The intersection of immunity and mental health: Immunotherapy's role in modulating depression and neuropsychiatric disorders.

Depression is increasingly recognized as a heterogeneous disorder, with a substantial subset of cases driven by immune dysregulation. This review synthesizes current evidence on the bidirectional relationship between the immune system and mental health, highlighting the dual role of immunotherapy as both a contributor to and a treatment for neuropsychiatric symptoms. Growing evidence links immune dysfunction characterized by altered inflammatory pathways, cytokine profiles, and immune cell activity to the pathophysiology of major depressive disorder. Notably, activation of the kynurenine pathway of tryptophan metabolism has emerged as a key mechanistic bridge between peripheral inflammation and central neurochemical alterations underlying depressive symptoms. Furthermore, the brain actively regulates peripheral immune responses through the hypothalamic-pituitary-adrenal axis and autonomic nervous system, particularly the cholinergic anti-inflammatory pathway, completing the bidirectional neuroimmune circuit. The immune-brain interface is clearly illustrated in autoimmune encephalitis, where autoantibodies targeting synaptic receptors induce severe psychiatric manifestations that often respond effectively to timely immunomodulatory therapy, demonstrating a direct immune-mediated pathway to neuropsychiatric disease. Conversely, although transformative in cancer therapy, immunotherapeutic strategies such as immune checkpoint inhibitors and chimeric antigen receptor (CAR) T-cell therapies are frequently associated with neurotoxicity and psychiatric sequelae, including depression, anxiety, and cognitive impairment. In addition, chronic inflammatory and autoimmune disorders such as multiple sclerosis, rheumatoid arthritis, and allergic diseases exhibit high rates of psychiatric comorbidity closely linked to disease activity. Importantly, immunomodulatory treatments in these conditions often improve both physical outcomes and mental well-being. Overall, this review integrates the immunobiological foundations of depression, examines representative disease models, and evaluates the neuropsychiatric impact of immunotherapies. It underscores the importance of precision medicine approaches using inflammatory biomarkers and advocates for routine mental health assessment in patients receiving immunomodulatory treatments. Taken together, these findings underscore the need for a precision medicine framework in which inflammatory biomarkers are used to stratify patients, identify those most likely to respond to immune-targeted interventions, and guide the integration of mental health monitoring as a standard component of immunotherapy management.