PD-L1 and TGF-beta (TGF-βRII trap)

Class

PD-L1/TGF-beta bifunctional fusion protein (retlirafusp alfa, Hengrui)

Pathway

Combined checkpoint blockade (PD-L1) and TGF-beta pathway sequestration

PD-L1 is a protein expressed on tumor cells and certain immune cells that binds the PD-1 receptor on T cells, dampening their ability to recognize and kill cancer cells. Blocking this interaction, checkpoint blockade, restores T cell anti-tumor activity. TGF-beta is a separate signaling protein that, within the tumor microenvironment, promotes immune suppression, fibrosis, and exclusion of T cells from tumor tissue. This mechanism combines both functions in a single bifunctional fusion protein: one domain blocks PD-L1, while a second domain, derived from the extracellular portion of the TGF-beta receptor type II, acts as a trap that binds and neutralizes TGF-beta before it can signal. The rationale for pairing these two activities is that TGF-beta signaling can limit the benefit of checkpoint blockade alone by sustaining an immunosuppressive, T-cell-excluded tumor microenvironment; neutralizing TGF-beta alongside PD-L1 blockade may render tumors more responsive than either approach individually. This dual mechanism is broadly relevant across solid tumors, particularly those marked by high TGF-beta activity, fibrotic stroma, and limited T cell infiltration, settings where checkpoint inhibition alone has shown limited effect.