黑色素瘤是一种异质性癌症，受黑色素瘤细胞的可塑性及其对微环境线索的动态适应的影响。黑色素瘤细胞在影响治疗反应和耐药性的明确转录细胞状态之间转变。在这项研究中，我们应用单细胞 RNA 测序来探究未接受免疫治疗和免疫治疗耐药的黑色素瘤肿瘤响应体外 BRAF/ 的分子特征。 MEK抑制剂治疗。我们确认了四种不同黑色素瘤细胞状态的存在——黑色素细胞、暂时性、神经嵴样和未分化，并确定了神经嵴样和未分化黑色素瘤细胞在免疫治疗抵抗性肿瘤中的富集。此外，我们引入了一种综合计算方法来识别转录细胞状态内响应和无响应黑色素瘤细胞的子集。无响应黑色素瘤细胞在所有转录细胞状态下均被识别，并且由于促炎性 IL6 和 TNFɑ 而易于对 BRAF/MEK 抑制剂产生耐药性发出信号。我们的研究提供了一个框架来研究不同黑色素瘤细胞状态下的治疗反应，并表明肿瘤内在的促炎信号传导有助于 BRAF/MEK 抑制剂耐药性。这项工作得到了麦格理大学、澳大利亚黑色素瘤研究所和国家健康与医学中心的支持澳大利亚研究委员会（NHMRC；授权 2012860、2028055）。版权所有 © 2024 作者。由 Elsevier B.V. 出版。保留所有权利。

Melanoma is a heterogeneous cancer influenced by the plasticity of melanoma cells and their dynamic adaptations to microenvironmental cues. Melanoma cells transition between well-defined transcriptional cell states that impact treatment response and resistance.In this study, we applied single-cell RNA sequencing to interrogate the molecular features of immunotherapy-naive and immunotherapy-resistant melanoma tumours in response to ex vivo BRAF/MEK inhibitor treatment.We confirm the presence of four distinct melanoma cell states - melanocytic, transitory, neural-crest like and undifferentiated, and identify enrichment of neural crest-like and undifferentiated melanoma cells in immunotherapy-resistant tumours. Furthermore, we introduce an integrated computational approach to identify subsets of responding and nonresponding melanoma cells within the transcriptional cell states.Nonresponding melanoma cells are identified in all transcriptional cell states and are predisposed to BRAF/MEK inhibitor resistance due to pro-inflammatory IL6 and TNFɑ signalling. Our study provides a framework to study treatment response within distinct melanoma cell states and indicate that tumour-intrinsic pro-inflammatory signalling contributes to BRAF/MEK inhibitor resistance.This work was supported by Macquarie University, Melanoma Institute Australia, and the National Health and Medical Research Council of Australia (NHMRC; grant 2012860, 2028055).Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.