Platelets as localized conduits of TGF-β1 in the tumor microenvironment: implications for cancer progression and...

Platelets are major circulating reservoirs of transforming growth factor-β1 (TGF-β1). After tumor-associated activation, they release latent TGF-β1 from α-granules or present it at the platelet surface through glycoprotein A repetitions predominant. The latent complex is then activated by integrins, proteases, mechanical forces, and local physicochemical conditions. Direct platelet-specific evidence supports roles for platelet-derived TGF-β1 in established tumor growth, epithelial-mesenchymal transition, immune suppression, and metastasis. Platelet-associated studies also suggest effects on stromal remodeling, circulating tumor cell adaptation, endothelial dysfunction, and pre-metastatic niche formation. However, the platelet origin of TGF-β1 remains unresolved in many settings. This review distinguishes platelet-specific evidence from platelet-associated findings and source-independent mechanistic extrapolations. It also examines whether the stage-dependent paradox of TGF-β signaling applies to platelet-derived TGF-β1. The current evidence mainly supports a tumor-promoting role in established and metastatic disease, whereas its role in tumor initiation remains unclear. We further compare systemic therapies with platelet-directed, platelet-guided, and other targeted TGF-β interventions.