ABSTRACT Liver cancer ranks the second leading cause of cancer‐related mortality globally, with a 5‐year overall survival rate of about 14.0%. And hepatocellular carcinoma (HCC) constitutes about 80% of it. Given that HCC often remains asymptomatic in its early stages, the diagnosis of the majority of patients occurs at the intermediate or advanced stages, leading to the missed opportunity for surgical resection. Furthermore, the incidence of recurrence after surgical resection for early‐stage HCC patients can be as high as 70%. In this context, systemic therapies, including targeted therapies and immunotherapies, have emerged as essential therapeutic strategies for advanced HCC. However, resistance and adverse effects limit their efficacy. This review provides an overview of the molecular signaling pathways underlying HCC and potential mechanisms underlying resistance to systemic therapies and discusses potential therapeutic targets within these pathways. We also examine the clinical outcomes of these systemic therapies, highlighting their efficacy, safety profiles, and the challenges of resistance and toxicity. Finally, we outline future directions for HCC treatment, including combination therapies and personalized treatment strategies, which may offer improved treatment outcomes for individuals with HCC.
He et al. (2026) studied this question.