Targeting CTGF+ cancer-associated fibroblasts disrupts tumor-stroma crosstalk in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a heavily fibrotic tumor microenvironment (TME), primarily driven by cancer-associated fibroblasts (CAFs). Due to the high heterogeneity and diverse biological behaviors of CAFs, the current strategies targeting CAFs have limited benefits in clinic. This study identifies a subset of CAFs marked by high expression of connective tissue growth factor (CTGF), which enhances tumor cell migration and correlates with advanced PDAC stages. By combining in silico screening and functional assays, we identified DP as a first-in-class small-molecule inhibitor targeting CTGF. Structural optimization of DP led to the synthesis of a series of derivatives, from which the optimal compound QX03-46 was identified. Targeting CTGF+ CAFs with QX03-46 significantly disrupted the CTGF/TGF-β1 signaling axis and suppressed CAF functions, resulting in decreased extracellular matrix deposition and oncogenic cytokine secretion. Furthermore, it enhanced the efficacy of anti-programmed cell death ligand 1 therapy, promoting a more favorable immune response. Our findings illuminate the critical role of CTGF+ CAFs in PDAC progression and position QX03-46 as a promising therapeutic candidate for targeting the fibrotic TME.