Cardiovascular disease (CVD) remains the leading global cause of mortality despite substantial advances in lipid-lowering therapies, underscoring the persistence of residual cardiovascular risk. Increasing evidence identifies chronic, low-grade inflammation as a central driver of atherosclerotic progression, plaque instability, and recurrent ischemic events independent of dyslipidemia. The vascular endothelium occupies a pivotal position in this process, serving as a dynamic interface that integrates immune activation with vascular dysfunction through cytokine signaling, leukocyte recruitment, and thrombo-inflammatory responses. Among inflammatory mediators, interleukin-1β (IL-1β) functions as a nodal cytokine linking innate immune sensing, endothelial activation, and downstream amplification via interleukin-6 and acute-phase reactants. The Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) provided definitive proof-of-concept that selective IL-1β neutralization reduces major adverse cardiovascular events independently of lipid lowering, establishing inflammation as a causal and therapeutically actionable pathway in atherosclerotic disease. Beyond clinical efficacy, emerging translational insights reveal that interindividual variability in treatment response may be driven by biomarker profiles and genetic modifiers, particularly clonal hematopoiesis of indeterminate potential (CHIP), which augments IL-1β–driven myeloid inflammation and endothelial dysfunction. This review synthesizes mechanistic, preclinical, and clinical evidence on immune–endothelial crosstalk in cardiovascular inflammation, with a focused appraisal of canakinumab as a precision anti-inflammatory therapy. By integrating cytokine biology, endothelial dysfunction, clinical trial outcomes, and emerging genomic stratifiers, it highlights opportunities and challenges in implementing biomarker- and genotype-guided strategies, treat-to-target approaches, and real-world considerations for cost-effectiveness and safety in secondary cardiovascular prevention.