Liver cancer, also known as hepatocellular carcinoma (HCC), remains a major global health concern, with high mortality driven by late-stage diagnosis, limited treatment efficacy, and frequent therapeutic resistance. Matrix metalloproteinases (MMPs), a large family of zinc-dependent endopeptidases, are central to the biological processes that drive liver tumor initiation and progression. By degrading and reorganizing extracellular matrix components, MMPs facilitate tumor expansion, tissue invasion, and metastatic dissemination. In addition, these enzymes regulate the availability of growth factors, cytokines, and chemokines, thereby influencing angiogenesis, inflammation, immune cell recruitment, and the development of an immunosuppressive tumor microenvironment. Aberrant expression or activity of multiple MMP family members is consistently associated with aggressive clinicopathologic features, including vascular invasion, increased metastatic potential, and reduced patient survival, highlighting their promise as prognostic markers and actionable therapeutic targets. Past attempts to modulate MMP activity were hindered by broad inhibition profiles and dose-limiting toxicities, underscoring the need for improved specificity and delivery strategies. Recent advances in molecular design, biologics engineering, and nanotechnology have revitalized interest in MMP targeting by enabling more selective, context-dependent modulation of proteolytic activity. Preclinical studies demonstrate that carefully tuned MMP inhibition can limit tumor invasion, enhance anti-angiogenic responses, and potentially improve the efficacy of existing systemic therapies, including immuno-oncology agents. This review synthesizes current knowledge on the multifaceted roles of MMPs in HCC pathobiology and evaluates emerging therapeutic strategies that may finally unlock the clinical potential of targeting these proteases.
肝癌，又称肝细胞癌（HCC），仍是全球主要的健康问题，其高死亡率主要由诊断晚、治疗效果有限及频繁产生治疗抵抗所驱动。基质金属蛋白酶（MMPs）作为一个依赖锌的内肽酶大家族，在驱动肝脏肿瘤发生与进展的生物学过程中处于核心地位。通过降解和重组细胞外基质成分，MMPs促进肿瘤扩张、组织浸润和转移扩散。此外，这些酶通过调节生长因子、细胞因子和趋化因子的生物利用度，进而影响血管生成、炎症反应、免疫细胞募集以及免疫抑制性肿瘤微环境的形成。多种MMP家族成员的异常表达或活性常与侵袭性临床病理特征相关，包括血管侵犯、转移潜力增强和患者生存期缩短，这凸显了它们作为预后标志物和可行治疗靶点的潜力。以往尝试调控MMP活性的努力因抑制谱过广和剂量限制性毒性而受阻，这凸显了对更高特异性和更优递送策略的需求。分子设计、生物制剂工程和纳米技术的最新进展，使得能够更选择性、更具环境依赖性地调控蛋白水解活性，从而重新激发了针对MMP靶向治疗的研究兴趣。临床前研究表明，精细调控的MMP抑制可限制肿瘤侵袭、增强抗血管生成反应，并可能提高包括免疫肿瘤药物在内的现有系统疗法的疗效。本文综述了当前关于MMPs在HCC病理生物学中多重作用的认识，并评估了新兴治疗策略，这些策略可能最终开启针对这些蛋白酶治疗的临床转化前景。
肿瘤(癌症)患者之家