Residual inflammatory risk and the plaque immune microenvironment in coronary artery disease: evidence and limits of precision immunotherapy

Cardiovascular events persist despite lipid-lowering therapy, motivating interventions against the inflammatory component of residual risk. The translational challenge is to distinguish prognostic biomarkers, causal pathways and treatment-responsive immune states. This narrative review links clinical trials with plaque biology and human single-cell and spatial studies to assess precision immunotherapy in coronary artery disease (CAD). CANTOS, COLCOT and LoDoCo2 demonstrated benefit in specific populations, whereas CIRT and CLEAR SYNERGY were neutral. Ziltivekimab lowered inflammatory biomarkers in RESCUE, while the sponsor-reported neutral ZEUS topline result underscores the need for cardiovascular outcomes. Low-dose IL-2 expanded regulatory T cells in the phase 2 IVORY imaging trial. Within plaques, retained and oxidized lipoproteins engage innate immune pathways alongside metabolic stress and diverse vascular and immune-cell states. Human datasets localize macrophage niches, microvascular interfaces and adaptive immunity, while experimental models test candidate functions. Most tissue evidence comes from carotid lesions or animal models. We evaluate IL-1β/NLRP3, IL-6 and macrophage-state pathways, then identify requirements for matching targets to patients, including plaque-focused biomarkers, coronary-relevant validation, functional perturbation and prospective trials that measure cardiovascular benefit and immune safety.