Neurotransmitters: an emerging target for therapeutic resistance to tumor immune checkpoint inhibitors.

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.