Perspectives for novel therapeutic concepts in hepatocellular carcinoma targeting the stromal and innate immune microenvironment

Hepatocellular carcinoma (HCC) is a major public health burden with increasing incidence and mortality worldwide. Arising almost exclusively on the background of chronic liver disease, the tumour microenvironment plays a tremendous role in the occurrence and progression of HCC. With the emergence of checkpoint inhibitor‐based combination therapies as first‐line therapy in advanced HCC, the tumour microenvironment has drawn increasing attention as a target for novel therapeutic approaches. In fact, checkpoint‐inhibitor‐based immunotherapies currently dominate clinical studies on HCC therapy. Importantly, whilst checkpoint‐inhibitor‐based immune‐oncology primarily targets T‐cells, the tumour microenvironment consists of a wide variety of different cell populations that show complex interactions with each other and the malignant tumour cells. Stromal cells and representatives of the innate immune system, such as macrophages, neutrophils and natural killer cells hereby orchestrate the initial immune response and thus appear as attractive targets for broad therapeutic effects, less susceptible to immune escape. In this review, we aim to discuss the current knowledge on the role of innate immune cells and stromal cell populations in HCC initiation and progression as well as related novel therapeutic concepts.