The onset and progression of cancer and chronic systemic diseases are driven not only by genetic and biological factors but also profoundly influenced by psychosocial stress, anxiety, depression, and other mental health states. This special issue explores the multifaceted impact of psychosocial stress, anxiety, and depression on gastrointestinal disorders, systemic diseases, and cancer progression. Beyond gastrointestinal malignancies, we welcome studies investigating how chronic affective distress drives metabolic dysregulation, mitochondrial dysfunction, and impaired oxidative phosphorylation across multiple comorbid conditions. Contributions may include mechanistic research on stress-tumor microenvironment crosstalk, epidemiological analyses linking social determinants to disease outcomes, and translational work on stress-modulating interventions. By bridging psychiatry, oncology, and metabolism, this issue aims to foster a holistic understanding of how mental health and psychosocial factors shape physical disease trajectories, offering new insights for prevention and treatment strategies.