Flaherty Keith T, Aplin Andrew E, Davies Michael A, Hacohen Nir, Herlyn Meenhard, Hoon Dave, Hwu Patrick, Lotem Michal, Mulé James, Wargo Jennifer A, Fisher David E
Massachusetts General Hospital Cancer Center, Boston, MA, United States.
Thomas Jefferson University, Philadelphia, PA, United States.
Clin Cancer Res. 2025 May 23. doi: 10.1158/1078-0432.CCR-25-0278.
Outcomes from advanced melanoma, the deadliest of the skin cancers arising from melanocytes and capable of widely metastasizing, have greatly improved with death rates decreasing for AJCC stage 4 melanoma patients by 3-5 percent annually over the past 10 years (1,2). This improvement is a result of advances in both targeted therapy and immunotherapy (Fig 1). BRAF and MEK inhibitors for advanced melanoma have led the way for targeted cancer strategies and first- in-class approvals for immune checkpoint blockers targeting CTLA4, PD1, and LAG3, T cell engager therapy targeting the antigen gp100 and tumor-infiltrating lymphocyte therapy (3). All of the preceding have contributed to enhanced outcomes including long-term durable responses in up to half of patients with advanced disease. In addition, adjuvant and neoadjuvant approaches are reducing the risk of relapse in patients with stage II and III disease. Because of its immunogenicity and defined targetable mutations, melanoma drug development has led the way for novel approaches in cancer research. Yet additional approaches are needed for patients with recurrent or non-responsive disease or rare subtypes including mucosal, acral and uveal melanomas. Progress in modified T cells, including TCR, CAR-T and CRISPR gene editing strategies holds promise for future therapeutics. Continued understanding of the molecular and immune tumor microenvironment and heterogeneity, understanding the microbiome and numerous diverse approaches to topics ranging from prevention, to mechanisms of treatment resistance and novel therapeutic approaches, will optimize opportunities to further decrease melanoma mortality.
晚期黑色素瘤是源自黑素细胞的最致命皮肤癌，具有广泛转移的能力。在过去10年中，AJCC 4期黑色素瘤患者的死亡率每年下降3%至5%，晚期黑色素瘤的治疗效果有了很大改善(1,2)。这一改善是靶向治疗和免疫治疗进展的结果(图1)。用于晚期黑色素瘤的BRAF和MEK抑制剂引领了靶向癌症治疗策略，针对CTLA4、PD1和LAG3的免疫检查点阻滞剂、针对抗原gp100的T细胞衔接疗法以及肿瘤浸润淋巴细胞疗法获得了同类首个批准(3)。上述所有疗法都有助于改善治疗效果，包括使高达一半的晚期疾病患者获得长期持久缓解。此外，辅助和新辅助治疗方法正在降低II期和III期疾病患者的复发风险。由于黑色素瘤具有免疫原性且有明确的可靶向突变，黑色素瘤药物研发引领了癌症研究的新方法。然而，对于复发或无反应疾病患者或罕见亚型（包括黏膜、肢端和葡萄膜黑色素瘤），还需要其他治疗方法。修饰T细胞方面的进展，包括TCR、CAR-T和CRISPR基因编辑策略，为未来治疗带来了希望。持续深入了解分子和免疫肿瘤微环境及异质性，了解微生物群以及从预防到治疗耐药机制和新治疗方法等众多不同主题的方法，将优化进一步降低黑色素瘤死亡率的机会。
