Heterogeneity of hepatocellular carcinoma: from mechanisms to clinical implications

Abstract Hepatocellular Carcinoma (HCC) is one of the most common types of primary liver cancer. Current treatment options have limited efficacy against this malignancy, primarily owing to difficulties in early detection and the inherent resistance to existing drugs. Tumor heterogeneity is a pivotal factor contributing significantly to treatment resistance and recurrent manifestations of HCC. Intratumoral heterogeneity is an important aspect of the spectrum of complex tumor heterogeneity and contributes to late diagnosis and treatment failure. Therefore, it is crucial to thoroughly understand the molecular mechanisms of how tumor heterogeneity develops. This review aims to summarize the possible molecular dimensions of tumor heterogeneity with an emphasis on intratumoral heterogeneity, evaluate its profound impact on the diagnosis and therapeutic strategies for HCC, and explore the suitability of appropriate pre-clinical models that can be used to best study tumor heterogeneity; thus, opening new avenues for cancer treatment.