The inner ear immune microenvironment in sensorineural hearing loss: mechanisms and therapeutic perspectives

Sensorineural hearing loss (SNHL) affects over 1.5 billion individuals worldwide and remains the most prevalent sensory deficit in humans. Although classical pathological models have emphasized hair cell death from oxidative stress and mitochondrial dysfunction, accumulating evidence over the past decade has redefined the cochlea as an immunologically active tissue rather than an immune-privileged organ. Resident macrophages populate the spiral ligament, stria vascularis, spiral ganglion, and modiolus, and they orchestrate both protective and damaging responses to acoustic, ototoxic, metabolic, and immunological stress. Recent single-cell transcriptomic data have identified disease-specific macrophage subsets, including a proinflammatory CD74+CD14+ population enriched in age-related and noise-induced hearing loss. Molecular drivers of cochlear inflammation include cytokines such as TNF-alpha, IL-1beta, and IL-6, danger-associated molecular patterns including HMGB1 and HSP70, NLRP3 inflammasome activation, complement signaling, and disruption of the blood-labyrinth barrier. These mechanisms converge across diverse SNHL etiologies, from noise-induced synaptopathy and inflammaging in presbycusis, to ototoxicity, autoimmune inner ear disease, sudden idiopathic SNHL, and viral or post-viral hearing loss. Therapeutically, the field is shifting from broad-spectrum corticosteroids toward immune-targeted strategies, including cytokine-directed biologics, NLRP3 inhibitors, complement-targeted agents, macrophage reprogramming, mesenchymal stem cell-derived exosomes, intratympanic nanoparticle delivery systems, and gene therapy approaches with regulated immune profiles. Perilymph sampling now offers a window into the cochlear microenvironment in living patients, enabling biomarker-guided precision medicine. This review synthesizes the cellular, molecular, and clinical evidence supporting the cochlear immune microenvironment as a unifying axis in SNHL pathogenesis, and outlines therapeutic perspectives that may transform the standard of care over the next decade.