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This last decade, immunotherapies have shaken up cancer treatment, but only a small percentage of patients benefit from current regimens targeting immune checkpoint inhibitors, including in hepatocellular carcinoma (HCC).1 Genetic and epigenetic intratumour heterogeneity, as well as diversity of immune cell infiltrates, significantly impacts tumour response to targeted therapies. In particular, tumour-associated macrophages (TAM), major components of the immune cell infiltrate, are strongly versatile immune cells. They acquire a large diversity of phenotypes according to cellular and non-cellular signals arising in the tumour niche.2 An ambivalent role is played by TAM during cancer development: they can either favour tumourigenesis and invasion through immunosuppressive and proangiogenic activities or can help suppress tumour growth by their robust phagocytic and immunopotentiation capabilities. Therefore, redirecting macrophage functions towards tumouricidal activities emerges as an interesting strategy to combat solid tumours.3 A range of strategies are used to exploit macrophages as therapeutic interventions: preventing their recruitment, depleting or reprogramming TAM, or infusing engineered macrophages. Transfer of monocyte-derived macrophages to patients fails to inhibit tumour growth due to defects in autologous cells and the need for additional signals to increase the efficiency of adoptive macrophages. Recent research has focused efforts on engineering chimeric antigen receptor macrophages (CAR-M) from peripheral blood mononuclear cells, human leukaemia monocytic THP-1 cell line or human-induced pluripotent stem cells. These preclinical studies, including in HCC, have demonstrated that macrophage effector functions are successfully reprogrammed in CAR-M, in particular their phagocytosis capacities.4 Nevertheless, precision immune-oncology requires a better and more precise understanding of TAM complexity to optimise their use for therapeutic purposes.