Psychological distress as a putative host-state determinant of cancer immunotherapy response

Cancer immunotherapy has transformed oncology, yet durable benefits remain limited to a subset of patients, and those cases are incompletely explained by tumor-intrinsic biomarkers alone. Growing evidence indicates that the host immune state is a critical contextual determinant of therapeutic response and may itself be shaped by psychological distress. In cancer patients, such distress-related states have been associated with altered neuroendocrine activity and related cortisol regulation, inflammation, reduced natural killer cell function, and broader immune dysregulation. In parallel, preclinical studies show that glucocorticoid and adrenergic signaling can impair antitumor immunity by promoting T-cell dysfunction, metabolic exhaustion, and increased inhibitory signaling, as well as suppressing antigen presentation. Emerging clinical studies in patients receiving immune checkpoint inhibitors further suggest that emotional distress before immunotherapy initiation is associated with poorer progression-free survival, response, and overall survival outcomes in several cancer settings, including non-small-cell lung cancer, gastroesophageal cancer, gastric cancer, and recurrent high-grade glioma. As these patient data remain largely observational, current evidence supports psychological distress as a putative host-state modifier or correlate, rather than as a proven causal determinant, of immunotherapy response. These observations support a psycho-neuro-immune framework in which psychological distress may identify or contribute to a host state that is less permissive for effective immunotherapy. Here, we review evidence linking host immune competence to immunotherapy efficacy, summarize clinical and molecular data connecting distress to immune dysregulation in cancer, and incorporate emerging evidence that brain-body signaling may shape tumor immunity through neural, endocrine, and immune pathways. We propose that psychological distress should be considered not merely as a parallel quality-of-life variable, but as a biologically relevant and clinically verifiable host-state factor with implications for biomarker development and future host-modulation immunotherapy trials.