The Tumor Neuroimmune Niche: A Unifying Framework for Cancer Progression and Its Neuropsychiatric Burden

Abstract

Background: Cancer has traditionally been framed as a cell-intrinsic genetic disease and, more recently, as a disorder of the tumor microenvironment (TME). An emerging third view reframes malignancy as a systems-level neuroimmune disorder, in which neurons, glia, immune cells, and tumor cells form a continuously communicating network, the tumor neuroimmune niche. Summary: This review synthesizes evidence that the nervous system actively regulates tumor initiation, proliferation, angiogenesis, invasion, and metastasis through autonomic, sensory, and neuroendocrine inputs, while tumors in turn remodel both peripheral nerves and central circuits. Sympathetic, parasympathetic, and sensory fibers shape the immune compartment, frequently driving T-cell exhaustion, macrophage repolarization, and an immunosuppressive milieu via β-adrenergic and neuropeptide signaling. The immune system operates as a central mediator of this dialogue: cytokines such as interleukin-6 (IL-6), interleukin-1 (IL-1), and tumor necrosis factor-α (TNF-α) relay tumor-derived signals to the brain through neural and humoral routes, activating the same circuits that produce sickness behavior, fatigue, depression, and cognitive impairment. These neuropsychiatric sequelae are common, durable, and poorly explained by tumor stage alone, positioning the central nervous system (CNS) at the center of the disease rather than at its periphery. Cancer therapies, chemotherapy, immune checkpoint inhibitors (ICIs), and radiation, further perturb the neuroimmune axis and contribute to lasting neurotoxicity. Translational opportunities include neuroimmune biomarkers, neural-activity signatures, and the repurposing of β-blockers, vagus nerve stimulation (VNS), and neurotransmitter-targeted agents as antitumor strategies. Key Messages: The circuits driving tumor progression and those producing the neuropsychiatric burden of cancer may substantially overlap. Integrating cancer neuroscience, immuno-oncology, and psycho-oncology is essential to convert this biology into therapy. Recognizing cancer as a neuroimmune disease opens a roadmap toward targeting the nervous system as a modifiable axis of oncologic care.