Harnessing Immune Pathways for Stroke Recovery: Overcoming Challenges to Clinical Translation

Despite advances in acute care, stroke remains a leading cause of death and long-term disability worldwide, with limited treatment options to improve recovery after stroke. Traditionally, the management of ischemic stroke has mostly focused on early reperfusion, yet growing evidence highlights a central role for inflammation in both acute and long-term pathophysiology of stroke. The inflammatory response post-stroke is complex and dynamic, beginning with early intravascular activation of platelets and neutrophils (thrombo-inflammation), followed by microglial activation and the subsequent infiltration of peripheral immune cells, which together paradoxically contribute to tissue repair but can also worsen tissue injury. Importantly, this evolving understanding opens new therapeutic opportunities. However, efforts to target inflammation in stroke have yielded limited clinical success, as many strategies that showed promise in preclinical studies have failed to translate into beneficial outcomes. Here, we systematically review the role of inflammatory responses in stroke, integrating insights from both experimental and clinical studies. We highlight the roles of key immune cell populations and signaling pathways in mediating tissue injury and repair, also discussing the progress and limitations of inflammation-targeting clinical trials. We further address translational challenges, including optimal timing of intervention, mechanistic target validity, and the relevance of preclinical models. Finally, we explore emerging approaches, including targeting thrombo-inflammation, modulation of the gut-brain axis, reverse translation, and adaptive data-driven trial designs as potential strategies to refine therapy development to improve stroke outcomes. These insights provide a foundation for advancing the long-elusive goal of clinically translating immune therapy into effective stroke recovery treatments.