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<p>The heterogeneity of the tumor microenvironment (TME) constitutes a major obstacle in cancer therapy. Emerging evidence reveals that the nervous, vascular, and immune systems form a complex, interactive regulatory network within the TME, termed the “neuro-vascular-immune triad.” This review systematically delineates the architecture and function of this network. Neural activity, via neurotransmitters and neurotrophic factors, promotes angiogenesis and induces immunosuppression. Aberrant vasculature creates hypoxia, which acts as a core hub by stabilizing Hypoxia-Inducible Factor-1α (HIF-1α) to further exacerbate immune suppression and neural remodeling. Immune cells, in turn, secrete inflammatory factors that feedback to nerves and vessels. This self-reinforcing vicious cycle collectively drives tumor progression and therapeutic resistance. Critically, the integrated status of this triad strongly correlates with clinical outcomes, highlighting its utility in prognostic stratification. Key signaling nodes, such as HIF-1α, β2-adrenergic receptor (β2-AR), calcitonin gene-related peptide (CGRP), and vascular endothelial growth factor (VEGF), emerge as prospective multi-dimensional biomarkers for monitoring TME dynamics and predicting treatment response. We further summarize emerging combination strategies targeting this network, such as the synergy between immune checkpoint inhibitors (ICIs), anti-angiogenic agents, and β-blockers, that aim to disrupt this malignant circuitry. Deciphering this cross-regulatory network provides an integrative new paradigm for overcoming treatment resistance and outlines promising translational avenues for next-generation cancer therapy.</p>

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The neuro-vascular-immune triad: the interactive network in the tumor microenvironment

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月30日

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  • Dan Li,
  • Qingqing Zhao,
  • Li Liu,
  • Feng Zeng

摘要

The heterogeneity of the tumor microenvironment (TME) constitutes a major obstacle in cancer therapy. Emerging evidence reveals that the nervous, vascular, and immune systems form a complex, interactive regulatory network within the TME, termed the “neuro-vascular-immune triad.” This review systematically delineates the architecture and function of this network. Neural activity, via neurotransmitters and neurotrophic factors, promotes angiogenesis and induces immunosuppression. Aberrant vasculature creates hypoxia, which acts as a core hub by stabilizing Hypoxia-Inducible Factor-1α (HIF-1α) to further exacerbate immune suppression and neural remodeling. Immune cells, in turn, secrete inflammatory factors that feedback to nerves and vessels. This self-reinforcing vicious cycle collectively drives tumor progression and therapeutic resistance. Critically, the integrated status of this triad strongly correlates with clinical outcomes, highlighting its utility in prognostic stratification. Key signaling nodes, such as HIF-1α, β2-adrenergic receptor (β2-AR), calcitonin gene-related peptide (CGRP), and vascular endothelial growth factor (VEGF), emerge as prospective multi-dimensional biomarkers for monitoring TME dynamics and predicting treatment response. We further summarize emerging combination strategies targeting this network, such as the synergy between immune checkpoint inhibitors (ICIs), anti-angiogenic agents, and β-blockers, that aim to disrupt this malignant circuitry. Deciphering this cross-regulatory network provides an integrative new paradigm for overcoming treatment resistance and outlines promising translational avenues for next-generation cancer therapy.