Natural Killer Cell Activation Signature Identifies Cyclin B1/CDK1 as a Druggable Target to Overcome Natural Killer Cell Dysfunction and Tumor Invasiveness in Melanoma

作者：Linbin Chen, Wanqian Liao, Jing Huang, Qiu-yue Ding, Junwan Wu, Qiong Zhang, Ya Ding, Dandan Li, Jingjing Li, Xizhi Wen, Xiaoshi Zhang · 发表于：Pharmaceuticals · 年份：2025 · DOI：10.3390/ph18050666 · 被引用次数：6 · 研究领域：Immune Cell Function and Interaction、Cancer Immunotherapy and Biomarkers、CAR-T cell therapy research

Background/Objectives: Natural killer (NK) cells play a crucial role in immune surveillance against melanoma, yet they frequently exhibit dysfunction in the tumor microenvironment. This study aims to establish an NK cell activation-related prognostic signature and identify potential druggable targets to overcome NK cell dysfunction. Methods: A prognostic signature was developed using the TCGA-SKCM cohort and validated across independent datasets. NK cell activation and cytotoxicity were evaluated in melanoma-NK-92MI co-culture systems via flow cytometry. Mechanistic studies employed Western blotting, co-immunoprecipitation, ELISA, and qRT-PCR. Single-cell RNA-seq data were used to analyze cell–cell communication. Results: A four-gene NK cell activation signature was identified and validated for prognostic significance across five independent melanoma datasets. Among the identified genes, cyclin B1 (CCNB1) emerged as a novel therapeutic target for overcoming NK cell resistance. In vivo, pharmacological inhibition of the CCNB1/Cyclin-dependent kinase 1 (CDK1) complex with RO-3306 significantly suppressed melanoma growth by enhancing NK cell infiltration and IFN-γ production. In vitro, CCNB1 knockdown in melanoma cells augmented NK-92MI activation, as evidenced by increased expression of CD69, CD107a, IFN-γ, and NKG2D, thereby improving NK cell-mediated cytotoxicity. Mechanistically, in melanoma cells, the CCNB1/CDK1 complex phosphorylates STAT3, activating the IL-6/STAT3 positi...