Sentinels or saboteurs, the Janus face of cochlear-resident macrophages in hearing loss: spatiotemporal distribution, pathophysiological functions, and translational potential

Neuroinflammation is a critical mechanism underlying various forms of sensorineural hearing loss (SNHL). Contrary to the conventional view that cochlea is an immune-privileged organ shielded by the blood-labyrinth barrier, it is now evident that it hosts a diverse immune landscape dominated by cochlear-resident macrophages (CoRMs). These CoRMs share a common developmental origin with central nervous system microglia. Despite this phylogenetic homology, CoRMs have evolved distinct phenotypic and functional profiles to adapt to the unique peripheral sensory environment of cochlea. Recent single-cell RNA sequencing studies have further shown a remarkable spatiotemporal heterogeneity among CoRMs subsets, which are strategically distributed across specific anatomical niches, such as the basilar membrane, stria vascularis, spiral ligament, osseous spiral lamina, spiral ganglions, and spiral limbus.​ This spatial and functional diversification may underlie their dual capacity to act as sentinels that maintain cochlear homeostasis and promote repair or as saboteurs that propagate neuroinflammatory injury. However, the functional diversity of CoRMs across regional compartments and the impact of dynamic subpopulation shifts on hearing loss progression remain poorly defined, representing a significant knowledge gap. This review systematically addresses this gap by synthesizing the developmental origins, spatial distribution, and functional heterogeneity of CoRMs. By integrating cutting-edge single-cell transcriptomics and fate-mapping studies, we elucidated the subset-specific roles within cochlear niches, proposing a dual guardian-saboteur paradigm. Furthermore, we explore novel macrophage-targeted therapeutic strategies—including pharmacological modulators, genetic interventions, and biomaterial engineering, designed to precisely regulate CoRMs function for hearing preservation. Our study provides a mechanism-oriented framework that bridges fundamental neuroimmunology with translational applications, offering insights into macrophage subpopulation functions and guiding future research toward targeted therapies for hearing disorders. Cochlear resident macrophages (CoRMs) are found in distinct anatomical locations, showing high spatiotemporal heterogeneity and performing divergent roles in auditory health and disorders. This graphical abstract illustrates the ontogenic origins and injury-response timelines of CoRMs (temporal heterogeneity), maps the niche-specific distribution of CoRM subsets across cochlear compartments (spatial heterogeneity), and highlights precision therapeutic strategies. By enhancing the protective functions of “Sentinel” subsets or inhibiting the inflammatory damage of “Saboteur” subsets, these approaches aim to prevent or halt irreversible hearing loss.