Microglia in CNS immunosurveillance and immunotherapy

Microglia are the brain’s resident innate immune cells, that originate from early yolk sac progenitors and enter the developing central nervous system (CNS) before the blood–brain barrier forms. Once established, they become the sole immune population within the brain parenchyma and safeguard CNS integrity throughout life. During development, microglia sculpt neural circuits by pruning excess synapses to ensure proper wiring. In adulthood, their highly motile processes constantly survey the environment, detecting and clearing debris, pathogens, and compromised cells to preserve healthy brain function.



Because microglia are central to brain health, deciphering the molecular pathways that govern their surveillance, phagocytosis, and broader immune functions is crucial. These mechanistic insights can reveal how microglia contribute to neurological and oncological diseases when surveillance is impaired, and they can guide new strategies to harness microglia in brain-targeted therapies. Although often labeled “brain-resident macrophages,” microglia possess specialized, CNS-specific capabilities: they continuously integrate complex molecular cues to maintain structural and functional homeostasis. Deficits in these processes—or active immune evasion by pathogenic cells—can drive disease initiation and progression.



This Research Topic showcases CNS-specific mechanisms of microglial surveillance and translational avenues to engage microglia therapeutically. We welcome Original Research, Reviews, and Mini-Reviews that:

• Define how microglia prevent and combat CNS pathologies, including neurodegeneration and brain cancers, and how dysfunction or immune evasion contribute to disease.

• Use single-cell and spatial multiomics to uncover microglial heterogeneity, states, and molecular targets.

• Apply CRISPR-based perturbations and functional genetic screens, complemented by advanced imaging, to map regulatory circuits and effector functions.

• Leverage live imaging to dissect the motility of microglial processes, its regulation across physiology, aging, cellular senescence and disease, and strategies to restore or enhance surveillance when it is inhibited.

• Elucidate molecular mechanisms that regulate microglial activation, phagocytosis, and synaptic interactions, and how their imbalance affects disease onset and progression.

• Develop brain-targeted immunotherapies that directly engage microglia as effector cells against cancer and other CNS disorders.

• Advance therapeutic innovations to boost microglial phagocytic capacity, including pharmacological modulators, microglial replacement, and engineered or potentiated microglia.

• Devise interventions that restore protective microglial functions in aging and disease, with the broader goal of extending the brain’s health span.



By bridging foundational biology with therapeutic innovation, this collection aims to chart a path from mechanistic insight to next-generation immunotherapies that harness microglia as potent, precisely tuned defenders of the CNS.