biostudies-literatureUnknown16Wang P<h4>Introduction</h4>Hyperactivation 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.<h4>Methods</h4>We 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 <i>in vitro</i> using MC38 cells and <i>in vivo</i> in murine tumor models.<h4>Results</h4><i>In vitro</i>, Bcl9@TP significantly inhibited MC38 cell proliferation by downregulating β-catenin and its downstream targets, inducing G1-phase cell cycle arrest. <i>In vivo</i>, 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.<h4>Discussion</h4>Our 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.Frontiers in immunology1662385https://www.ebi.ac.uk/biostudies/studies/S-EPMC12425980biostudies-literatureDisrupting β-Catenin/BCL9 interaction with a peptide prodrug boosts immunotherapy in colorectal cancer.PMC12425980Qu SWang PYao YZheng XShang XYou WWang JfalseDisrupting β-Catenin/BCL9 interaction with a peptide prodrug boosts immunotherapy in colorectal cancer.<h4>Introduction</h4>Hyperactivation 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.<h4>Methods</h4>We 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 <i>in vitro</i> using MC38 cells and <i>in vivo</i> in murine tumor models.<h4>Results</h4><i>In vitro</i>, Bcl9@TP significantly inhibited MC38 cell proliferation by downregulating β-catenin and its downstream targets, inducing G1-phase cell cycle arrest. <i>In vivo</i>, 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.<h4>Discussion</h4>Our 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.2025-01-01T00:00:00Z20252026-06-01T12:04:46.109Z2026-04-08T12:03:11.21ZS-EPMC124259804094880110.3389/fimmu.2025.1662385