TGF-β-driven immune suppression is not uniform within tumors. It is often strongest in the tumor stroma, where CAF activity and extracellular matrix remodeling create barriers that limit lymphocyte entry. In many immune-excluded tumors, immune cells are present but remain trapped at the invasive margin or in stromal areas, rather than reaching tumor nests. Checkpoint blockade alone may not overcome this physical and stromal barrier. In addition, TGF-β is frequently present in an inactive (latent) form and becomes activated locally. Therefore, the benefit of a TGF-β trap may depend not only on drug levels in blood, but also on whether it can neutralize active TGF-β in these stromal regions where exclusion is generated.

TGF-β-driven immune suppression is not uniform within tumors. It is often strongest in the tumor stroma, where CAF activity and extracellular matrix remodeling create barriers that limit lymphocyte entry. In many immune-excluded tumors, immune cells are present but remain trapped at the invasive margin or in stromal areas, rather than reaching tumor nests. Checkpoint blockade alone may not overcome this physical and stromal barrier. In addition, TGF-β is frequently present in an inactive (latent) form and becomes activated locally. Therefore, the benefit of a TGF-β trap may depend not only on drug levels in blood, but also on whether it can neutralize active TGF-β in these stromal regions where exclusion is generated.