Journal Article

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

Zhou, Jian, Shen, Li-An, Wang, Chun-Yan, Fan, Jia, Nie, Yan-Yan, Huang, Cheng, Wang, Yu-Lei, Yang, Xin-Rong, Hu, Bo, Zhu, Di, Xu, Yang, Qiu, Shuang-Jian, Zhu, Andrew X., Wu, Sui-Yi, Zhu, Yuan-Yuan, Sun, Jia-Lei, He, Tian, Chen, Zhong, Huang, Xun, Song, Fei

2025

Overview

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, hsBCL9 Z96 , 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. Immune checkpoint inhibitors have shown promise in tumour immunotherapy but resistance has been seen. Here using pre-treatment hepatocellular carcinoma patient biopsies from patients scheduled for immunotherapy, the authors implicate BCL9 and show that a BCL9-targeting peptide promotes anti-tumour immunity in mouse models through targeting macrophages and promoting anti-tumour T cell responses.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/105 / 13/21 / 13/31 / 13/62 / 631/250/2504/342 / 631/250/580/1884 / 631/67/1059/2325 / 631/67/1059/2326 / 631/67/1504/1610 / Animal models / Animals / Antigen presentation / Antigen Presentation - drug effects / Antigen Presentation - immunology / Antigens / B-cell lymphoma / Biopsy / Cancer / Carcinoma, Hepatocellular - drug therapy / Carcinoma, Hepatocellular - genetics / Carcinoma, Hepatocellular - immunology / Carcinoma, Hepatocellular - pathology / Carcinoma, Hepatocellular - therapy / Cell death / Cell Line, Tumor / Colorectal cancer / Drug Resistance, Neoplasm - drug effects / Drug Resistance, Neoplasm - immunology / Female / Hepatocellular carcinoma / Humanities and Social Sciences / Humans / Immune checkpoint inhibitors / Immune Checkpoint Inhibitors - pharmacology / Immune Checkpoint Inhibitors - therapeutic use / Immunity / Immunotherapy / Immunotherapy - methods / Inhibitors / Kinases / Liver cancer / Liver Neoplasms - drug therapy / Liver Neoplasms - genetics / Liver Neoplasms - immunology / Liver Neoplasms - pathology / Liver Neoplasms - therapy / Lymphocytes / Lymphocytes T / Lymphoma / Macrophages / Macrophages - drug effects / Macrophages - immunology / Medical prognosis / Mice / Mice, Inbred C57BL / multidisciplinary / Patients / PD-L1 protein / Phagocytosis / Phagocytosis - drug effects / Phagocytosis - immunology / Phenotypes / Response rates / Science / Science (multidisciplinary) / Toxicity / Transcription Factors / Tumor cells / Tumor microenvironment / Tumor Microenvironment - drug effects / Tumor Microenvironment - immunology / Tumors / Wnt protein / Wnt Signaling Pathway / β-Catenin