Wu Sulin, Anand Namrata, Guo Zhoubo, Li Mingyang, Santiago Figueroa Marcos, Jung Lauren, Kelly Sarah, Franses Joseph W
Section of Hematology and Oncology, Department of Internal Medicine, University of Chicago, 900 E. 57th St., KCBD 7114, Chicago, IL 60637, USA.
Cancers (Basel). 2025 May 31;17(11):1860. doi: 10.3390/cancers17111860.
Hepatocellular carcinoma (HCC) remains one of the most lethal cancers globally, driven by chronic liver disease and a complex tumor microenvironment (TME). Recent advances in spatial omics, single-cell analyses, and AI-driven digital pathology have shed light on the intricate heterogeneity of HCC, highlighting key roles for immune suppression, angiogenesis, and fibrosis in tumor progression. This review synthesizes current epidemiological trends, noting a shift from viral hepatitis to metabolic syndrome as a primary etiology in Western populations, and elucidates how TME components-such as tumor-associated macrophages, cancer-associated fibroblasts, vascular endothelial cells, and immunosuppressive cytokines-contribute to resistance against conventional therapies. We detail the evolution of immunotherapeutic strategies from monotherapy to combination regimens, including dual immune checkpoint blockade and the integration of antiangiogenic agents. Emerging circulating and tissue-based biomarkers offer promise for enhanced patient stratification and real-time monitoring of treatment responses. Collectively, these innovations herald a paradigm shift toward TME-directed precision oncology in HCC, emphasizing the need for multi-targeted approaches to synergistically modulate interacting cellular constituents and ultimately improve clinical outcomes.
肝细胞癌（HCC）仍然是全球最致命的癌症之一，由慢性肝病和复杂的肿瘤微环境（TME）驱动。空间组学、单细胞分析和人工智能驱动的数字病理学的最新进展揭示了HCC复杂的异质性，突出了免疫抑制、血管生成和纤维化在肿瘤进展中的关键作用。本综述综合了当前的流行病学趋势，指出在西方人群中，主要病因已从病毒性肝炎转变为代谢综合征，并阐明了TME成分，如肿瘤相关巨噬细胞、癌症相关成纤维细胞、血管内皮细胞和免疫抑制细胞因子，如何导致对传统疗法的耐药性。我们详细介绍了免疫治疗策略从单一疗法到联合方案的演变，包括双重免疫检查点阻断和抗血管生成药物的联合应用。新兴的循环和基于组织的生物标志物有望改善患者分层和实时监测治疗反应。总体而言，这些创新预示着HCC治疗向TME导向的精准肿瘤学范式转变，强调需要采用多靶点方法协同调节相互作用的细胞成分，最终改善临床结果。
