From M7824 to SHR-1701: lessons for dual PD-L1/TGF-β targeting.

Retlirafusp alfa (SHR-1701), a bifunctional programmed death-ligand 1 (PD-L1) antibody fused to a TGF-β trap, was approved in China on January 7, 2026 for first-line treatment of PD-L1-positive advanced gastric or gastroesophageal junction adenocarcinoma with chemotherapy. This first-in-class milestone revisits a key question raised by bintrafusp alfa (M7824): why can dual PD-L1/TGF-β targeting be active in selected settings yet inconsistent across tumors? We highlight that TGF-β-driven immune suppression and immune exclusion are often spatially organized within stromal niches, vary across indications, and are not always the dominant barrier even when PD-L1 is expressed. SHR-1701's approval provides proof of principle in a defined context and supports mechanism-aligned development using biomarker-driven selection, rational combinations and sequencing, and pharmacodynamic endpoints that directly test these assumptions.