Neuroinflammation in stroke—A review of implications for precision immunomodulation

Stroke remains a leading cause of mortality and long-term disability worldwide, and secondary injury mechanisms-particularly neuroinflammation-continue to limit functional recovery despite advances in reperfusion therapies. Post-stroke neuroinflammation is not a static or uniformly deleterious process but a temporally evolving and spatially heterogeneous continuum shaped by cellular transcriptional plasticity, metabolic reprogramming, and systemic modifiers such as aging and comorbidities. Across hyperacute, acute, subacute, and chronic phases, microglia, astrocytes, and neurovascular unit components undergo dynamic state transitions that may either exacerbate neuronal injury or promote debris clearance, angiogenesis, synaptic remodeling, and circuit reorganization. Emerging transcriptomic and spatial profiling studies challenge simplified polarization frameworks and highlight the need for multidimensional models of immune activation. We propose a precision-based framework in which neuroinflammation is interpreted through the integration of temporal dynamics, cellular heterogeneity, and responsiveness to rehabilitation. Within this context, the concept of an "immune window" underscores the importance of aligning immunomodulatory interventions with phase-specific inflammatory states to enhance neuroplasticity without suppressing reparative signaling. Although targeted strategies-including cytokine inhibition, metabolic reprogramming, gene-editing approaches, and biomarker-guided stratification-show mechanistic promise, translational progress has been limited by model heterogeneity, blood-brain barrier constraints, safety concerns, and insufficient validation in aged and comorbid populations. Future advances will depend on biomarker-driven patient stratification, phase-informed trial design, and integration of immunomodulation with reperfusion and rehabilitation. Rather than indiscriminate suppression, calibrated and context-aware immunoregulation may represent the most rational path forward in optimizing stroke recovery.