Cardiovascular-kidney-metabolic syndrome in the tumor host macroenvironment: organ crosstalk, treatment trajectories, and net clinical benefit

Cardiovascular-kidney-metabolic (CKM) syndrome links metabolic dysfunction, chronic kidney disease, and cardiovascular disease, yet oncology commonly treats these conditions as separate comorbidities. This review examines CKM as a measurable component of the tumor host macroenvironment that may influence treatment tolerance and competing mortality. We integrate adipose, cardiorenal, and immune-metabolic pathways; clonal hematopoiesis is considered as a candidate link between inflammation, vascular injury, and treatment exposure, rather than a CKM staging criterion. Cancer and its treatment can also alter CKM status through organ injury and catabolism. Population studies associate higher CKM stages with cancer incidence and adverse host outcomes, but evidence for cancer-specific mortality and treatment efficacy remains inconsistent or limited. The central question is therefore whether CKM captures biologically meaningful host variation that changes tumor natural history, treatment tolerance, or both. Our oncology-adapted phenotyping framework retains the original American Heart Association CKM stages and adds organ reserve and activity, tumor and treatment context, and longitudinal change. It applies to both patients with active cancer and survivors, without introducing a new stage or stage-specific treatment recommendation. We outline assessment from pretreatment to survivorship and distinguish established cardiorenal indications from exploratory anticancer effects of CKM therapies. Net clinical benefit requires joint assessment of tumor control, treatment delivery, cardiorenal events, function, and patient priorities. Prospective validation is needed before the added phenotypes can guide cancer-treatment selection.