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

Jie Liu; Chengming Qu; Yingyi Liu; Xiangdong Gongye; Minghe Zhang; Tianyin Ma; Wenzhi He; Haitao Wang; Xi Chen; Peng Xia; Yufeng Yuan

doi:10.1038/s41556-025-01815-6

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

Nat Cell Biol. 2025 Nov 28. doi: 10.1038/s41556-025-01815-6. Online ahead of print.

Authors

Jie Liu^#^{1

2}, Chengming Qu^#^{1

3}, Yingyi Liu^#¹, Xiangdong Gongye^{1

4}, Minghe Zhang¹, Tianyin Ma¹, Wenzhi He¹, Haitao Wang¹, Xi Chen⁵, Peng Xia^#^{6

7

8}, Yufeng Yuan^{9

10}

Affiliations

¹ Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, People's Republic of China.
² Department of Chemistry, The University of Chicago, Chicago, IL, USA.
³ Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL, USA.
⁴ Department of Chemistry and Molecular Biology, Sahlgrenska Akademin, Göteborg Universitet, Gothenburg, Sweden.
⁵ Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, People's Republic of China. chenxi2022@whu.edu.cn.
⁶ Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, People's Republic of China. pengxia@uchicago.edu.
⁷ Department of Chemistry, The University of Chicago, Chicago, IL, USA. pengxia@uchicago.edu.
⁸ Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL, USA. pengxia@uchicago.edu.
⁹ Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, People's Republic of China. yuanyf1971@whu.edu.cn.
¹⁰ TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, People's Republic of China. yuanyf1971@whu.edu.cn.

^# Contributed equally.

PMID: 41315768
DOI: 10.1038/s41556-025-01815-6

Abstract

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.