EIF2B4 promotes hepatocellular carcinoma progression and immune evasion by driving STAT3 translation via a GEF-dependent mechanism.

Abstract

Background: Eukaryotic translation regulators have emerged as pivotal modulators of cancer progression and immune evasion. However, their mechanistic contributions in hepatocellular carcinoma (HCC) remain poorly understood. EIF2B4, the δ-subunit of the eukaryotic initiation factor 2B (eIF2B) complex, has not been previously characterized in HCC.

Methods: EIF2B4 expression was analyzed using public datasets and validated in clinical HCC samples. Functional assays, including gain- and loss-of-function experiments, were performed to assess its impact on cell proliferation, apoptosis, migration, and the cell cycle. RNA immunoprecipitation (RIP), luciferase reporter assays, immunoblotting, and mutational rescue were employed to elucidate EIF2B4-mediated translational regulation of STAT3. In vivo mouse models and immune co-culture systems were used to investigate the role of EIF2B4 in antitumor immunity and response to anti-PD-1 therapy.

Results: EIF2B4 was significantly upregulated in HCC and associated with poor prognosis. EIF2B4 promoted oncogenic phenotypes, including proliferation, migration, and cell cycle progression, while suppressing apoptosis. Mechanistically, EIF2B4 enhanced STAT3 protein expression by directly binding its mRNA and facilitating translation without affecting mRNA levels. EIF2B4 interacted with the eIF2 complex and required GEF activity to promote STAT3 translation via the 5' untranslated region (5'UTR). GEF-inactivating mutations abolished EIF2B4's translational and tumor-promoting effects. In vivo, EIF2B4 impaired CD8⁺ T cell-mediated cytotoxicity, reduced immune infiltration, and diminished the efficacy of anti-PD-1 therapy. Conversely, EIF2B4 knockout restored antitumor immunity and sensitized tumors to immune checkpoint blockade.

Conclusions: EIF2B4 functions as a previously unrecognized translational regulator that promotes HCC progression and immune evasion by enhancing STAT3 translation through a GEF-dependent mechanism. These findings highlight EIF2B4 as a potential therapeutic target and biomarker to improve immunotherapy responsiveness in HCC.

Clinical trial number: Not applicable.