WDR4 Drives Tumor-Associated Macrophage Reprogramming and Tumor Progression via eIF4E-Mediated mRNA Translation

Tumor-associated macrophages (TAMs) play a pivotal role in shaping the tumor microenvironment of hepatocellular carcinoma (HCC), profoundly influencing disease progression and clinical outcomes. WDR4, a tRNA-binding scaffold protein involved in N7-methylguanosine (m7G) methylation, remains poorly characterized in terms of its independent biological functions. Here, we report that WDR4 is markedly upregulated in HCC-infiltrating TAMs and correlates with poor patient prognosis. Using HCC tumorigenesis models, we demonstrate that selective deletion of Wdr4 in monocyte-derived macrophages—but not in Kupffer cells—drives TAM polarization toward an anti-tumor phenotype, thereby restraining HCC progression. Mechanistically, cytoplasmic WDR4 exerts a non-m7G-dependent role in promoting translation by directly interacting with eIF4E2. This interaction selectively enhances eIF4E-mediated translation of ABCA1, facilitating cholesterol efflux and consequently promoting tumor progression. For translational application, we developed a CpG-conjugated siRNA delivery system that specifically targets Wdr4 in TAMs, reprogramming the microenvironment toward a tumor-suppressive state and inhibiting tumor growth. Notably, this strategy, when combined with PD-1 blockade, elicits durable anti-tumor immune responses. Overall, the WDR4/eIF4E2/ABCA1 axis regulates TAM polarization and drives HCC progression, offering a promising therapeutic target for enhancing the efficacy of HCC immunotherapy. Overall design: An orthotopic HCC model was established in Wdr4^f/f and Wdr4^f/f Lyz2-Cre(Wdr4^cKO) mice using Hepa1-6 cells. Tumour tissues were harvested, and CD45+ immune cells were isolated for scRNA-sequencing transcriptome analysis.