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

Jiyuan Yang1, Yu Wu1, Xinhui Lv1

  • 1Dept. of Laboratory Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, Jiangsu, China.

Molecular Cancer
|August 12, 2025
PubMed

Insights

Neurotransmitters significantly impact resistance to immune checkpoint inhibitors (ICIs) in cancer. Targeting the neural-immune axis offers new strategies to improve ICI therapy efficacy.

Area of Science:

  • Oncology
  • Immunology
  • Neuroscience

Background:

  • Immune checkpoint inhibitors (ICIs) like anti-PD-1/PD-L1 and anti-CTLA-4 enhance antitumor immunity but face significant drug resistance.
  • Tumor microenvironment factors and tumor cell intrinsic changes contribute to ICI resistance, limiting durable efficacy in many patients.
  • The neural-immune axis, involving neurotransmitters and nerve fibers, is increasingly recognized for its role in immune evasion and cancer progression.

Purpose of the Study:

  • To review the mechanisms by which neurotransmitters influence the tumor microenvironment and contribute to resistance against ICIs.
  • To explore the potential of targeting the neural-immune axis, specifically neurotransmitters and their receptors, as a therapeutic strategy to overcome ICI resistance.
  • To provide insights into novel approaches for enhancing cancer immunotherapy.

Main Methods:

  • Literature review of studies investigating the role of neurotransmitters in cancer immunity.
  • Analysis of the impact of neurotransmitters (dopamine, norepinephrine, serotonin) on immune checkpoint expression and immune cell function within the tumor microenvironment.
  • Exploration of therapeutic strategies targeting neurotransmitter pathways to enhance ICI efficacy.

Main Results:

  • Neurotransmitters can modulate immune cell function and immune checkpoint expression, promoting immune escape and contributing to ICI resistance.
  • Dysregulated neurotransmitter signaling in the tumor microenvironment can impair antitumor immune responses.
  • Targeting neurotransmitter pathways presents a promising avenue for overcoming resistance to current immunotherapies.

Conclusions:

  • Neurotransmitters play a critical role in the resistance to immune checkpoint inhibitors.
  • Modulating the neural-immune axis through neurotransmitter-targeted therapies holds potential for improving cancer treatment outcomes.
  • Further research into the neural-immune interactions in cancer is crucial for developing next-generation immunotherapies.
Keywords:
Drug resistanceImmune checkpoint inhibitorsImmunotherapyNeurotransmittersTumor microenvironment

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