AUTHOR=Wang Peili , Shang Xiao , Wang Jinmei , You Weiming , Qu Shoufei , Yao Yu , Zheng Xiaoqiang 

TITLE=Disrupting β-Catenin/BCL9 interaction with a peptide prodrug boosts immunotherapy in colorectal cancer

JOURNAL=Frontiers in Immunology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1662385

DOI=10.3389/fimmu.2025.1662385

ISSN=1664-3224

ABSTRACT=IntroductionHyperactivation of the Wnt/β-catenin pathway serves as a central mechanism underlying tumor progression, immune evasion, and resistance to immune checkpoint inhibitor 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 immune-suppressive tumor milieu. Consequently, targeting this interaction offers a promising approach to suppress tumor progression and potentiate antitumor immune responses.MethodsWe developed a peptide-based prodrug, Bcl9@TP, designed to competitively bind the BCL9 interface on β-catenin, destabilize the transcriptional complex, and suppress Wnt/β-catenin signaling. Its antitumor efficacy and immune potentiation were assessed in vitro using MC38 cells and in vivo in murine tumor models.ResultsIn vitro, Bcl9@TP significantly inhibited MC38 cell proliferation by downregulating β-catenin and its downstream targets, inducing G1-phase cell cycle arrest. In vivo, Bcl9@TP treatment markedly reduced tumor burden, with a tumor growth inhibition (TGI) rate of ~62%, significantly higher than the control group. In contrast, anti-PD-1 monotherapy yielded a TGI of only 41%. Notably, combination therapy (Bcl9@TP plus anti-PD-1) produced a more pronounced antitumor effect, with the TGI reaching 82%. Importantly, Bcl9@TP demonstrated favorable systemic biocompatibility and safety.DiscussionOur findings indicate that disrupting the β-catenin/BCL9 interaction with a peptide-based nanoprodrug represents a compelling strategy to suppress oncogenic signaling and enhance immunotherapy responses in CRC, providing a new angle to boost checkpoint sensitivity.