WDR4 drives tumour-associated macrophage reprogramming and tumour progression via selective translation and membrane...

Tumour-associated macrophages (TAMs) play a pivotal role in shaping the immune microenvironment of hepatocellular carcinoma (HCC), influencing tumour progression and immunotherapy response. WDR4, a tRNA-binding cofactor of the N⁷-methylguanosine (m⁷G) methyltransferase complex, remains poorly understood in its independent functions. Here we show that WDR4 is significantly upregulated in HCC-associated TAMs and correlates with poor prognosis. Loss of WDR4 in monocyte-derived macrophages, but not in resident Kupffer cells, reprogrammes TAMs towards an antitumoral phenotype and suppresses HCC progression. Mechanistically, cytoplasmic WDR4 acts independently of m⁷G modification by directly interacting with eIF4E2 to enhance eIF4E-mediated selective translation of ABCA1, thereby promoting membrane cholesterol efflux and maintaining pro-tumoral polarization. Targeted silencing of WDR4 in TAMs using a CpG-small interfering RNA delivery system enhances antitumour immunity, inhibits tumour progression and improves the efficacy of anti-PD-1 therapy. Our findings identify WDR4 as a key regulator of TAM polarization and a promising therapeutic target to enhance immunotherapeutic outcomes.