The role of platelets in the hepatocellular carcinoma immune microenvironment and their clinical prospects: a comprehensive review.

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide. Platelets, traditionally recognized for hemostatic functions, have emerged as critical modulators of the HCC tumor microenvironment, yet their complex roles remain incompletely understood. This review synthesizes current mechanistic and clinical evidence on platelet functions in HCC pathophysiology and translational applications. Platelets exert dual, context-dependent effects in HCC. Their pro-tumorigenic mechanisms include circulating tumor cell shielding, epithelial-mesenchymal transition induction via TGF-β1/AMPK/mTOR signaling, and immunosuppression through GARP-TGF-β and GITRL pathways. Conversely, P2Y12-mediated CD40L secretion confers anti-tumor immunity in metabolic dysfunction-associated steatohepatitis-driven HCC (MASLD-HCC). Platelet functions vary by etiology, differs significantly between viral hepatitis and metabolic liver disease, and shift dynamically from early to advanced disease stages. Platelets remodel the immune microenvironment through interactions with T cells, NK cells, and macrophages, with platelet-derived extracellular vesicles and non-coding RNAs serving as key mediators. This offers potential translational applications including platelet-based biomarkers, etiology-stratified antiplatelet strategies, platelet membrane-coated nanoparticles for targeted drug delivery, and management of platelet-drug interactions in systemic therapy. Bridging mechanistic insights and clinical observations offers a potential framework for developing platelet-targeted precision approaches to improve HCC management.