Miao Linxuan, Lu Chenglin, Zhang Bin, Li Huili, Zhao Xu, Chen Haoran, Liu Ying, Cui Xiaonan
Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, People's Republic of China.
Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, 116000, People's Republic of China.
J Transl Med. 2024 Mar 3;22(1):229. doi: 10.1186/s12967-024-05033-w.
Natural killer (NK) cells are unique from other immune cells in that they can rapidly kill multiple neighboring cells without the need for antigenic pre-sensitization once the cells display surface markers associated with oncogenic transformation. Given the dynamic role of NK cells in tumor surveillance, NK cell-based immunotherapy is rapidly becoming a "new force" in tumor immunotherapy. However, challenges remain in the use of NK cell immunotherapy in the treatment of solid tumors. Many metabolic features of the tumor microenvironment (TME) of solid tumors, including oxygen and nutrient (e.g., glucose, amino acids) deprivation, accumulation of specific metabolites (e.g., lactate, adenosine), and limited availability of signaling molecules that allow for metabolic reorganization, multifactorial shaping of the immune-suppressing TME impairs tumor-infiltrating NK cell function. This becomes a key barrier limiting the success of NK cell immunotherapy in solid tumors. Restoration of endogenous NK cells in the TME or overt transfer of functionally improved NK cells holds great promise in cancer therapy. In this paper, we summarize the metabolic biology of NK cells, discuss the effects of TME on NK cell metabolism and effector functions, and review emerging strategies for targeting metabolism-improved NK cell immunotherapy in the TME to circumvent these barriers to achieve superior efficacy of NK cell immunotherapy.
自然杀伤（NK）细胞与其他免疫细胞不同，一旦细胞显示出与致癌转化相关的表面标志物，它们就可以在无需抗原预致敏的情况下迅速杀死多个相邻细胞。鉴于NK细胞在肿瘤监测中的动态作用，基于NK细胞的免疫疗法正迅速成为肿瘤免疫疗法中的一支“新生力量”。然而，在实体瘤治疗中使用NK细胞免疫疗法仍然存在挑战。实体瘤肿瘤微环境（TME）的许多代谢特征，包括氧气和营养物质（如葡萄糖、氨基酸）剥夺、特定代谢产物（如乳酸、腺苷）的积累以及允许代谢重组的信号分子可用性有限，免疫抑制性TME的多因素塑造会损害肿瘤浸润性NK细胞功能。这成为限制NK细胞免疫疗法在实体瘤中取得成功的关键障碍。恢复TME中的内源性NK细胞或明显转移功能改善的NK细胞在癌症治疗中具有巨大潜力。在本文中，我们总结了NK细胞的代谢生物学，讨论了TME对NK细胞代谢和效应功能的影响，并综述了针对TME中改善代谢的NK细胞免疫疗法的新兴策略，以克服这些障碍，实现NK细胞免疫疗法的卓越疗效。
