Dynamic interplay of neuroendocrine signaling and immuno-surveillance in tumor niche remodeling

The complex crosstalk between the nervous system and the tumor immune microenvironment (TIME) plays a key role in cancer progression, immune evasion, and therapy resistance. This review summarizes and critically examines bidirectional neuroimmune interactions within the TIME, focusing on how neural elements shape immune responses and how immune signals remodel neural circuits. Neurotransmitters, neuropeptides, and stress hormones such as norepinephrine and cortisol modulate dendritic-cell priming, natural killer (NK) and CD8⁺ T-cell cytotoxicity, and myeloid polarization, thereby establishing immunosuppression that supports tumor growth and metastasis. We also highlight how tumor-derived cues drive tumor-associated neurogenesis and nerve ingrowth, which reinforces metastasis through neural remodeling and immune regulation. In addition, we discuss therapeutic strategies that target these pathways, including β-adrenergic blockade, calcitonin gene-related peptide (CGRP) receptor antagonism, and inhibition of neurotrophic factors such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), as avenues to improve cancer treatment. Combining immune checkpoint inhibitors (ICIs) with neuromodulation is being investigated as a means to overcome drug resistance and enhance clinical benefit. Future work should apply spatially resolved and molecular technologies to define these circuits in situ and to guide biomarker-driven, patient-tailored multimodal therapies.