A novel bispecific antibody targeting Frizzled7/PD-L1 overcomes NSCLC resistance to atezolizumab by reprogramming tumor microenvironment

Immunotherapy efficacy in non-small cell lung cancer (NSCLC) remains limited, and aberrant activation of the Wnt/β‑Catenin pathway plays a significant role. However, the precise involvement of its receptor, Frizzled7 (Fzd7), in immune checkpoint inhibitor (ICI)-resistance remains unexplored. Here, we elucidate the role of Fzd7 in shaping the immunosuppressive tumor microenvironment (TME) and develop a novel bispecific antibody (BsAb, named SHH-YN-Bi) that co-targets Fzd7 and programmed cell death ligand 1 (PD-L1). This study reveals that Fzd7 is remarkably enriched in human NSCLC tissues and correlates with PD-L1 expression and immune exclusion. SHH-YN-Bi was generated via “Knob-into-Hole”, exhibited effective dual binding to both Fzd7 and PD-L1, and demonstrated superior tumor targeting compared with Atezolizumab. Mechanistically, SHH-YN-Bi concurrently recruited and activated CD8 + T cells into the TME in a basic leucine zipper transcriptional factor ATF-like 3 (Batf3) + conventional type 1 dendritic cells (cDC1s)-dependent manner, leading to robust anti-tumor activity in ICI-resistant orthotopic NSCLC models. Furthermore, scRNA-seq analysis uncovered a potent correlation between Fzd7 and cancer-associated fibroblast (CAF)-mediated extracellular matrix (ECM) deposition. Notably, SHH-YN-Bi treatment induced a phenotypic switch of CAFs from a highly oncogenic to a normal state, which was associated with elevated CD8 + T cell infiltration. Collectively, SHH-YN-Bi overcomes ICI resistance in NSCLC by simultaneously blocking the oncogenic Wnt3a/Fzd7/β-Catenin signaling and PD-1/PD-L1 axis. Our findings highlight the critical role of Fzd7 in immunosuppressive TME and offer an innovative approach for NSCLC treatment.