Diabetes and Colorectal Cancer Risk and Survival According to Tumor Immunity Status

Abstract

PURPOSE Type 2 diabetes (T2D) has been associated with an increased risk of colorectal cancer (CRC) and poorer survival outcomes. However, the role of tumor immune status in influencing these relationships remains unclear. METHODS We conducted a population-based matched case-control study (n = 4,724) with prospective long-term follow-up of CRC cases (n = 2,321; median follow-up, 9.5 years). Tumor immune status was assessed using an immune cell score (ICS), derived from CD3 + and CD8 + T-cell densities measured at the invasive margin and tumor core of resected specimens. ICS was stratified into high (ICS Hi ), intermediate (ICS Int ), and low (ICS Low ) immune infiltration on the basis of standard cutoffs (25% and 70%). Multivariable logistic regression estimated CRC risk, whereas time-dependent Cox regression evaluated survival outcomes. Primary end points included CRC-specific survival and disease-free survival (DFS). RESULTS The association between T2D and CRC risk differed significantly by ICS ( P for heterogeneity = .02). T2D was associated with an increased risk of CRC (odds ratio [OR], 1.39 [95% CI, 1.17 to 1.66]), particularly for ICS Low (OR, 1.80 [95% CI, 1.35 to 2.39]) and ICS Int subtypes (OR, 1.42 [95% CI, 1.17 to 1.66]), but not for ICS Hi CRC subtype (OR, 1.16 [95% CI, 0.88 to 1.52]). Patients with T2D with ICS Low tumors showed poorer CRC-specific survival (hazard ratio [HR], 1.99 [95% CI, 1.30 to 3.05]) and DFS (HR, 1.53 [95% CI, 1.05 to 2.26]) than those without T2D, but not for ICS Int and ICS Hi CRC subtypes. Patients with T2D showed inferior overall and non–cancer-related survival regardless of immune subtypes. CONCLUSION T2D disproportionately affects CRC risk and survival in tumors with low immune infiltration, suggesting a continuum of T2D's impact from tumorigenesis to prognosis, through systemic and tumor-specific immune modulation. These findings highlight the need for precision prevention strategies integrating metabolic and immune-based interventions to mitigate CRC burden in patients with T2D.