Cardiovascular-Kidney-Metabolic Syndrome Staging and Cancer Risk

BACKGROUND: Cardiovascular-kidney-metabolic (CKM) syndrome is an emerging integrative framework and a critical determinant of overall disease risk; however, its relationship with cancer risk and underlying mechanisms remains poorly understood. OBJECTIVES: This study sought to investigate the association between CKM staging and incident cancer and elucidate mediators underlying this association, thereby uncovering pathways and potential targets for risk mitigation based on multiomics analysis. METHODS: UK Biobank participants were categorized into CKM stages 0 to 4 according to the American Heart Association staging framework based on International Classification of Diseases, 10th Revision codes. Cox regression was conducted to evaluate associations between CKM staging and overall cancer incidence. Proteomic and metabolomic mediators linking adjacent stages and cancer were identified using Cox regression, logistic regression, and mediation analysis and underwent Gene Ontology enrichment and interaction network analyses. RESULTS: Overall cancer risk increased stepwise from CKM stages 1 to 3, with slight attenuation but persistent elevation in stage 4. Stage-specific mediators and mechanisms were identified: leukocyte/lymphocyte activation and cell-cell adhesion in stage 1; T cell-related immunity and emerging immune tolerance induction in stage 2; emerging natural killer (NK) cell tolerance induction and respiratory burst involved in the inflammatory response in stage 3; and dominant NK cell tolerance induction and tissue-resident chronic pathology in stage 4. Dominant metabolomic mediation evolved from high-density lipoproteins (HDLs) and triglyceride-rich lipoproteins (TRLs) to low-density lipoproteins (LDLs). Protein-metabolite interaction networks revealed distinct profiles for each stage, including angiopoietin-like protein 1/HDL and asialoglycoprotein receptor 1/TRL interactions in early stages and phospholipid transfer protein/HDL, apolipoprotein M/LDL, and fibroblast growth factor-binding protein 1/intermediate-density lipoprotein/LDL correlations in advanced stages. CONCLUSIONS: CKM staging is associated with incremental cancer risk and stage-specific immune-metabolic pathways, highlighting potential prevention targets.