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  • Neuro-Cancer Crosstalk in the Tumor Immune Microenvironment: Molecular Mechanisms of Immune Evasion and Tumor-Promoting Inflammation

  • Zahra Seifi ,1,* Delnia Khadiri ,2 Rasoul Amiri,3
    1. Student research committee, Kermanshah university of Medical sciences
    2. Student research committee, Kermanshah university of Medical sciences
    3. Student research committee, Kermanshah university of Medical sciences


  • Introduction: The tumor microenvironment (TME) is increasingly recognized as a dynamic ecosystem in which cancer cells interact with immune, stromal, vascular, and neural components. Emerging evidence indicates that the nervous system can actively shape anti-tumor immunity and, in certain contexts, be co-opted by cancer cells to establish an immunosuppressive microenvironment. Neurons, neurotransmitters, neurotrophins, and neuronal regulatory proteins can influence immune-cell recruitment, activation, and function, thereby affecting tumor progression. However, the molecular mechanisms linking neural signaling to tumor immune regulation remain incompletely understood. This review summarizes current evidence regarding neuro-cancer crosstalk as an emerging regulator of the tumor immune microenvironment.
  • Methods: A narrative review was conducted of experimental and translational studies investigating interactions among neuronal signaling, cancer cells, and immune components of the TME. Studies addressing neurotransmitters, neurotrophins, neuronal activity, neural regulatory proteins, immune-cell recruitment, inflammatory signaling, and immune evasion were examined across different malignancies. Particular attention was given to molecular pathways connecting neural signals with T cells, myeloid cells, chemokines, and immunoregulatory signaling networks.
  • Results: Accumulating evidence demonstrates that neural signaling can influence tumor immunity through several interconnected mechanisms. In neurofibromatosis type 1-associated low-grade gliomas, neurons can release midkine, promoting the recruitment and activation of CD8+ lymphocytes. Rather than producing effective anti-tumor responses, these recruited cells can contribute to a tumor-promoting inflammatory circuit involving CCL4 production and subsequent activation of microglial and myeloid cells to produce CCL5, which promotes cancer-cell proliferation and suppresses apoptotic signaling. This illustrates an unconventional mechanism in which immune-cell recruitment does not necessarily translate into effective tumor elimination. Neuronal signaling can also directly modulate immune evasion through cancer-cell-intrinsic pathways. GABA, produced by cancer cells through glutamic acid decarboxylases, can activate GABA-B receptors and downstream β-catenin signaling. This pathway has been associated with suppression of CCL4/CCL5 expression, reduced recruitment of T cells and dendritic cells, and impaired anti-tumor immunity. Conversely, inhibition of GABA signaling can promote an immunostimulatory TME and enhance immune-mediated tumor control. The neuronal regulatory protein fragile X mental retardation protein (FMRP) represents another link between neuronal biology and tumor immunology. FMRP expression in cancer cells can promote secretion of immunomodulatory cytokines, increase regulatory T-cell abundance, and induce immunosuppressive macrophage programs. Genetic disruption of FMRP has been associated with conversion toward a more immunostimulatory TME, characterized by increased T-cell activation and impaired tumor growth. Together, these findings indicate that neuronal pathways can regulate both the composition and functional state of immune cells within tumors.
  • Conclusion: Neuro-cancer crosstalk represents an emerging layer of tumor immune regulation in which neuronal signals and cancer-cell-intrinsic neural pathways can shape inflammation, immune-cell recruitment, immune suppression, and anti-tumor immunity. Understanding the molecular connections between neural signaling and immune regulation may provide new insights into tumor heterogeneity and immune resistance. Targeting selected neural-immune signaling axes, potentially in combination with immunotherapy, warrants further investigation as a strategy for modifying the tumor immune microenvironment.
  • Keywords: Neuro-cancer crosstalk; Tumor immunology; Tumor microenvironment; Immune evasion; Neural signaling

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