Immune dysregulation in recurrent in-stent restenosis: mechanisms, biomarkers, and therapy

Recurrent in-stent restenosis (RISR), defined as two or more episodes of luminal renarrowing at the same stent site despite technically successful revascularization, remains among the most intractable problems in contemporary interventional cardiology. It affects a substantial share of patients with multivessel coronary disease and is associated with an approximately two-fold higher adjusted hazard of repeat revascularization than first-time restenosis (adjusted HR 2.09). Conventional models treat restenosis as a largely mechanical phenomenon, yet identical procedural technique and lesion preparation yield divergent outcomes across individuals, implicating biological determinants that current paradigms do not capture. This review examines the evidence that immune dysregulation is a potentially important and therapeutically targetable driver of RISR, with particular emphasis on multivessel disease. We synthesize human biomarker studies, preclinical mechanistic experiments, and clinical trial data into an integrated five-hit model incorporating systemic immune priming, cumulative mechanical injury, biomaterial hypersensitivity, amplified perivascular adipose inflammation, and impaired resolution pathways. Experimental studies indicate that NLRP3 inflammasome activation, endothelial pyroptosis, trained immunity, and T-cell subset imbalance each contribute to neointimal hyperplasia, while translational analyses link routine inflammatory indices, including the systemic immune-inflammation index, albumin-to-globulin ratio, and triglyceride-glucose index, to elevated restenosis risk. Anti-inflammatory trials in unselected cardiovascular populations have produced paradoxical results; we reconcile these disparate outcomes as a function of population selection, endpoint choice, stent era and background therapy, rather than of patient selection alone. On this basis we outline a tiered immunophenotyping strategy spanning routine hematology, flow cytometry, autoantibody and cytokine profiling, and high-dimensional proteomics, and propose an endotype-guided therapeutic algorithm organized around biomarker-directed patient selection, time-limited treatment courses, mechanism-matched agent choice, and structured safety monitoring. The algorithm is a research framework that requires prospective validation. We conclude that endotype-based immunomodulation, rather than indiscriminate anti-inflammatory therapy, is the most credible path toward better outcomes in recurrent restenosis, and that dedicated randomized trials incorporating immune stratification are now the field’s priority.