Targeting tumor-intrinsic BCL9 reverses immunotherapy resistance by eliciting macrophage-mediated phagocytosis and antigen presentation

Sui-Yi Wu, Yuan-Yuan Zhu, Jia-Lei Sun, Chun-Yan Wang, Yu-Lei Wang, Yan-Yan Nie, Fei Song, Xun Huang, Zhong Chen, Tian He, Li-An Shen, Yang Xu, Cheng Huang, Shuang-Jian Qiu, Jian Zhou, Andrew X. Zhu (), Jia Fan (), Di Zhu (), Bo Hu () and Xin-Rong Yang ()
Additional contact information
Sui-Yi Wu: Fudan University
Yuan-Yuan Zhu: Fudan University
Jia-Lei Sun: Fudan University
Chun-Yan Wang: Shanghai Jiao Tong University School of Medicine
Yu-Lei Wang: Genentech, Inc.
Yan-Yan Nie: Shanghai Laboratory Animal Research Center
Fei Song: Affiliated Hospital of Nantong University
Xun Huang: Lingang Laboratory
Zhong Chen: Affiliated Hospital of Nantong University
Tian He: Fudan University
Li-An Shen: Fudan University
Yang Xu: Fudan University
Cheng Huang: Fudan University
Shuang-Jian Qiu: Fudan University
Jian Zhou: Fudan University
Andrew X. Zhu: Jiahui Health
Jia Fan: Fudan University
Di Zhu: Fudan University
Bo Hu: Fudan University
Xin-Rong Yang: Fudan University

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract Immune checkpoint inhibitors (ICI) benefit some cancer patients but de novo resistance remains poorly understood. Analyzing transcriptional data from two clinical trial cohorts, GO30140 and IMbrave150, we find B cell lymphoma 9 (BCL9), a Wnt/β-catenin co-factor, associated with resistance. We develop a BCL9-targeting peptide, hsBCL9Z96, which suppresses tumor growth in combination with anti-PD-L1 ab in preclinical hepatocellular carcinoma (HCC) mouse models. Multi-omics analyses implicate targeting BCL9 inhibits BMP4 secretion and downregulates CD24 on tumor cells, reprogramming macrophages toward a tumor-suppressive phenotype and promoting macrophage phagocytosis. This in turn rejuvenates T cell immunity via enhanced macrophage-mediated antigen presentation. Our data extend our understanding of how tumor-derived Wnt/β-catenin signaling impedes the innate and adaptive immune responses in the tumor microenvironment and provide preliminary evidence that targeting BCL9 is a promising preclinical strategy to mitigate ICI resistance in HCC.

Date: 2025
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DOI: 10.1038/s41467-025-65945-z

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