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Simple Summary  The tumour microenvironment comprise cellular and non-cellular components and is a dedicive factor in determining anti-cancer treatment efficiency. The extracellular matrix is profoundly remodelled in cancer, with direct effects on cancer cell growth and local immunity. In this review, we outline how the matrix is altered in liver cancer and the importance of including the matrix and other features of the tumour microenvironment in disease models.    Abstract  Hepatocellular carcinoma (HCC) is one of the most common and lethal cancers worldwide. Currently, treatments available for advanced HCC provide dismal chances of survival, thus there is an urgent need to develop more effective therapeutic strategies. While much of the focus of recent decades has been on targeting malignant cells, promising results have emerged from targeting the tumour microenvironment (TME). The extracellular matrix (ECM) is the main non-cellular component of the TME and it profoundly changes during tumorigenesis to promote the growth and survival of malignant cells. Despite this, many in vitro models for drug testing fail to consider the TME leading to a high failure rate in clinical trials. Here, we present an overview of the function and properties of the ECM in the liver and how these change during malignant transformation. We also discuss the relationship between immune cells and ECM in the TME in HCC. Lastly, we present advanced, 3D culture techniques of cancer modelling and argue that the incorporation of TME components into these is essential to better recapitulate the complex interactions within the TME.

Interplay between Cellular and Non-Cellular Components of the Tumour Microenvironment in Hepatocellular Carcinoma