A Self‐Assembling LYTAC Mediates CTGF Degradation and Remodels Inflammatory Tumor Microenvironment for Triple‐Negative Breast Cancer Therapy

Abstract As a multifunctional extracellular protein, connective tissue growth factor (CTGF/CCN2) is significantly associated with the progression and prognosis of triple‐negative breast cancer (TNBC). However, current blockade therapies targeting CTGF's multiple domains are limited, creating substantial challenges in treatment. Lysosome‐targeting chimeras (LYTACs) have emerged as a promising approach for achieving complete protein degradation and inhibiting CTGF's various bioactivities. In this study, a self‐assembling LYTAC nanoplatform, NanoCLY, designed to tumor microenvironment (TME)‐responsively degrade CTGF is presented. The complete degradation of CTGF downregulates the TGF‐β signaling pathway and disrupts the CTGF‐IL‐6 cell crosstalk within the TME, which further inhibits the activation of inflammatory cancer‐associated fibroblasts (CAFs) and alleviates the inflammatory TME. Notably, the anti‐TNBC effect of LYTAC‐based CTGF degradation therapy surpasses that of antibody‐based blockade therapy in both in vitro and in vivo models. The findings provide a proof of concept for CTGF degradation in TNBC and introduce the first CTGF‐LYTAC nanoplatform aimed at TME‐directed therapy.