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

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.