Narrative review conceptualizes CVD as systemic immune–metabolic–inflammatory disease.

Cardiovascular disease (CVD) remains the leading cause of mortality and disability worldwide, imposing a substantial burden on individuals, families, and healthcare systems. Despite major advances in controlling conventional risk factors (e.g., blood pressure, glycaemia, and lipids), a considerable residual risk persists, highlighting the need to elucidate additional pathogenic mechanisms and to develop more effective preventive and therapeutic strategies. Accumulating experimental and clinical evidence indicates that immune dysregulation and chronic low-grade inflammation are not merely associated with CVD but actively drive disease progression—from lesion initiation to acute thrombotic events. These processes are further shaped by metabolic status, lifestyle factors, psychosocial stress, and environmental exposures, and age-related genetic immune changes such as clonal hematopoiesis of indeterminate potential (CHIP). Atherosclerosis, the predominant pathological substrate of most CVDs, is now widely recognized as a chronic immune-inflammatory disease. Emerging concepts including immunometabolic reprogramming, trained immunity(distinguished by central and peripheral subtypes), the thrombo-inflammatory axis, and allostatic load provide an integrative framework for understanding CVD as a systemic disorder. Here, we synthesize recent advances in innate and adaptive immune mechanisms, immunometabolic dysregulation, and inflammation–thrombosis crosstalk that collectively govern plaque formation, destabilization, and clinical events. We also discuss how lifestyle-related factors (e.g., diet, fasting, physical activity, and stress) may modulate long-term cardiovascular risk through trained immunity and inflammatory pathways, and we highlight progress in immune biomarkers and anti-inflammatory interventions, and the immunometabolic effects of modern cardiometabolic drugs (GLP-1 receptor agonists, SGLT2 inhibitors). Additionally, we elaborate on the translational potential of short chain fatty acid derivatives in reversing innate immune inflammatory memory, and clarify the distinct cardiovascular toxic mechanisms of immune checkpoint inhibitors (ICIs) and chimeric antigen receptor T-cell (CAR-T) therapy in cardio-oncology. Conceptualizing CVD as a systemic immune–metabolic–inflammatory disease may facilitate improved risk stratification and inform precision prevention and treatment strategies.