The neuro-immune axis in cancer: mechanisms of neural regulation of immunity within the tumor microenvironment to promote cancer progression

Abstract

The tumor microenvironment (TME) is a complex and dynamic ecosystem composed of cancer cells, stromal cells, immune cells, and the extracellular matrix, which significantly influences the initiation, progression, and therapeutic response of cancer. Emerging evidence indicates a crucial interaction between the nervous and immune systems within the TME, forming a “neuro-immune axis” that profoundly impacts tumor biology. This review not only synthesizes current knowledge on this critical bidirectional crosstalk but also offers a fresh perspective by critically evaluating underappreciated aspects such as the neural differentiation of cancer stem cells and the challenges in translating preclinical findings into clinical therapies. On one hand, tumor cells actively promote nerve recruitment and remodeling through tumor innervation, neurogenesis, and perineural invasion. In turn, neural signals-including adrenergic, cholinergic, and sensory neuropeptides-orchestrate immunosuppression by modulating key immune cell populations such as T cells, macrophages, and myeloid-derived suppressor cells (MDSCs). Consequently, neural signaling promotes immune escape, tumor progression and therapeutic resistance. This review further critically evaluates the translational potential of targeting these neuro-immune interactions, highlighting combination strategies designed to enhance the efficacy of cancer immunotherapy.