Immunotherapies, including checkpoint inhibitor antibodies, have precipitated significant improvements in clinical outcomes for melanoma. However, approximately half of patients do not benefit from approved treatments. Additionally, apart from Tebentafusp, which is approved for the treatment of uveal melanoma, there is a lack of immunotherapies directly focused on melanoma cells. This is partly due to few available targets, especially those expressed on the cancer cell surface. Chondroitin sulfate proteoglycan 4 (CSPG4) is a cell surface molecule overexpressed in human melanoma, with restricted distribution and low expression in non-malignant tissues and involved in several cancer-promoting and dissemination pathways. Here, we summarize the current understanding of the expression and functional significance of CSPG4 in health and melanoma, and we outline immunotherapeutic strategies. These include monoclonal antibodies, antibody–drug conjugates (ADCs), chimeric-antigen receptor (CAR) T cells, and other strategies such as anti-idiotypic and mimotope vaccines to raise immune responses against CSPG4-expressing melanomas. Several showed promising functions in preclinical models of melanoma, yet few have reached clinical testing, and none are approved for therapeutic use. Obstacles preventing that progress include limited knowledge of CSPG4 function in human cancer and a lack of in vivo models that adequately represent patient immune responses and human melanoma biology. Despite several challenges, immunotherapy directed to CSPG4-expressing melanoma harbors significant potential to transform the treatment landscape.
免疫疗法，包括检查点抑制剂抗体，已显著改善黑色素瘤的临床预后。然而，约半数患者未能从已获批的治疗中获益。此外，除获批用于治疗葡萄膜黑色素瘤的Tebentafusp外，目前缺乏直接靶向黑色素瘤细胞的免疫疗法。这部分归因于可用靶点稀少，尤其是癌细胞表面表达的靶点。硫酸软骨素蛋白聚糖4（CSPG4）是一种在人类黑色素瘤中过度表达的细胞表面分子，其在非恶性组织中分布有限且表达水平较低，并参与多种促癌及转移通路。本文综述了目前对CSPG4在健康状态及黑色素瘤中表达与功能意义的认识，并概述了针对该靶点的免疫治疗策略，包括单克隆抗体、抗体-药物偶联物（ADC）、嵌合抗原受体（CAR）T细胞，以及通过抗独特型疫苗和模拟表位疫苗等策略激发针对表达CSPG4的黑色素瘤的免疫应答。多项策略在黑色素瘤临床前模型中展现出良好前景，但仅有少数进入临床试验阶段，且尚无获批疗法。阻碍进展的因素包括对CSPG4在人类癌症中功能的认知有限，以及缺乏能充分模拟患者免疫反应和人类黑色素瘤生物学的体内模型。尽管面临诸多挑战，针对表达CSPG4的黑色素瘤的免疫疗法仍具有改变治疗格局的巨大潜力。
Chondroitin Sulfate Proteoglycan 4 (CSPG4) as an Emerging Target for Immunotherapy to Treat Melanoma
肿瘤(癌症)患者之家