Immune cell reprogramming after ischemic stroke: From damage control to functional restoration

This review provides a comprehensive overview of immune cell reprogramming and its therapeutic potential in ischemic stroke. We define immune reprogramming as coordinated rewiring of transcriptional, metabolic, and epigenetic programs that reorients immune trajectories across disease stages and along the central–peripheral immune axis, rather than a catch-all descriptor for plasticity or phenotype switching. Stroke is not merely an acute cerebrovascular event but a systemic disorder that spans acute injury, subacute repair, and chronic remodeling. Microglia, macrophages, neutrophils, and T and B lymphocytes adopt dynamic, partially reversible functional states, playing context-dependent roles in limiting tissue injury, inflammation resolution, angiogenesis, synaptic remodeling, and remyelination. Single-cell and spatially resolved multi-omics studies have delineated diverse immune cell populations in the post-ischemic brain, providing a mechanistic basis for mapping and therapeutically steering immune reprogramming trajectories beyond the traditional M1/M2 paradigm. The central–peripheral immune axis, comprising the spleen, gut microbiota, bone marrow, and the meningeal lymphatic system, dynamically modulates central inflammation and repair via neuroimmune interactions. This review underscores the importance of targeting immune cell functional states rather than specific cell types and proposes stage-specific interventions. Key feasibility constraints include interspecies differences between rodent models and human immune architecture, substantial heterogeneity across stroke subtypes and comorbidities, limited real-time, noninvasive tools for monitoring reparative immune states, and safety trade-offs between immunomodulation and heightened susceptibility to post-stroke infections. Collectively, these concepts establish a theoretical framework and a translational roadmap toward stage-specific, biomarker-guided precision neuro-immunotherapies grounded in immune reprogramming in stroke.