Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system that causes demyelination, axonal degeneration and astrogliosis, resulting in progressive neurological disability. Fuelled by an evolving understanding of MS immunopathogenesis, the range of available immunotherapies for clinical use has expanded over the past two decades. However, MS remains an incurable disease and even targeted immunotherapies often fail to control insidious disease progression, indicating the need for new and exceptional therapeutic options beyond the established immunological landscape. In this Review, we highlight such non-canonical targets in preclinical MS research with a focus on five highly promising areas: oligodendrocytes; the blood–brain barrier; metabolites and cellular metabolism; the coagulation system; and tolerance induction. Recent findings in these areas may guide the field towards novel targets for future therapeutic approaches in MS.

多发性硬化症 (MS) 是一种免疫介导的中枢神经系统疾病，会导致脱髓鞘、轴突变性和星形胶质细胞增生，从而导致进行性神经功能障碍。在对 MS 免疫发病机制的不断理解的推动下，在过去二十年中，临床使用的可用免疫疗法的范围已经扩大。然而，MS 仍然是一种无法治愈的疾病，即使是靶向免疫疗法也常常无法控制隐匿的疾病进展，这表明需要超越既定免疫学领域的新的和特殊的治疗选择。在这篇综述中，我们强调了临床前 MS 研究中的此类非规范目标，重点关注五个极具前景的领域：少突胶质细胞；血脑屏障；代谢物和细胞代谢；凝血系统；和耐受诱导。