Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, with metastasis representing a pivotal factor in poor prognosis and high fatality rates. This review offers a comprehensive examination of the key molecular events and regulatory mechanisms driving HCC metastasis, with a particular focus on genetic mutations, epigenetic alterations, and dysregulated signaling pathways. Special emphasis is placed on the role of three-dimensional genome structural remodeling in HCC initiation and metastatic progression. Additionally, the latest advances in targeted therapies for advanced HCC are summarized, including both first-line and second-line treatments, highlighting their impact on controlling metastatic disease. The review also examines a variety of potential biomarkers linked to HCC metastasis, including circulating tumor cells, circulating tumor DNA, and exosomal contents, all of which demonstrate significant promise for the early detection, diagnosis, and therapeutic monitoring of HCC metastasis. By bridging molecular insights with clinical applications, this review provides valuable perspectives to guide future research in the diagnosis and treatment of HCC metastasis.

Background: Myeloid-derived suppressor cells (MDSCs) drive immunosuppression in the hepatocellular carcinoma (HCC) tumor microenvironment (TME), contributing to immune checkpoint blockade (ICB) resistance. This review explores underlying mechanisms and therapeutic strategies. Methods: We synthesize the recent literature on MDSC biology in HCC, focusing on signaling pathways, metabolic/epigenetic reprogramming, and novel interventions, including AI-driven analyses. Results: Key mechanisms include JAK–STAT3 activation for MDSC expansion, CXCL12-CXCR4 for recruitment, enhanced glycolysis/lipid metabolism for suppressive function, and epigenetic changes sustaining immunosuppression. Therapeutic approaches encompass inhibitors, differentiation promoters, metabolic modulators, transcriptional reprogramming, microbiome modulation, and combinations with ICB/locoregional therapies or standard chemoimmunotherapy, yielding improved outcomes in trials. Conclusions: Targeting MDSC redundancies via multi-modal strategies offers a roadmap for overcoming resistance, with AI enhancing biomarker-guided precision immunotherapy in HCC.