RBM4 Stabilizes S100A10 mRNA to Remodel the Tumor Immune Microenvironment and Promote Immune Evasion in Hepatocellular Carcinoma.

Abstract

RNA-binding protein RBM4 regulates post-transcriptional programs, but its role in shaping the hepatocellular carcinoma (HCC) tumor immune microenvironment (TIME) is unclear. We hypothesized that RBM4 enhances S100A10 mRNA stability to drive immune evasion. RBM4-S100A10 coupling was interrogated by expression profiling, RIP-qPCR, actinomycin D chase, and 3'UTR reporter assays. Gain/loss models (OE-RBM4, shS100A10) were used to assess migration/invasion and apoptosis. Immune consequences were evaluated by CD8+ T-cell co-culture (ELISA for Granzyme B, IFN-γ, TNF-α; IL-10, TGF-β) and immunofluorescence. Western blots probed cPLA2/5-LOX signaling. Subcutaneous/orthotopic models measured tumor growth, CD8+ infiltration, and effector subsets; S100A10 silencing and PD-1 blockade served as interventions. RBM4 positively correlated with S100A10 and bound the S100A10 3'UTR, increasing mRNA stability and 3'UTR-dependent reporter activity. RBM4 overexpression promoted migration/invasion and reduced apoptosis, whereas S100A10 knockdown reversed these phenotypes. In the TIME context, RBM4 reduced CD8+ T-cell effector function (lower Granzyme B/IFN-γ/TNF-α) while elevating IL-10/TGF-β, accompanied by diminished CD8+ infiltration and fewer CD8+GZMB+/CD8+TNF-α+ cells in vivo. Mechanistically, RBM4 activated the cPLA2/5-LOX axis (increased phospho-forms with stable totals). S100A10 silencing or PD-1 blockade mitigated immune suppression and restrained tumor growth, indicating pathway specificity and therapeutic tractability. RBM4 enhances S100A10 mRNA stability, remodels the HCC TIME, suppresses CD8+ T-cell effector function, and promotes immune evasion; targeting the RBM4-S100A10 axis may improve responses to PD-1 immunotherapy.