Targeting Neuroinflammation in Adult Ischemic Stroke: Direct Immunotherapy, Regenerative Cell-Based Strategies, and...

Neuroinflammatory and immune-mediated processes are increasingly recognized as important contributors to adult ischemic stroke pathobiology, contributing not only to acute neuronal injury and secondary tissue damage, but also to later phases of repair and recovery. Experimental and early clinical evidence suggests that immunotherapeutic interventions may modulate post-ischemic inflammatory cascades and immune-cell activation, thereby potentially contributing to neuroprotective and neurorestorative responses. However, the clinical efficacy, safety, and translational relevance of these approaches remain incompletely defined. This systematic review aimed to critically synthesize contemporary preclinical and clinical evidence on neuroinflammation-targeted immunotherapeutic strategies in adult ischemic stroke, while distinguishing direct immunotherapy from regenerative cell-based approaches with immunomodulatory relevance. A systematic search of PubMed/MEDLINE and Embase was conducted in October 2025 and updated in January 2026 to identify original English-language studies published between January 2020 and December 2025. Eligible studies included preclinical and clinical investigations evaluating direct immunotherapeutic interventions or regenerative cell-based therapies with immunomodulatory relevance in adult ischemic stroke, compared with placebo, standard care, or control conditions appropriate to study design. In total, 913 records were screened, of which 55 studies met all inclusion criteria and were included in the qualitative synthesis. Of these, three randomized controlled trials (N = 637) provided comparatively compatible, although methodologically heterogeneous, outcome data for an exploratory meta-analysis of excellent functional outcome at day 90. Methodological quality was assessed using validated design-specific tools for randomized controlled trials, observational studies, and preclinical animal experiments. Primary outcomes included functional recovery and infarct-related measures, while secondary outcomes encompassed neuroinflammatory biomarkers, immune modulation, and safety. Therapeutic approaches were categorized into molecular immunotherapy, biological immunotherapy, and regenerative cell-based therapies with immunomodulatory properties, according to their dominant mechanism of action and translational rationale. Molecular interventions targeting inflammatory and immunometabolic signaling pathways were associated with reductions in neuroinflammatory signaling and infarct-related measures in preclinical models in preclinical models, although corresponding human evidence remained limited. Regenerative cell-based therapies, including mesenchymal stromal/stem cells, progenitor cells, and related cellular products, demonstrated neuroregenerative, paracrine, and immunomodulatory characteristics in preclinical and early translational studies with favorable safety profiles; however, clinical functional benefits remained modest, heterogeneous, and inconsistent. Biological approaches, particularly monoclonal antibodies targeting leukocyte adhesion and immune-cell trafficking, demonstrated generally acceptable safety profiles but did not demonstrate consistent functional benefit across currently available randomized clinical trials. In the exploratory quantitative synthesis, no significant pooled clinical benefit was observed (OR = 0.87; 95% CI, 0.27-2.77), with moderate between-study heterogeneity (I² = 46.3%). Cross-study comparability was further limited by substantial heterogeneity in intervention timing, dosing regimens, patient selection, biological targets, and outcome definitions, precluding definitive conclusions regarding efficacy. Neuroinflammation-targeted immunotherapy in adult ischemic stroke, together with selected regenerative cell-based strategies of immunomodulatory relevance, appears biologically plausible and mechanistically supported by current preclinical and early clinical evidence based on current preclinical and early clinical evidence and has demonstrated generally acceptable safety profiles in early-phase studies; however, current evidence remains insufficient to support consistent clinical benefit, and available trials may be insufficiently powered to reliably detect moderate but clinically meaningful treatment effects. Future research should prioritize mechanism-driven trial designs, standardized outcome measures, biomarker-informed patient stratification, optimized therapeutic windows, and integrative strategies combining immunomodulation with established reperfusion therapies. Well-powered, methodologically harmonized clinical trials aligned with the temporal and biological heterogeneity of post-stroke inflammation are essential to clarify translational potential and define the role of immune-targeted therapies in stroke management. Importantly, the present review supports a mechanistically differentiated framework in which direct immunotherapy and regenerative cell-based therapy should not be treated as interchangeable categories, even when both modulate post-stroke neuroinflammation. Overall, the available evidence may support further investigation of a stage-specific and mechanistically differentiated model of immune-targeted intervention in ischemic stroke.