Intratumoral heterogeneity of hepatocellular carcinoma: From single-cell to population-based studies

Hepatocellular carcinoma (HCC) is characterized by high heterogeneity in both intratumoral and interpatient manners. While interpatient heterogeneity is related to personalized therapy, intratumoral heterogeneity (ITH) largely influences the efficacy of therapies in individuals. ITH contributes to tumor growth, metastasis, recurrence, and drug resistance and consequently limits the prognosis of patients with HCC. There is an urgent need to understand the causes, characteristics, and consequences of tumor heterogeneity in HCC for the purposes of guiding clinical practice and improving survival. Here, we summarize the studies and technologies that describe ITH in HCC to gain insight into the origin and evolutionary process of heterogeneity. In parallel, evidence is collected to delineate the dynamic relationship between ITH and the tumor ecosystem. We suggest that conducting comprehensive studies of ITH using single-cell approaches in temporal and spatial dimensions, combined with population-based clinical trials, will help to clarify the clinical implications of ITH, develop novel intervention strategies, and improve patient prognosis.