Perioperative Systemic Stress Phenotypes Predict Immune Recovery Failure, Molecular Residual Disease, and Long‐Term Outcomes After Colorectal Cancer Surgery: A Prospective Cohort Study

BACKGROUND: A major surgery represents a profound psychoneuroendocrine stressor that elicits coordinated inflammatory, immune, and metabolic responses. Although acute stress-related immune dysregulation is well-recognized, whether the magnitude and persistence of perioperative systemic stress phenotypes are associated with immune recovery failure, molecular residual disease (MRD), and long-term clinical outcomes, remains unclear. METHODS: In a prospective longitudinal cohort of 950 patients undergoing curative-intent colorectal cancer surgery, we characterized perioperative systemic stress phenotypes using a multidomain, time-structured Aging Shock Index (ASI). Conceptualized as an integrated perioperative stress-response phenotype rather than a direct measure of biological aging, the ASI was derived from inflammatory, immune surveillance, and immunometabolic biomarkers measured preoperatively and at postoperative days 1, 3, 7, and 30. Clinically significant postoperative complications (Clavien-Dindo grade ≥ II), circulating tumor DNA-defined MRD at postoperative day 30, and disease-free survival (DFS) over 60 months were evaluated. Multivariable regression and Cox proportional hazards models were used to examine associations between ASI and outcomes. RESULTS: Surgery induced marked, time-locked systemic stress responses characterized by inflammatory amplification and delayed immune recovery, as summarized by the ASI. Higher ASI was associated with increased postoperative complications (adjusted odds ratio per SD increase: 1.48, 95% CI 1.31-1.67) and greater MRD positivity at postoperative day 30 (adjusted odds ratio: 1.62, 95% CI 1.34-1.96). Over long-term follow-up, elevated ASI predicted worse DFS (hazard ratio per SD increase: 1.41, 95% CI 1.25-1.59), independent of clinicopathologic factors. These associations were primarily driven by early postoperative stress amplification and impaired resolution rather than baseline biomarker levels. CONCLUSIONS: Perioperative systemic stress phenotypes reflecting sustained psychoneuroendocrine-immune dysregulation are associated with immune recovery failure, molecular residual disease, and adverse long-term outcomes following a major surgery. Quantifying dynamic stress-related biological responses may provide a biologically grounded framework for understanding how acute psychoneuroendocrine stress translates into persistent immune vulnerability and may inform future risk stratification research in perioperative oncology.