Single-cell T-cell landscape in atherosclerosis: implications for targeted therapy and beyond

BACKGROUND: Atherosclerosis (AS) progression is profoundly influenced by dynamic T-cell heterogeneity and functional plasticity. MAIN BODY: This review consolidates the latest insights derived from single-cell transcriptomic technologies, which are transforming our understanding of the role of the immune system in plaque pathogenesis. Recent evidence revealed previously unrecognized T-cell subsets within murine and human atherosclerotic lesions, distinguished by unique transcriptional profiles and adaptability driven by their microenvironment. Spatial mapping techniques have revealed compartment-specific distributions of T cells across vascular layers, whereas temporal analyses have highlighted age-related changes in the balance between effector and regulatory functions. Notably, single-cell resolution delineated transitional states between cytotoxic and regulatory lineages, suggesting that local inflammatory signals play a crucial role in determining T-cell fate. Despite these advancements, challenges remain in fully understanding T-cell lineage commitment, plasticity, and interactions with vascular niches. The integration of emerging multiomics approaches and spatial transcriptomics holds promise for addressing these challenges, providing a roadmap for novel therapeutic strategies. This includes not only the development of targeted immunotherapies but also the identification of key molecular targets for drug intervention and precision diagnostics, ultimately broadening the horizon for clinical applications in atherosclerosis. CONCLUSIONS: This review synthesizes single-cell RNA sequencing-driven discoveries in AS immunology, highlighting the heterogeneity and plasticity of plaque T-cell subsets. These insights lay the groundwork for developing targeted immunotherapies and identifying novel molecular targets and diagnostic biomarkers, ultimately advancing precision medicine for AS patients.