Bidirectional Neurobiological Interactions Between Cancer and PTSD: Mechanisms and Emerging Therapeutic Implications.

Abstract

Purpose: This review aims to illustrate the bidirectional neurobiological mechanisms underlying cancer and Post-Traumatic Stress Disorder (PTSD) comorbidity, highlight the active regulatory role of the nervous system, and propose targeted intervention strategies.

Methods: This narrative review was conducted by searching PubMed, Google Scholar, and Web of Science for all years up to 2025. The following search terms were combined: "PTSD" AND "Tumor microenvironment" OR "Neural circuit" AND "cancer". Of the 1182 articles initially identified, 115 were enrolled in integrative analysis after duplicate removal, initial title/abstract screening, and overall text eligibility.

Results: As a traumatic stressor, cancer induces PTSD via diagnostic distress, treatment-related brain structural alterations, fear circuit activation, and neuroinflammation. PTSD, in turn, increases the risk of neoplastic development by disrupting the Hypothalamic-Pituitary-Adrenal (HPA) axis, leading to hyperactivity of the Sympathetic Nervous System (SNS) and restructuring immune functions to create a pro-tumor microenvironment. Moreover, cancer cells can actively hijack neuronal functions to promote malignant progression by forming neuron-tumor synapses, internalizing neuronal mitochondria, and integrating into neural networks. The mechanisms we mentioned in the article - such as tumor synapse formation and transfer of neuronal mitochondria - mainly come from preclinical studies and have not yet obtained direct clinical evidence in humans.

Discussion: Mental illness and cancer have a wide positive bidirectional relationship, which poses a challenge to the traditional dichotomy between physical illness and psychological disorders. This highlights the need to integrate mind-body treatment in the practice of oncology and psychiatry.

Conclusion: The nervous system is an active regulator and not a passive responder in patients with comorbid cancer and PTSD. Disruption of this pathological cycle requires the development of specific interventions that target neural signaling, metabolic crosstalk, and neuroendocrine pathways.