Cardiovascular-kidney-metabolic (CKM) syndrome is associated with incremental cancer risk and stage-specific immune-metabolic pathways, according to a study using data from the UK Biobank published July 16 in JACC: CardioOncology. These findings highlight potential prevention targets.

In this large, prospective cohort study, Xixi Xiao, MD, et al., categorized the more than 500,000 UK Biobank participants included between 2006 and 2010 into CKM stages 0 to 4. After excluding participants with a cancer history at recruitment or who developed cancer within one year of recruitment, 448,323 participants were eligible for analysis.

Associations between CKM staging and overall cancer incidence were evaluated using Cox regression. Proteomic and metabolomic mediators linking adjacent stages and cancer underwent Gene Ontology enrichment and interaction network analyses, and were identified using Cox regression, logistic regression and mediation analysis.

Over a median follow-up of 4.3 years, 27,251 participants developed cancer. Results showed that overall cancer risk increased from CKM stages 1 to 3, with a slight attenuation and persistent elevation in stage 4.

Stage-specific mediators and mechanisms were identified as 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.

Additionally, dominant metabolomic mediation evolved from high-density lipoproteins (HDLs) and triglyceride-rich lipoproteins (TRLs) to low-density lipoproteins (LDLs). Protein-metabolite interaction networks revealed stage-specific profiles, 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 the later stages.

“…these findings elucidate biological pathways linking CKM stages to oncogenesis and highlight stage-specific immune-metabolic pathways as potential targets for integrated cardiometabolic and cancer prevention,” write the authors. “…the mediating mechanisms require further validation in experimental and interventional studies.”