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.
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.
Bizonyítékszint: Korai humán adat. Kis vagy feltáró emberi adat.
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