Targeting the Heterogeneous Tumour-Associated Macrophages in Hepatocellular Carcinoma

SIMPLE SUMMARY: Hepatocellular carcinoma (HCC) is a highly lethal disease with an increasing incidence. Despite the advancements in diagnosis and recent therapeutic options, improving the prognosis of HCC patients remains challenging. One of the reasons of the unsatisfactory outcome of patients with HCC is the complex tumour microenvironment (TME), which is composed of immune and stromal cells, limiting effective treatments. Recent research has highlighted the importance of macrophages in the development and progression of HCC, opening new possibilities for therapy. This review focuses on the heterogeneity of tumour-associated macrophages (TAMs) in HCC, the mechanisms through which HCC tumour cells polarize macrophages, and the therapeutic targets that are currently being tested to explore novel therapies that can improve the prognosis and quality of life of HCC patients. ABSTRACT: Hepatocellular carcinoma (HCC) is a prevalent and aggressive cancer that comprises a complex tumour microenvironment (TME). Tumour-associated macrophages (TAMs) are one of the most abundant immune cells present in the TME, and play a key role both in the development and in the progression of HCC. Thus, TAM-based immunotherapy has been presented as a promising strategy to complement the currently available therapies for HCC treatment. Among the novel approaches focusing on TAMs, reprogramming their functional state has emerged as a promising option for targeting TAMs as an immunotherapy in combination with the currently available treatment options. Nevertheless, a further understanding of the immunobiology of TAMs is still required. This review synthesizes current insights into the heterogeneous nature of TAMs in HCC and describes the mechanisms behind their pro-tumoural polarization focusing the attention on their interaction with HCC cells. Furthermore, this review underscores the potential involvement of TAMs’ reprogramming in HCC therapy and highlights the urgency of advancing our understanding of these cells within the dynamic landscape of HCC.