Huaxiu Wei

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.

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.

γδT cells, a distinct group of T lymphocytes, serve as a link between innate and adaptive immune responses. They are pivotal in the pathogenesis of various liver disorders, such as viral hepatitis, nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), liver fibrosis, autoimmune liver diseases, and hepatocellular carcinoma (HCC). Despite their importance, the functional diversity and regulatory mechanisms of γδT cells remain incompletely understood. Recent advances in high-throughput single-cell sequencing and spatial transcriptomics have revealed significant heterogeneity among γδT cell subsets, particularly Vδ1⁺ and Vδ2⁺, which exhibit distinct immunological roles. Vδ1⁺ T cells are mainly tissue-resident and contribute to tumor immunity and chronic inflammation, while Vδ2⁺ T cells, predominantly found in peripheral blood, play roles in systemic immune surveillance but may undergo dysfunction in chronic liver diseases. Additionally, γδT17 cells exacerbate inflammation in NAFLD and ALD, whereas IFN-γ-secreting γδT cells contribute to antiviral and antifibrotic responses. These discoveries have laid the foundation for the creation of innovative solutions. γδT cell-based immunotherapeutic approaches, such as adoptive cell transfer, immune checkpoint inhibition, and strategies targeting metabolic pathways. Future research should focus on harnessing γδT cells’ therapeutic potential through targeted interventions, offering promising prospects for precision immunotherapy in liver diseases.