted 1‐/3‐/5‐year survival. Conclusion Driven by genetic alterations including gene amplification, RBM27 promotes HCC progression by remodeling an immunosuppressive microenvironment via OXPHOS activation, acting as a biomarker for diagnosis and prognosis along with a potential therapeutic target, it could assist in combating immune escape.