Neuro-immune crosstalk in the tumor microenvironment: mechanisms and therapeutic implications for cancer...

The nervous system is a critical regulator of the tumor microenvironment (TME), extending beyond structural innervation to influence tumor initiation, progression, and therapeutic response. Neural regulation operates through synapse-like interactions and paracrine, neurotransmitter-mediated, and electrochemical signaling, thereby shaping both malignant and stromal compartments. These signals modulate immune-cell phenotypes, promote T-cell exhaustion, and expand immunosuppressive populations, thereby contributing to immune evasion and resistance to immunotherapy. Emerging evidence highlights bidirectional crosstalk, whereby neural activity supports tumor growth, metastasis, metabolic reprogramming, and immune suppression, while tumor-derived signals reciprocally remodel neural activity. This dynamic crosstalk defines a neuro-immune-tumor regulatory network that represents an important layer of tumor biology. Despite recent advances, how neural, immune, and metabolic pathways are integrated within the TME remains incompletely understood. Cancer neuroscience has therefore emerged as an interdisciplinary field for elucidating these mechanisms and identifying therapeutic vulnerabilities. Targeting the neuro-immune axis through neuromodulation, neuroactive agents, and combination immunotherapy may improve immunotherapy efficacy and advance precision oncology.