Stress and Neuroendocrine Dysregulation in Colorectal Cancer: Clinical Assessment, HPA–HPT Axis Interactions, and Translational Implications

Colorectal cancer (CRC) is associated with psychological, metabolic, inflammatory, and endocrine disturbances that may influence patient well-being and clinical outcomes. Psychological distress and circadian disruption can affect hypothalamic–pituitary–adrenal (HPA) axis activity, whereas systemic inflammation, nutritional deterioration, disease burden, and anticancer therapies may alter hypothalamic–pituitary–thyroid (HPT) axis function. This narrative review critically examines the clinical and translational evidence linking psychological stress, neuroendocrine regulation, systemic thyroid function, and tumor-specific thyroid hormone signaling in CRC. A structured PubMed/MEDLINE search prioritized studies published between January 2020 and July 2026, supplemented by selected earlier landmark studies. Available evidence supports the clinical relevance of psychological distress and suggests that cortisol dynamics and allostatic load may provide complementary information on systemic stress adaptation. Reduced free triiodothyronine (FT3) concentrations and altered FT3/FT4 ratios have been associated with unfavorable outcomes in selected CRC populations, although these associations are influenced by non-thyroidal illness syndrome, inflammation, nutritional status, disease severity, and treatment exposure. Importantly, circulating thyroid hormone parameters do not directly reflect thyroid hormone signaling within the tumor microenvironment, where local hormone metabolism, receptor-mediated pathways, and interactions with stromal and immune cells may contribute to tumor biology. Emerging evidence also implicates neuropeptide signaling in neuroendocrine–tumor communication, although its clinical significance remains uncertain. Collectively, these findings support an integrated approach to assessing psychological, circadian, inflammatory, nutritional, and endocrine alterations in CRC while highlighting the limitations of interpreting isolated biomarkers. Prospective longitudinal studies incorporating standardized neuroendocrine assessments, treatment-related variables, and matched tumor analyses are needed to establish whether integrated neuroendocrine profiles offer prognostic or predictive value beyond established clinicopathological factors.