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A Self-Assembling LYTAC Mediates CTGF Degradation and Remodels Inflammatory Tumor Microenvironment for

Jia-Yi Lin1, Ye Wu1, Xiao-Hui Liang1

  • 1State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research and Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|May 11, 2025
PubMed

Insights

This study introduces NanoCLY, a novel nanoplatform that degrades connective tissue growth factor (CTGF) to treat triple-negative breast cancer (TNBC). This targeted degradation therapy shows superior efficacy over traditional blockade methods.

Area of Science:

  • Biochemistry
  • Oncology
  • Nanotechnology

Background:

  • Connective tissue growth factor (CTGF/CCN2) promotes triple-negative breast cancer (TNBC) progression.
  • Current CTGF blockade therapies face limitations due to CTGF's multiple functional domains.
  • Lysosome-targeting chimeras (LYTACs) offer a novel strategy for complete protein degradation.

Purpose of the Study:

  • To develop a tumor microenvironment (TME)-responsive LYTAC nanoplatform for CTGF degradation in TNBC.
  • To investigate the therapeutic potential of CTGF degradation via LYTACs in TNBC.
  • To compare the efficacy of CTGF degradation therapy with antibody-based blockade therapy.

Main Methods:

  • Design and synthesis of a self-assembling LYTAC nanoplatform (NanoCLY).
  • Evaluation of NanoCLY's ability to responsively degrade CTGF within the TME.
  • Assessment of CTGF degradation's impact on TGF-β signaling, CTGF-IL-6 crosstalk, and cancer-associated fibroblast (CAF) activation.
  • In vitro and in vivo testing of NanoCLY's anti-TNBC effects.

Main Results:

  • NanoCLY effectively degrades CTGF in a TME-responsive manner.
  • CTGF degradation downregulates TGF-β signaling and disrupts CTGF-IL-6 crosstalk.
  • The therapy inhibits inflammatory CAF activation and alleviates the inflammatory TME.
  • LYTAC-based CTGF degradation demonstrated superior anti-TNBC effects compared to antibody blockade.

Conclusions:

  • CTGF degradation is a viable therapeutic strategy for TNBC.
  • The developed NanoCLY platform represents the first CTGF-LYTAC nanoplatform for TME-directed TNBC therapy.
  • This approach offers a promising alternative to conventional blockade therapies for TNBC.
Keywords:
connective tissue growth factorlysosome‐targeting chimerasself‐assembling nanoparticletriple‐negative breast cancertumor microenvironment

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