Hepatic stellate cells drive tumour microenvironment remodelling in hepatocellular carcinoma

Liver cancer ranks sixth in global cancer incidence and is the third leading cause of cancer-related death, making it a substantial health burden. Hepatocellular carcinoma (HCC) accounts for approximately 80% of liver cancers. Yet tumour development is not determined by malignant cells alone: immune and stromal cells, together with the extracellular matrix (ECM), also shape disease behaviour. These interactions within the tumour microenvironment (TME) influence prognosis, treatment response and drug resistance, and may expose new therapeutic targets. Hepatic stellate cells (HSCs) are liver-resident pericytes in the space of Disse. Persistent liver injury activates these normally quiescent cells. They then acquire a myofibroblastic phenotype, marked by increased α-SMA expression and excessive ECM deposition, and become activated HSCs (aHSCs). As a major source of cancer-associated fibroblasts (CAFs), aHSCs participate in reciprocal crosstalk with HCC cells and other TME components that favours tumour proliferation, invasion and metastasis. This review examines HSC–HCC crosstalk and the interactions between HSCs and other components of the TME, with emphasis on their contribution to HCC initiation and progression. A clearer understanding of these mechanisms may help guide precision treatment strategies.