Turning a Targeting β-Catenin/Bcl9 Peptide Inhibitor into a GdOF@Au Core/Shell Nanoflower for Enhancing Immune Response to Cancer Therapy in Combination with Immune Checkpoint Inhibitors

Abstract

Combination administration is becoming a popular strategy in current cancer immunotherapy to enhance tumor response to ICIs. Recently, a peptide drug, a protein–protein interaction inhibitor (PPI), that disrupts the β-catenin/Bcl9 interaction in the tumoral Wnt/β-catenin pathway has become a promising candidate drug for immune enhancement and tumor growth inhibition. However, the peptide usually suffers from poor cell membrane permeability and proteolytic degradation, limiting its adequate accumulation in tumors and ultimately leading to side effects. Herein, a gadolinium–gold-based core/shell nanostructure drug delivery system was established, where Bcl9 was incorporated into a gadolinium–gold core–shell nanostructure and formed GdOFBAu via mercaptogenic self-assembly. After construction, GdOFBAu, when combined with anti-PD1 antibodies, could effectively inhibit tumor growth and enhance the response to immune therapy in MC38 tumor-bearing mice; it not only induced the apoptosis of cancer cells, but also promoted the tumor infiltration of Teff cells (CD8+) and decreased Treg cells (CD25+). More importantly, GdOFBAu maintained good biosafety and biocompatibility during treatment. Taken together, this study may offer a promising opportunity for sensitizing cancer immunotherapy via metal–peptide self-assembling nanostructured material with high effectiveness and safety.

Modulating β-catenin/BCL9 interaction with cell-membrane-camouflaged carnosic acid to inhibit Wnt pathway and enhance tumor immune response

“…Extensive research conducted over the past three decades has emphasized the significant involvement of Wnt/β-catenin signaling in lung cancer development, leading to numerous investigations exploring the potential of Wnt inhibition as an anti-tumor strategy ( 23 ). Currently developed Wnt inhibitors, including small molecules, peptides, and antibodies, face challenges associated with the implementation: small molecules exhibit a relatively high level of toxicity; peptides are prone to degradation and present difficulties in direct cellular utilization; antibodies pose complexities in production and their in vivo retention time remains unsatisfactory ( 47 – 50 ). To reconcile the intended acting mechanism of inhibitors with their practical application in vivo , researchers employ synthetic constituents like polyethylene glycol (PEG) to encapsulate inhibitors, thereby rendering them inconspicuous to the immune system and enabling their targeted recognition and utilization by tumor cells ( 51 ).…”