Anti-CTGF/PD-1 bispecific antibody Y126S effectively restrains desmoplastic and immunosuppressive microenvironment in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a highly desmoplastic and immunosuppressive tumor microenvironment (TME), which plays a critical role in driving resistance to immunotherapy. Within this TME, cancer-associated fibroblasts (CAFs) emerge as pivotal contributors, orchestrating fibrotic remodeling and immune suppression through extracellular matrix (ECM) deposition, cytokine secretion, and modulation of immune responses. Notably, overexpression of connective tissue growth factor (CTGF) has been strongly associated with the development of fibrotic ECM, therapeutic resistance, and poor prognosis in PDAC. Furthermore, emerging evidence indicates that CTGF actively promotes CAF differentiation, enhances ECM deposition, and exacerbates immune suppression within the TME. In this study, we employed exogenous recombinant human CTGF (rhCTGF) protein to stimulate human CAFs isolated from clinical PDAC specimens, aiming to elucidate the impact of CTGF on CAF phenotypic alterations and associated signaling pathways.