进入伊皮利姆单抗批准后的第二个十年，免疫检查点抑制剂（ICIs）显然显著改善了黑色素瘤的预后。尽管当前的优势已经很高，辅助性尼伐单抗4年生存率为77.9％，转移期尼伐单抗/伊皮利姆单抗联合治疗6.5年生存率为49％，但许多晚期黑色素瘤患者没有从免疫治疗中获益，或在治疗的头几个月经历早期疾病复发/进展，并且存活时间更短。因此，对ICIs的原发性和获得性耐药性已进入临床研究的焦点，包括积极的（例如尼伐单抗和雷特利马布联合）和消极的反馈（例如尼伐单抗与聚乙二醇化IL2，帕姆单抗与T-VEC，尼伐单抗与艾帕卡多斯塔特以及BRAF / MEK抑制剂与免疫治疗的组合三联疗法）。许多内在（细胞内或肿瘤内）以及外在（系统性）事件被认为参与了该抗体耐药性的发展：i）黑色素瘤细胞免疫原性（例如 肿瘤突变负荷，抗原处理机器和免疫原性细胞死亡，新抗原亲和力和异质性，基因组不稳定性，黑色素瘤分化和表型可塑性），ii）免疫细胞转运，T细胞初次充电和细胞死亡逃逸，iii）黑色素瘤新生血管形成，细胞TME成分（例如 Tregs，CAFs）和细胞外基质调节，iv）TME 中的代谢拮抗（高度糖酵解状态，上调的CD39 / CD73 / 腺苷酸途径，iDO依赖的色氨酸分解），v）T细胞疲劳和负免疫检查点，以及vi）肠道菌群。在本综述中，我们讨论这些参数如何影响ICIs的疗效，重点介绍最新黑色素瘤研究中所学到的课程；同时，我们描述了克服免疫治疗抗性的主要进行方法。总结这些信息将提高对这些复杂动态如何促成免疫逃逸的理解，并有助于开发更有效的策略，以克服ICIs不敏感黑色素瘤的现有障碍。版权所有©2022 Elsevier Ltd.保留所有权利。

Marching into the second decade after the approval of ipilimumab, it is clear that immune checkpoint inhibitors (ICIs) have dramatically improved the prognosis of melanoma. Although the current edge is already high, with a 4-year OS% of 77.9% for adjuvant nivolumab and a 6.5-year OS% of 49% for nivolumab/ipilimumab combination in the metastatic setting, a high proportion of patients with advanced melanoma have no benefit from immunotherapy, or experience an early disease relapse/progression in the first few months of treatment, surviving much less. Reasonably, the primary and acquired resistance to ICIs has entered into the focus of clinical research with positive (e.g., nivolumab and relatlimab combination) and negative feedbacks (e.g., nivolumab with pegylated-IL2, pembrolizumab with T-VEC, nivolumab with epacadostat, and combinatorial triplets of BRAF/MEK inhibitors with immunotherapy). Many intrinsic (intracellular or intra-tumoral) but also extrinsic (systematic) events are considered to be involved in the development of this resistance to ICIs: i) melanoma cell immunogenicity (e.g., tumor mutational burden, antigen-processing machinery and immunogenic cell death, neoantigen affinity and heterogeneity, genomic instability, melanoma dedifferentiation and phenotypic plasticity), ii) immune cell trafficking, T-cell priming, and cell death evasion, iii) melanoma neovascularization, cellular TME components(e.g., Tregs, CAFs) and extracellular matrix modulation, iv) metabolic antagonism in the TME(highly glycolytic status, upregulated CD39/CD73/adenosine pathway, iDO-dependent tryptophan catabolism), v) T-cell exhaustion and negative immune checkpoints, and vi) gut microbiota. In the present overview, we discuss how these parameters compromise the efficacy of ICIs, with an emphasis on the lessons learned by the latest melanoma studies; and in parallel, we describe the main ongoing approaches to overcome the resistance to immunotherapy. Summarizing this information will improve the understanding of how these complicated dynamics contribute to immune escape and will help to develop more effective strategies on how anti-tumor immunity can surpass existing barriers of ICI-refractory melanoma.Copyright © 2022 Elsevier Ltd. All rights reserved.