ADAM (A Disintegrin and Metalloproteinase) family members are multifunctional transmembrane proteases that govern tumorigenesis and metastasis by cleaving membrane-bound substrates such as growth factors, cytokines, and cell adhesion molecules. Several ADAMs, including ADAM8, ADAM9, ADAM10, ADAM12, and ADAM17, are overexpressed in malignancies and are linked with a poor prognosis. These proteases contribute to tumour growth by regulating cell proliferation, cell fate, invasion, angiogenesis, and immune evasion. ADAM10 and ADAM17, especially, facilitate the shedding of critical developmental and growth factors and their receptors, as well as immuno-regulatory molecules, hence promoting tumour progression, immune escape, and resistance to therapy. Recent work has unveiled multiple regulatory pathways that modulate ADAM functions, which include trafficking, dimerization, and conformational modifications that affect substrate accessibility. These observations have rekindled efforts to produce selective ADAM inhibitors, avoiding the off-target consequences reported with early small molecule inhibitors targeting the enzyme active site, which is conserved also in matrix metalloproteinases (MMPs). Promising approaches tested in preclinical models and, in some cases, clinical settings include more selective small-molecule inhibitors, monoclonal antibodies, and antibody–drug conjugates designed to specifically target ADAMs. In this review, we will discuss the emerging roles of ADAMs in cancer biology, as well as the molecular processes that control their function. We further discuss the therapeutic potential of targeting ADAMs, with a focus on recent advances and future directions in the development of ADAM-specific cancer therapies.
ADAM（解整合素-金属蛋白酶）家族成员是多功能跨膜蛋白酶，通过切割膜结合底物（如生长因子、细胞因子和细胞黏附分子）调控肿瘤发生和转移。包括ADAM8、ADAM9、ADAM10、ADAM12和ADAM17在内的多个ADAM家族成员在恶性肿瘤中过度表达，并与不良预后相关。这些蛋白酶通过调节细胞增殖、细胞命运、侵袭、血管生成和免疫逃逸促进肿瘤生长。特别是ADAM10和ADAM17，能够介导关键发育因子、生长因子及其受体以及免疫调节分子的脱落，从而推动肿瘤进展、免疫逃逸和治疗抵抗。近期研究揭示了调控ADAM功能的多条通路，包括影响底物可及性的运输、二聚化和构象修饰等机制。这些发现重新激发了开发选择性ADAM抑制剂的努力，旨在避免早期针对酶活性位点的小分子抑制剂（该位点在基质金属蛋白酶中同样保守）所报道的脱靶效应。临床前模型及部分临床研究中验证的潜在策略包括更具选择性的小分子抑制剂、单克隆抗体以及专门靶向ADAM的抗体-药物偶联物。本综述将探讨ADAM在癌症生物学中的新兴作用及其功能调控的分子机制，并进一步讨论靶向ADAM的治疗潜力，重点关注ADAM特异性癌症疗法的最新进展与未来发展方向。
ADAM Proteases in Cancer: Biological Roles, Therapeutic Challenges, and Emerging Opportunities
肿瘤(癌症)患者之家