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黑色素瘤前沿进展篇——《中国恶性肿瘤学科发展报告(2024)》
2025-04-24 12:23

概述

黑色素瘤是一种恶性程度极高的皮肤肿瘤,在过去几十年里,全球范围内的发病率都呈现出快速增长的态势。在中国,黑色素瘤的整体发病率相对较低,所以大多数医生接触的病例数量有限,导致诊疗经验不足。更为棘手的是,黑色素瘤的诊疗涉及多个学科领域,包括皮肤科、肿瘤内科、骨科、整形科、普通外科、烧伤科、口腔科、眼科、耳鼻喉科、妇科、肛肠科、泌尿科等,其规范化诊疗是长期困扰中国黑色素瘤诊治的难题。

中国抗癌协会黑色素瘤专业委员会的成立,是中国黑色素瘤学科发展历程中的重要里程碑。专委会委员来自全国各省市,涵盖各个相关学科领域。专委会特组建了由两个中心及31个分中心的中国黑色素瘤临床研究中心,并成立了科普宣传、继续教育、学术会议等多个专业团队,此外,专委会还积极协助各省抗癌协会组建省级黑色素瘤专委会,为中国黑色素瘤学科建设、人才培养、继续教育以及科普宣传等工作奠定了坚实的组织基础。专委会成立两年多来,针对中国黑色素瘤的特性,包括:肢端和黏膜亚型占比超过80%、免疫检查点抑制剂疗效低于欧美人群、驱动基因与欧美人群存在显著差异、手术规范性欠佳、干扰素α1b在肢端及黏膜黑色素瘤中展现出的卓越疗效等问题,从基础研究到临床应用进行了广泛而深入的探讨,取得了显著的进展。展望未来,尽管中国黑色素瘤的诊治工作仍面临诸多挑战,但通过黑色素瘤专委会卓有成效的努力,以及科学技术的飞速发展,我们有理由相信,专委会提出的10年内将黑色素瘤致死率降低90%的目标定能实现。

2024年中国黑色素瘤学科

十大前沿进展

基础研究

(1)肢端黑色素瘤的分子进化与免疫微环境动态分析

团队/单位:北京大学第一医院李航团队

期刊Cancer Cell[17](2024年封面文章)

学术内容:通过整合基因组学、单细胞转录组学及空间蛋白组学技术,该研究系统解析了肢端黑色素瘤(AM)从原位(AMis)向侵袭性(iAM)演化的分子机制。分析147例患者样本发现,iAM中NRAS、KRAS等驱动突变富集,且侵袭早期呈现单克隆播散特征。分子分型鉴定出预后最差的C3亚型,其特征为EMT高表达及APOE+/CD163+巨噬细胞富集。功能实验证实,APOE+/CD163+巨噬细胞通过IGF1/IGF1R轴驱动EMT进程,抑制该通路可逆转侵袭表型。此外,附属器受累和驱动突变被确定为AMis侵袭的早期标志物,APOE/CD163则作为iAM预后标志物。该研究为AM的早期干预及免疫治疗靶点开发提供了多组学依据。

(2)酪氨酸酶编织黑色素网络实现线粒体靶向光热治疗

团队/单位:澳门大学Ruibing Wang团队

期刊Advanced Materials[65](2024年)

学术内容:该研究开发了一种双功能化多糖,修饰酪氨酸和三苯基膦,利用酪氨酸酶催化黑色素在线粒体周围交联成网,实现线粒体固定并降低肿瘤代谢速率。结果表明黑色素网络使光热转换效率提升2倍,局部温度升高至50℃以上,显著抑制黑色素瘤生长。该策略首次实现无药物干预的细胞器精准调控,为光热治疗黑色素瘤提供了新型生物材料平台,在小鼠模型中验证了其高效性与安全性,被评价为“肿瘤代谢-光热协同治疗的范式突破”。

(3)基于免疫调控水凝胶的黑色素瘤术后复发防控与创口修复

团队/单位:南方医科大学第十附属医院喻志强团队

期刊:Bioactive Materials[66](2024年)

学术内容:团队研发的GelMA-CJCNPs水凝胶将光敏剂Ce6、BRD4抑制剂JQ1及谷氨酰胺酶抑制剂C968整合至甲基丙烯酸酐明胶基质中,通过抑制谷氨酰胺代谢降低谷胱甘肽水平,增强光动力疗效。水凝胶逆转M2型巨噬细胞极化,促进CD8+ T细胞浸润。动物实验结果表明可显著降低术后复发率,缩短创口愈合时间,为黑色素瘤术后综合治疗提供了新型多功能材料。

(4)MerTK巨噬细胞调控黑色素瘤免疫耐受及AhR靶向治疗

团队/单位:华中科技大学同济医学院附属协和医院陶娟团队

期刊:Science Advances[22](2024年10月)

学术内容:研究通过单细胞测序鉴定出黑色素瘤中MerTK+巨噬细胞亚群,其AhR-ALKAL1信号激活导致CD8+ T细胞功能抑制及肿瘤进展加速。开发的CH223191-MMic纳米载体靶向递送AhR拮抗剂,联合抗PD-L1治疗后显著抑制小鼠肿瘤增殖。该成果揭示了MerTK巨噬细胞介导免疫逃逸的新机制,并提出AhR/PD-L1双靶向治疗策略。

(5)单细胞测序揭示转移性结膜黑色素瘤的肿瘤异质性

团队/单位:上海交通大学医学院附属第九医院范先群团队

期刊:Cell Discovery[19](2024年)

学术内容:单细胞RNA测序技术发现转移性结膜黑色素瘤(CoM)中CAFs丰度增加,VEGFR表达上调驱动血管生成。同时,转移灶CD8+ T细胞比例下降,且初始T细胞占比显著升高。基于此发起的临床试验(ChiCTR2100045061)显示,VEGFR抑制剂联合PD-1抗体相比单用免疫治疗患者生存时间更长,为转移性CoM提供了首个基于单细胞数据的精准治疗模式。

临床研究

(1)NRAS突变靶向药妥拉美替尼获批上市

团队/单位:北京大学肿瘤医院斯璐团队

期刊/成果:European Journal of Cancer[67](2024年),NMPA批准

学术内容:全球首个靶向NRAS突变晚期黑色素瘤的MEK抑制剂妥拉美替尼(HL-085)基于II期研究获批。研究显示,ORR为35.8%,mPFS为4.2个月,1年OS率为57.2%,既往接受过免疫治疗的患者ORR达到39.1%。3级不良反应发生率<20%,显著优于传统化疗。

(2)肢端黑色素瘤新辅助免疫联合溶瘤病毒疗法

团队/单位:北京大学肿瘤医院郭军团队

期刊/成果:Signal Transduction and Targeted Therapy[46](2024年封面)

学术内容:特瑞普利单抗联合溶瘤病毒OrienX010用于高危肢端黑色素瘤术前治疗,pCR率达77.8%,1年RFS 85.2%。机制研究显示,溶瘤病毒使肿瘤内CD8+ T细胞密度显著增加,并与PD-1抑制剂协同激活抗肿瘤免疫。

(3)特瑞普利单抗一线治疗晚期黑色素瘤III期研究

团队/单位:北京大学肿瘤医院郭军团队

期刊/成果:MELATORCH研究

学术内容:MELATORCH III期研究表明特瑞普利单抗组中位PFS 2.3个月(vs. 对照组2.1个月,HR=0.71),中位OS 15.1个月(vs. 9.4个月,HR=0.68)。研究首次证实PD-1抑制剂一线治疗亚洲人群的生存获益,获NMPA常规批准适应症。

(4)黏膜黑色素瘤新辅助免疫联合抗血管生成治疗

团队/单位:北京大学肿瘤医院崔传亮团队

期刊/成果:Annals of Oncology[68](2024年)

学术内容:特瑞普利单抗联合阿昔替尼用于可切除黏膜黑色素瘤新辅助治疗,病理缓解率33.3%(含16.7%完全缓解),病理缓解患者的mRFS达11.7个月。研究证实抗血管生成治疗可显著降低VEGF水平,逆转免疫抑制微环境,并建立“病理缓解-生存获益”预测模型,为高复发风险患者提供新策略。

(5)PD-1/IL-2α双抗IBI363获FDA快速通道资格

团队/单位:信达生物制药

期刊/成果: FDA快速通道认定

学术内容:IBI363通过PD-1靶向与IL-2α激活双机制,在I期研究中显示ORR为28.1%,DCR为71.9%;在既往经过免疫治疗的受试者中, ORR为32.0%,DCR为80.0%,且耐受性良好。FDA基于其初步疗效授予快速通道资格,拟用于PD-1耐药晚期黑色素瘤,有望成为首个获批的双特异性免疫疗法。

【主编】

高天文   空军军医大学第一附属医院

杨吉龙   天津医科大学附属肿瘤医院

陈 勇   复旦大学附属肿瘤医院

粟 娟   中南大学湘雅医院

朱冠男   南方医科大学皮肤病医院

【副主编】

徐 宇   复旦大学附属肿瘤医院

李 涛   浙江省肿瘤医院

付来华   中国医学科学院附属肿瘤医院深圳医院

章 恋   南方医科大学皮肤病医院

郭也也   中南大学湘雅医院

石 琼   空军军医大学第一附属医院

王 璐   空军军医大学第一附属医院

郭伟楠   空军军医大学第一附属医院

【编委】(按姓氏拼音排序)

陈嵘祎   南方医科大学皮肤病医院

陈永锋   南方医科大学皮肤病医院

郭 佳   中南大学湘雅医院

何仁亮   南方医科大学皮肤病医院

胡 涂   复旦大学附属肿瘤医院

刘 茜   空军军医大学第一附属医院

林 晶   福建省肿瘤医院

宋建民   甘肃省人民医院

孙 伟   复旦大学附属肿瘤医院

王 晋   天津市中医研究院附属皮肤病医院

杨 柳   华中科技大学同济医学院附属协和医院

姚 煜   西安交通大学附属第一医院

张晓伟   复旦大学附属肿瘤医院

赵建红   空军军医大学第一附属医院

赵 涛   空军军医大学第一附属医院

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