ORIGINAL RESEARCH article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1662385
This article is part of the Research TopicDeciphering Membrane and Intracellular Protein Targets in Cancer: Subcellular Mechanisms, Drug Discovery, and Translational InterventionsView all articles
Disrupting β-Catenin/BCL9 Interaction with a Peptide Prodrug Boosts Immunotherapy in Colorectal Cancer
Provisionally accepted
- 1Department of Hepatology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi'an, China
- 2Department of Medical Oncology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- 3Institute for Stem Cell & Regenerative Medicine,The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- 4National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi'an, China
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Hyperactivation of the Wnt/β-catenin pathway serves as a central mechanism underlying tumor progression, immune evasion, and resistance to immune checkpoint inhibitors (ICIs) therapy in colorectal cancer (CRC). A pivotal contributor to this process is the binding of β-catenin to B-cell lymphoma 9 (BCL9)， which promotes transcription of oncogenes and fosters an immunesuppressive tumor milieu. Consequently, targeting this interaction offers a promising approach to suppress tumor progression and potentiate antitumor immune responses. Here, we developed a peptide-based prodrug, Bcl9@TP, designed to competitively bind the BCL9 interface on β-catenin, destabilize the transcriptional complex, and shut off Wnt/β-catenin activity. In vitro, Bcl9@TP significantly inhibited MC38 cell proliferation by downregulating β-catenin and its downstream targets, inducing G1-phase cell cycle arrest. Treatment with Bcl9@TP resulted in a marked reduction in tumor burden, achieving a tumor growth inhibition (TGI) rate of approximately 62%, significantly surpassing that of the control group. In contrast, anti-PD-1 monotherapy yielded a TGI of only 41%. Notably, the combination therapy (Bcl9@TP and anti-PD-1) produced a more pronounced antitumor effect, with the TGI reaching 82%. Importantly, Bcl9@TP demonstrated favorable systemic biocompatibility and safety. Collectively, our study demonstrates that a peptide-based nanoprodrug capable of disrupting β-catenin/BCL9 is a compelling strategy to suppress oncogenic signaling and potentiate the response to immunotherapy in CRC, providing a new angle to boost checkpoint sensitivity.
Keywords: colorectal cancer, peptide, protein-protein interaction, β-catenin, Immunotherapy
Received: 09 Jul 2025; Accepted: 15 Aug 2025.
Copyright: © 2025 Wang, Shang, Wang, You, Yao and Zheng. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Yu Yao, Department of Medical Oncology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
Xiaoqiang Zheng, Institute for Stem Cell & Regenerative Medicine,The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
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