Chronic stress and myeloid immunosuppression in cancer: A neuroimmune link to behavioral dysfunction

Abstract

Cancer progression is profoundly influenced by the complex interplay between the tumor microenvironment (TME), the immune system, and the patient's psychological state. This review delineates a critical pathway linking chronic stress to worsened cancer outcomes through inflammatory factors, anti-tumor immune suppression, and the induction of behavioral comorbidities. We postulate that sustained stress hormone signaling via the sympathetic nervous system and hypothalamic-pituitary-adrenal axis activation orchestrates a systemic immunosuppressive cascade. A central mechanism is the stress-induced expansion and functional polarization of myeloid cells, including myeloid-derived suppressor cells, tumor-associated macrophages, and neutrophils within the TME. These cells foster a pro-tumoral milieu by impairing T-cell function, promoting angiogenesis, and facilitating metastasis, among other processes. Beyond the local TME, stress-mediated inflammation propagates to the central nervous system, compromising the blood-brain barrier and activating microglia. This neuroinflammatory response drives structural and functional remodeling in key brain regions such as the prefrontal cortex, hippocampus, and amygdala, providing a biological basis for depression and anxiety often seen in patients with cancer. This creates a vicious cycle wherein psychological distress exacerbates tumor-promoting inflammation and immune evasion, which in turn worsens behavioral symptoms. Critically, clinical evidence now links psychological stress to chemoresistance and poor responses to immunotherapy. We argue that integrating stress-reducing interventions and strategies targeting neuroinflammation into cancer care is not merely supportive but essential to disrupt this detrimental cycle. A multidisciplinary approach that concurrently targets the tumor, the immune system, and the patient's mental well-being holds the promise of improving both survival and quality of life.