Yang Jiyuan, Wu Yu, Lv Xinhui, Liu Sicong, Yuan Ziwen, Chen Yafang, Ding Xiangyu, Li Zhong, Wang Xudong
Dept. of Laboratory Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, Jiangsu, China.
Dept. Of Laboratory Medicine, People's Hospital of Haimen District, Nantong, Jiangsu, China.
Mol Cancer. 2025 Aug 11;24(1):216. doi: 10.1186/s12943-025-02413-8.
The critical role of neurotransmitters in the resistance to tumor immune checkpoint inhibitor (ICI) is becoming increasingly significant in therapeutic contexts. ICIs work by enhancing antitumor immunity through the blockade of the PD-1/PD-L1 and CTLA-4 pathways. However, only 20% of patients experience durable efficacy, and the challenge of drug resistance limits the clinical application of these therapies. Drug resistance is closely linked to various factors within the tumor microenvironment, including the distribution of tumor-infiltrating lymphocytes, the function of tumor-associated macrophages, low expression levels of PD-L1, variations in tumor mutational burden, dysregulation of antigen presentation, and both genetic and epigenetic changes in tumor cells. In recent years, the importance of the neural-immune axis has gained attention. Abnormal nerve fiber growth or irregular secretion of neurotransmitters can contribute to immune evasion. Neurotransmitters such as dopamine, norepinephrine, and serotonin influence the tumor microenvironment by regulating the expression of immune checkpoints and the function of immune cells, which can promote immune escape. As a result, therapeutic strategies that target neurotransmitters and their receptors hold promise for overcoming resistance to ICIs. These strategies may significantly enhance the efficacy of ICIs and pave the way for new approaches in cancer therapy. This article reviews the relevant mechanisms and proposes potential therapeutic strategies, offering new insights for the field.
神经递质在肿瘤免疫检查点抑制剂（ICI）耐药中的关键作用在治疗背景下正变得越来越重要。ICI通过阻断PD-1/PD-L1和CTLA-4通路来增强抗肿瘤免疫力。然而，只有20%的患者能获得持久疗效，耐药问题限制了这些疗法的临床应用。耐药与肿瘤微环境中的多种因素密切相关，包括肿瘤浸润淋巴细胞的分布、肿瘤相关巨噬细胞的功能、PD-L1低表达水平、肿瘤突变负荷的变化、抗原呈递失调以及肿瘤细胞的基因和表观遗传变化。近年来，神经免疫轴的重要性受到关注。神经纤维异常生长或神经递质分泌异常可导致免疫逃逸。多巴胺、去甲肾上腺素和血清素等神经递质通过调节免疫检查点的表达和免疫细胞的功能来影响肿瘤微环境，从而促进免疫逃逸。因此，针对神经递质及其受体的治疗策略有望克服ICI耐药。这些策略可能显著提高ICI的疗效，并为癌症治疗的新方法铺平道路。本文综述了相关机制并提出了潜在的治疗策略，为该领域提供了新的见解。
