Neurodegenerative disorders such as Alzheimer's (AD) and Parkinson's (PD) have traditionally been examined from the perspectives of neurons or microglia, resulting in constrained therapeutic achievements. Recent findings endorse a cohesive neuroimmune framework in which central nervous system (CNS)-resident microglia, border-associated macrophages, clonally proliferated CD8+ T cells, and peripheral signaling centers (IL-20 family, gut-brain axis) perpetuate chronic maladaptive inflammation via feed-forward mechanisms. This review critically examines investigational immunotherapies aimed at this network: the CNS‑penetrant NLRP3 inhibitor NT-0796 (Phase 1b/2a) demonstrated preliminary biomarker reductions in axonal damage and T-cell activation in PD but remains unapproved and necessitates further confirmatory trials; the anti‑SIGLEC10 antibody ONC-841 improved microglial phagocytosis of Aβ and tau in preclinical studies but has yet to commence human trials; and CAR‑based platforms (CAR-T/NK) remain in the nascent preclinical phase, facing significant delivery and toxicity challenges. A three-part biomarker framework, encompassing target engagement (CSF IL-1β, caspase-1), pharmacodynamic responses (neurofilament light chain, ASC specks), and predictive endotyping (T-cell clonality, complement profiles), is proposed to facilitate patient stratification by neuroimmune endotype. None of these agents have received regulatory approval for neurodegenerative conditions; all findings are preliminary. Effective immunotherapy may ultimately necessitate multi-node, network-aware combinations (e.g., inflammasome inhibition coupled with Treg augmentation) rather than single-target suppression. Embracing this complexity offers a roadmap for future disease-modifying therapies, though rigorous clinical validation remains essential.
