The BLB functions as a critical physiological interface, isolating the delicate inner ear environment from the systemic circulation. Primarily found in the spiral ligament and the capillaries of the stria vascularis, the BLB is composed of specialized endothelial cells interconnected by tight junctions, pericytes, and a continuous basement membrane (3). Its fundamental role is to preserve the special ionic milieu of the inner ear fluids, specifically the potassium-rich endolymph and the sodium-rich perilymph, which is essential for the generation of the endocochlear potential (EP) and mechanical transduction by sensory hair cells.

Beyond its function in ionic homeostasis, the BLB serves as a highly selective barrier, meticulously controlling the passage of waste products and nutrients while limiting the entrance of most blood-borne cells, pathogens, and macromolecules. This selective permeability, which exhibits an inverse correlation with molecular size (molecules less than 100 Da cross more readily), significantly influences the specialized immune status of the cochlea (4). However, this barrier exhibits dynamic regulation rather than absolute impermeability. The integrity of the BLB can be compromised by several pathogenic disorders including acoustic trauma, inflammatory processes, ototoxic drugs like cisplatin and aminoglycosides, and acoustic trauma. Such disturbances can cause an influx of inflammatory mediators, immune cell invasion, and changes in inner ear fluid composition, which can either temporarily or permanently impair hearing (4).

Over the past decade, research has focused intensely on several key aspects concerning the BLB. These comprise studies on molecular mechanisms behind BLB disruption in different diseases, the development of more complex in vitro models to investigate their features, and the investigation of techniques to either transiently and safely alter the permeability for therapeutic drug delivery. Currently, novel non-invasive delivery strategies are under active investigation to bypass or temporarily open the BLB for enhanced therapeutic access; these include ultrasound combined with microbubbles, inner ear-targeting peptides, and even sound therapy.

The BLB presents a dual role in cochlear health and therapeutic intervention. Although its normal operation is crucial for preserving the delicate sensory structures and preserving the exact electrochemical gradients required for hearing, its constrictive character presents a major challenge for the systemic treatment agent delivery to the inner ear. Many cochlear pathologies are now understood to be related to a compromised BLB, which can be a consequence of the initial insult (e.g., noise, ototoxicity) and a factor that perpetuates additional damage by facilitating the uncontrolled influx of inflammatory cells and cytotoxic molecules (4). If precisely timed or if permeability can be transiently and controllably modulated, this pathological breach may ironically present a window of opportunity for therapeutic intervention. Therefore, a critical research direction involves developing methods to either protect and restore BLB integrity in conditions when its breakdown is detrimental or to induce a controlled, transient opening of the BLB to facilitate the targeted delivery of drugs for treating underlying cochlear diseases. The development of non-invasive techniques to achieve this modulation represents a significant advancement towards more effective inner ear therapies.

Rather than being an immunologically inert environment, the cochlea harbors a range of resident immune populations that are vital to homeostasis maintenance, damage response, and immune surveillance (5). A scoping review published in 2024 systematically collected data on these cells, confirming the presence of macrophages, lymphocytes, leukocytes, and mast cells in various inner ear structures of different mammalian species under steady-state conditions (Table 1). This underscores the need for further research on their specific roles (5).

An unusual but important inflammatory disorder compromising the inner ear is AIED. Often bilateral but can start unilaterally, it is defined by fast progressive sensorineural hearing loss and may be accompanied by vestibular problems including tinnitus or dizziness. Less than 5 per 100,000 people are thought to be involved yearly (20). AIED can present as a primary disorder, wherein the pathology is limited to the inner ear, or as a secondary condition accompanying systemic autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus (SLE), Cogan syndrome, granulomatosis with polyangiitis, and others (20).

For cases with severe-to-profound SNHL, cochlear implantation represents a highly effective surgical intervention that directly stimulates the auditory nerve to restore hearing. However, the implantation process itself, which involves the insertion of an electrode array into the delicate cochlea, inevitably causes trauma and triggers an immune response characterized by inflammation and subsequent wound-healing cascades in which macrophages are rather important (8).

A common consequence of this immune response is the development of fibrous scar tissue (fibrosis) around the electrode array. While some degree of tissue encapsulation is a natural aspect of healing, excessively robust or aggressive inflammatory reactions can lead to significant fibrosis. This excessive fibrosis is detrimental as it can increase the electrical impedance between the electrode contacts and neural elements, thereby diminishing the quality and efficiency of electrical stimulation. Moreover, unchecked inflammation can directly damage surviving cochlear structures, potentially resulting in the loss of any residual hearing a patient may have had prior to implantation, ultimately leading to poorer overall hearing outcomes with the implant. Research has revealed both CD68-positive and Iba1-positive macrophage populations in the fibrous sheath encircling the CI path and within fibrotic zones in the scala tympani and scala vestibuli. Although results can vary, some studies have observed an elevated density of these macrophages in implanted cochleae relative to non-implanted controls. The precise function of these macrophages, whether they predominantly contribute to adverse fibrosis or also assist in tissue repair and integration, remains an active area of ongoing research (6).

A notable characteristic of the post-CI inflammatory response is individual variation (23). Not all patients exhibit the same reaction to the implant, and the factors precipitating an excessive inflammatory response remain to be fully elucidated. This individual variability emphasizes the need for research aimed at defining and predicting these reactions. For example, the Cochlear Implants and Inner Ear Inflammation (CHIEF) study is a cross-sectional study designed to collect tissue and fluid samples from children and young people who have undergone cochlear implantation, in order to define the inflammatory state of the ear and investigate its relationship with long-term hearing outcomes. Elucidating these unique inflammatory variations could help to improve clinical treatment and provide CI users with better, more consistent hearing results.

By its nature as a foreign material inserted into a sensitive biological environment, the cochlear implant electrode can be considered a chronic foreign body. This perspective aids in understanding the continuous immune response as a sustained interaction that influences long-term device efficacy, rather than just as an acute reaction to surgical trauma. Following implantation, the initial acute inflammation may evolve into a chronic foreign body reaction, marked by ongoing macrophage activity and the progressive development of fibrosis around the electrode array. This continuous process can cause gradual changes in electrode impedance, potentially leading to a decline in hearing performance over time. Therefore, plans meant to improve CI results have to go beyond perfecting surgical methods to reduce initial trauma. They ought to also cover strategies to control the long-term immune response to the implant. This can entail the creation of drug-eluting electrodes that are able to directly release anti-inflammatory drugs or pro-resolving mediators at the electrode-tissue interface. Furthermore, advancements in biomaterials may lead to less immunogenic and more biocompatible electrode surfaces, thereby reducing adverse tissue reactions. Moreover, the ability to predict an individual’s inflammatory predisposition, as targeted by studies such as CHIEF, could enable customized pre-operative or peri-operative immunomodulatory treatments to optimize the cochlear environment for the implant.

NIHL is a commonly acquired form of sensorineural hearing loss resulting from exposure to loud noise. Beyond direct mechanical damage, a significant number of studies has emphasized the important role of inflammatory and immune reactions in NIHL pathophysiology (7). Reactive oxygen species (ROS), which in turn starts an inflammatory response, activates apoptotic (programmed cell death) pathways, causes DNA fragmentation, and finally results in the death of sensory hair cells and auditory neurons. Acoustic overexposure sets off a cascade of events within the cochlea (24).

Pathways of inflammatory signaling and key molecules: Following noise exposure, transcriptome studies of cochlear tissue have revealed the activation of several inflammatory signaling pathways. Among these are the Tumor Necrosis Factor (TNF) signaling pathway, the Interleukin-17 (IL-17) signaling pathway, the Nuclear Factor-kappa B (NF-κB) signaling pathway, the Toll-like receptor (TLR) signaling pathway, and many chemokine signaling pathways (25). For example, the activation of NF-κB results in the synthesis of pro-inflammatory cytokines, caspases (enzymes involved in cell death), and other pro-apoptotic molecules, leading to hearing loss. Ten specific genes, including Relb (a component of the NF-κB pathway), Ccl2 (Monocyte Chemoattractant Protein-1, MCP-1), Ptgs2 (Prostaglandin-Endoperoxide Synthase 2, also known as COX-2, an enzyme vital for prostaglandin synthesis), and Ccl17 (a chemokine) have been identified to be upregulated in NIHL and linked with these inflammatory processes (25).

Immune Cell Involvement: CX3CL1/CX3CR1 Axis: After acoustic trauma, immune cells infiltrate the cochlea. Responses to cytokines and broader immune reactions are considered crucial components in NIHL pathogenesis. A particularly significant recent discovery is the function of the chemokine fractalkine (CX3CL1) and its receptor CX3CR1. Inner hair cells and cochlear neurons express CX3CL1, while CX3CR1 is found on resident cochlear macrophages (11). This signaling axis is widely thought to be vital for neuroprotection and repair. Research on CX3CR1-positive resident macrophages has revealed that they can protect against damage driven by other infiltrating immune cells (10). Moreover, the CX3CL1/CX3CR1 pathway actively repairs ribbon synapses (essential for auditory signaling) and modulates the inflammatory response following noise trauma. Local delivery of a soluble form of CX3CL1 (soluble fractalkine, sFKN) has been shown in preclinical studies to be able to restore these synapses, raise hearing thresholds, and reduce cochlear inflammation in a macrophage-dependent fashion. On the other hand, genetic disturbance of this pathway or depletion of CX3CR1-expressing macrophages can hinder synaptic repair and increase SGN loss and inflammation following noise trauma (14).

Growing evidence suggests that inflammation is not only a side effect of noise-induced damage but also a central and maybe modifiable factor of NIHL pathogenesis. This understanding facilitates the integration of complex biological reactions beyond purely mechanical damage. The identification of specific inflammatory pathways (such as TNF, NF-κB, and IL-17 signaling) (25) and mediators (like ROS, different cytokines, and chemokines) (24) activated by noise exposure opens new avenues for pharmacological intervention. Targeting these inflammatory pathways to either prevent or treat NIHL has therapeutic potential, as demonstrated by the encouraging outcomes of preclinical models employing antioxidants, anti-inflammatory drugs, or tailored immunomodulators such as sFKN (24). The success of sFKN in promoting synaptic repair and reducing inflammation in animal models is a particularly compelling illustration of how immunomodulatory strategies might be leveraged for hearing protection and restoration.

ARHL, also known as presbycusis, is the most prevalent sensory disability among the elderly, characterized by a progressive, typically bilateral decline in hearing sensitivity, especially at higher frequencies (1). This condition entails degenerative changes in the central auditory paths and the peripheral cochlea. Recent studies have reported “inflammaging” a phenomenon characterized by persistent, low-grade inflammation, plays a significant role in the onset and advancement of ARHL (26).

Macrophage Dysregulation in ARHL: With aging, cochlear macrophages undergo remarkable changes, including alterations in their morphology (e.g., becoming more amoeboid, less ramified), abundance and distribution within cochlear tissues, and a general increase in their activation state. It is hypothesized that this age-associated macrophage dysregulation contributes to the chronic neuroinflammatory environment and tissue degradation seen in ARHL (9). The CX3CL1/CX3CR1 chemokine axis, which is crucial in NIHL, is widely thought to be relevant in ARHL since CX3CL1 gene expression is upregulated in the aging mouse cochlea, potentially influencing macrophage activity (11).

Cytokines and Complement System: Elevated systemic and local levels of inflammatory markers are associated with ARHL. These comprise components of the complement system, including C3 and C1q (26). C-reactive protein (CRP), pro-inflammatory cytokines including Tumor Necrosis Factor-alpha (TNF-α) and Interleukin-1 beta (IL-1β). For instance, while increased IL-1β is linked to synapse loss and worsening hearing thresholds in ARHL models, TNF-α can be neurotoxic at high concentrations and impair mitochondrial function in the aging ear. Interestingly, Mendelian randomization studies have indicated that although these inflammatory markers are elevated, a genetic inclination to systemic chronic inflammation may not, by itself, directly cause ARHL. This suggests that the age-related inflammatory processes in the auditory system may be driven more directly by local cochlear factors or the cumulative impact of environmental stresses over a lifetime.

Microglial activation in auditory centers: Beyond the cochlea, inflammation in the central auditory pathways also contributes to ARHL. Studies in aged mice have revealed heightened activation of microglia, the resident immune cells of the central nervous system, as indicated by increased expression of markers such as Iba1 and CD16, a marker of M1 microglial activation, in the cochlear nucleus. This central neuroinflammation further exacerbates hearing loss.

Although ARHL has been associated with inflammation, the relationship is complex. ARHL is widely believed to result from a complex interaction between intrinsic aging processes within the cochlea, the development of a local “inflammaging” state, and the cumulative effects of environmental factors and stresses throughout life; genetic predisposition to systemic inflammation alone does not appear to be the primary driver. The observation that cochlear macrophages exhibit pro-inflammatory changes with age, coupled with the finding that systemic genetic inflammatory tendencies may not directly correlate with ARHL risk, suggests that the cochlear-specific inflammatory milieu or the organ’s response to a lifetime of local stressors is particularly critical. This understanding suggests that rather than relying solely on systemic anti-inflammatory treatments, successful ARHL interventions may need to target these local cochlear inflammatory and aging pathways (27). Furthermore, the influence of lifestyle and environmental factors in modulating cochlear inflammaging warrants more extensive investigation to identify potential preventive strategies.

Meniere’s disease is an inner ear disorder characterized by a classic triad of symptoms: episodic vertigo, fluctuating sensorineural hearing loss (typically affecting the low frequencies initially), and tinnitus or aural fullness. The precise etiology of Meniere’s disease remains elusive, though endolymphatic hydrops is a consistent histopathological finding. Notably, not all individuals with hydrops develop Meniere’s disease (28).

Potential Immunological Link: There is growing interest in the potential role of the immune system and inflammation in the pathophysiology of Meniere’s disease. Several autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, and ankylosing spondylitis, have been associated with Meniere’s disease, suggesting a possible shared autoimmune predisposition or pathogenic mechanism in a subset of patients (28). Some studies have also proposed a role for IgE in some instances.

Inflammatory Markers and Cytokine Profiles: Recent pilot studies have begun to explore specific inflammatory markers in Meniere’s disease. A study published in late 2024 compared proinflammatory cytokine profiles in patients with Meniere’s disease with those in patients with vestibular migraine and controls. Patient-derived peripheral blood mononuclear cells (PBMCs) from Meniere’s disease patients, when stimulated in vitro, tended to release higher levels of TNF-α and Interferon-gamma (IFN-γ), and lower levels of Epithelial Neutrophil-Activating Peptide 78 (ENA-78, also known as CXCL5), compared to vestibular migraine patients (29). These findings, though preliminary, suggest that distinct inflammatory pathways might contribute to Meniere’s disease.

Distinct cytokine profiles (elevated TNF-α and Interferon-gamma (IFN-γ), reduced ENA-78) have been observed in Meniere’s disease patients compared to those with vestibular migraine. Given that these two conditions can present with overlapping symptoms such as vertigo and auditory disturbances, identifying differential immune signatures could be of significant diagnostic value. If validated in larger cohorts, these immune markers may help differentiate between these disorders, which currently rely heavily on clinical criteria and the exclusion of other causes (29). This differentiation is crucial as it could lead to more targeted therapeutic approaches. For instance, if a specific inflammatory profile is consistently associated with Meniere’s disease, it could identify a subgroup of patients more likely to benefit from immunomodulatory treatments, potentially offering a new avenue for managing this challenging condition. Further research is warranted to confirm these immune signatures and understand their pathogenic role in Meniere’s disease.

Cytokines are small proteins that act as critical intercellular messengers, regulating the intensity and duration of immune responses. An imbalance in their production or signaling can lead to aberrant immune cell activity and the establishment of a chronic pro-inflammatory microenvironment, ultimately causing damage to inner ear structures and function (11).

Chemokines represent a family of small proteins that play a fundamental role in directing the migration of immune cells to specific locations within the body, both during normal immune surveillance (homeostasis) and in response to inflammation or injury (11). They bind to G protein-coupled receptors on target cells, triggering intracellular signaling pathways that lead to cell movement and activation (32, 33).

Lipid mediators, including prostaglandins (PGs) and leukotrienes (LTs), are powerful signaling molecules derived from fatty acids (primarily arachidonic acid) that play complex roles in inflammation and homeostasis (31).

Role in Inflammation: Prostaglandins, such as PGD2 and PGE2, and various leukotrienes are rapidly generated at sites of inflammation, acting as potent pro-inflammatory mediators that contribute to vasodilation, increased vascular permeability, pain, and fever. For instance, the early phase of inflammation is characterized by PGD2 upregulation (42). However, these roles exhibit considerable complexity; PGE2, for instance, demonstrates context-dependent biological activity, displaying either anti-inflammatory or pro-resolving properties that are determined by specific receptor engagement and cellular microenvironmental factors.

Cochlear Blood Flow: The vasoactive properties of these lipid mediators can influence cochlear blood flow. Foundational studies establishing the physiological framework have indicated that PGE2 can increase cochlear blood flow, while the leukotriene LTC4 can decrease it, suggesting that imbalances in these mediators could contribute to SNHL by affecting cochlear perfusion (43).

NIHL: The gene Ptgs2, which encodes cyclooxygenase-2 (COX-2), a key enzyme in prostaglandin synthesis, has been implicated in the pathogenesis of NIHL (44, 45). This suggests that increased prostaglandin production via COX-2 activity contributes to noise-induced cochlear damage.

Resolution of Inflammation: Crucially, the inflammatory process is not just about initiation and propagation but also involves an active resolution phase. Specialized pro-resolving mediators (SPMs), a class of lipid mediators derived from polyunsaturated fatty acids (including lipoxins, resolvins, protectins, and maresins), are endogenously produced and play a vital role in actively terminating inflammation, promoting the clearance of debris, and stimulating tissue repair and regeneration (31). The switch from pro-inflammatory eicosanoid production (like PGs and LTs) to SPM production is a key step in the resolution cascade.

A paradigm shift is emerging in therapeutic approaches to inflammation, transitioning from passive suppression to active promotion of resolution. While inflammation constitutes an essential physiological response to injury or infection, pathological persistence of inflammatory processes leads to chronic tissue damage and dysfunction (46–48). The cochlea, like other organ systems, maintains intrinsic resolution mediated by these SPMs. Traditional anti-inflammatory drugs, such as corticosteroids or non-steroidal anti-inflammatory drugs (NSAIDs) that inhibit prostaglandin synthesis (49–51), can be effective in reducing acute inflammation but may also have significant side effects with long-term use and might not fully restore tissue homeostasis or promote optimal healing. Therefore, therapeutic development is increasingly focusing on agents that mimic or enhance the production or action of SPMs. Such pro-resolution therapies could actively orchestrate the termination of cochlear inflammation and stimulate endogenous repair processes, potentially offering a more nuanced and effective approach with fewer adverse effects for conditions like NIHL, ARHL, or chronic inflammatory states in the inner ear.

Immunosuppressive therapies, primarily corticosteroids, have long been the mainstay for conditions presumed to have an autoimmune or significant inflammatory component.

Corticosteroids: These remain the first-line treatment for AIED and are widely used for idiopathic SSNHL (3, 52).

Administration Route: Corticosteroids can be administered systemically (e.g., oral prednisolone, intravenous methylprednisolone) or locally via intratympanic injection (e.g., dexamethasone, methylprednisolone). Intratympanic delivery aims to achieve higher local concentrations in the inner ear while minimizing systemic side effects.

Efficacy and Limitations: In AIED, systemic corticosteroids achieve a response in approximately 60-70% of patients; however, responsiveness can diminish with prolonged use, and hearing loss may relapse upon tapering or discontinuation of the drug (22). For SSNHL, a network meta-analysis suggested that combination therapy (intratympanic plus systemic steroids) might offer the most significant improvement in hearing thresholds (23).

Use in Cochlear Implantation: Glucocorticoids are also employed in the context of CI to reduce acute inflammation and subsequent fibrosis associated with electrode insertion, which can positively impact electrode impedance and preservation of residual hearing. Both systemic and local (intracochlear or perioperative intratympanic) administration routes have been explored.

Disease-Modifying Antirheumatic Drugs (DMARDs) and Biologics: These agents are typically considered as steroid-sparing options or for patients with AIED who are refractory to corticosteroids.

Methotrexate: A randomized controlled trial found no benefit for methotrexate as a steroid-sparing agent in AIED patients who had initially responded to one month of prednisone (53). However, other reports and clinical experience suggest it may have some efficacy in some instances.

Anti-TNF Agents: Biologics targeting TNF-α, such as infliximab, etanercept, and adalimumab, have been investigated for AIED with variable results (54, 55). A case report highlighted the success of infliximab in a patient with AIED and co-existing ulcerative colitis, leading to hearing stabilization and cessation of oral steroid use. Other case reports also suggest potential benefits of infliximab. Conversely, a pilot placebo-controlled study of etanercept did not demonstrate efficacy over placebo in AIED patients (56).

Other Biologics: IL-6 receptor antagonists (57) and B-cell-depleting agents like rituximab are also being explored, primarily based on case series or small studies (58).

Challenges in Research: The rarity of AIED and the lack of standardized diagnostic criteria pose significant challenges to conducting large, robust randomized controlled trials (RCTs) for these biologic agents.

The heterogeneity in response to immunosuppressive treatments for AIED is a significant clinical challenge. The standard “one-size-fits-all” approach, typically starting with corticosteroids, often proves insufficient for long-term disease control or is limited by side effects. This variability strongly suggests that AIED is not a single, uniform disease entity. It can manifest as a primary condition, affecting only the inner ear, or as a secondary complication of various systemic autoimmune conditions, and likely involves different underlying autoimmune mechanisms and target antigens in different individuals. Biologic therapies, which target specific immune pathways (e.g., TNF-α, B cells), offer the potential for more directed treatment. The reported success of infliximab in an AIED patient with concomitant ulcerative colitis (56) underscores the possibility that matching the therapeutic agent to the patient’s specific immunologic profile or associated systemic inflammatory disease could be key to improving outcomes. Therefore, the future of AIED management will likely involve a transition towards personalized treatment strategies. This will require a better understanding of AIED subtypes, the development of reliable biomarkers to guide diagnosis and predict treatment response, and careful consideration of individual patient characteristics and comorbidities.

The advent of inner ear stem cell therapy represents a paradigm shift in treating SNHL, transitioning from augmenting existing neural structures with hearing aids or implants to regenerating damaged neural frameworks (23). However, a significant hurdle limiting the clinical translation of stem cell therapy is the host immune system’s potential rejection of donor cells.

Immunosuppressive Regimens in Translational Models: To address the challenge of immune rejection, various immunosuppressive strategies are being explored, primarily in animal models, given that human trials for inner ear stem cell therapy are not yet prevalent (23).

Ciclosporin: This calcineurin inhibitor has been the most frequently used immunosuppressive agent in animal studies of cochlear stem cell transplantation. Systemic administration (subcutaneous or intraperitoneal) of ciclosporin has been shown to increase the survival, integration, and migration of transplanted stem cells in species like guinea pigs, mice, and gerbils. Dosages have varied widely depending on the animal model.

Steroids: While extensively used for other inner ear pathologies, corticosteroids (e.g., dexamethasone) have been less systematically investigated in animal models specifically for stem cell therapy. Some studies have suggested that systemic administration—rather than local delivery—may be required for optimal efficacy, as systemic corticosteroids can modulate both cochlear inflammation and host immune responses to transplanted cells (59).

Necessity of Immunosuppression: Some studies indicate that systemic immunosuppression is crucial for the successful transplantation and survival of otic progenitor cells, particularly when using allogeneic or xenogeneic cells.

Cochlear Immune Privilege in the Context of Stem Cell Therapy: Interestingly, several animal studies involving intracochlear stem cell transplantation did not employ immunosuppression and reported no significant evidence of immune or inflammatory reactions in the short term. This suggests that the cochlea might possess a degree of immunological privilege that could be conducive to cell-based therapies. However, this is not a universal finding, as one study reported an immune response to transplanted human otic progenitor cells in guinea pigs even without overt rejection (23).

Recommendations and Future Directions: Based on current evidence from cochlear animal studies and drawing parallels from human stem cell trials in related fields (e.g., retinal and spinal tissues), calcineurin inhibitors like tacrolimus or ciclosporin are often suggested as potentially useful immunosuppressive agents. Steroids may also play a role, particularly during the peri-transplant period, in managing acute inflammation related to the surgical procedure.

The concept of cochlea immune privilege within the context of stem cell transplantation appears to be “conditional” rather than absolute. While the inner ear may offer a relatively protected environment compared to other systemic sites, this privilege can likely be overwhelmed, especially when dealing with allogeneic (same species, different individual) or xenogeneic (different species) stem cells. The type of stem cell used (e.g., mesenchymal stem cells, which have inherent immunomodulatory properties, versus more immunogenic pluripotent stem cell derivatives), the method of delivery, the degree of surgical trauma, and the underlying immune status of the host are all factors that likely influence the necessity and intensity of immunosuppression. The variability in outcomes in animal studies, with some demonstrating cell survival without immunosuppression and others indicating rejection or immune responses, underscores this complexity. Therefore, a deeper understanding of the specific immune responses elicited by different types of stem cells within the cochlear microenvironment is crucial. Future strategies will likely need to be tailored, potentially involving not only systemic immunosuppression but also local delivery of immunomodulatory factors, the use of less immunogenic cell sources (such as autologous cells or induced pluripotent stem cells (iPSCs) differentiated into otic lineages), or genetic engineering of stem cells to reduce their immunogenicity. Optimizing the timing, duration, and type of immunosuppression will be critical for the success of regenerative therapies for hearing loss.

Beyond established immunosuppressants, research is actively exploring novel therapeutic agents and strategies that target the specific immune and inflammatory mechanisms underlying NIHL and ARHL.

Gene therapy is emerging as a highly promising future therapeutic modality for SNHL, with an initial emphasis on congenital forms of hearing loss caused by single-gene defects. The fundamental principle of gene therapy is to introduce genetic material into target cells to replace or correct a defective or missing gene, thereby restoring normal cellular function and, in the context of hearing loss, potentially restoring auditory capabilities (71).

Several active clinical trials are currently underway, testing the safety and efficacy of gene therapy approaches for specific genetic forms of hearing loss. While no gene therapy for hearing loss has yet received FDA approval for routine clinical use, the progress in this field is rapid, fueled by advancements in vector technology (e.g., adeno-associated viruses, AAVs) and gene editing tools like CRISPR/Cas9. Recent news highlights include promising results in preclinical models for genetic deafness and early human trials (72–75). Damage to various cellular components in the cochlea, including hair cells and the ribbon synapses between inner hair cells and spiral ganglion neurons, can cause SNHL. Many genes associated with deafness have been identified in these structures, providing targets for gene therapy (76).

While the primary aim of many current gene therapies for hearing loss is to correct genetic defects, the intersection of gene therapy with cochlear immunology is an important consideration and a potential area for future development. The introduction of viral vectors or transgene products can itself elicit an immune response within the cochlea, potentially limiting the efficacy or durability of the therapy. Therefore, understanding and managing these host immune responses is crucial for the long-term success of cochlear gene therapy. Conversely, gene therapy also offers a powerful tool for actively modulating the cochlear immune environment to achieve therapeutic benefits. It could be engineered to deliver genes encoding anti-inflammatory cytokines (e.g., IL-10), factors that promote regulatory T cell development or function, proteins that enhance the integrity of the BLB, or neurotrophic factors that protect auditory neurons from inflammatory damage. Such immunomodulatory gene therapies could be beneficial not only for genetic forms of hearing loss with an inflammatory component but also for acquired conditions like AIED or to create a more favorable environment for the survival and integration of transplanted stem cells. Thus, the immunogenicity of gene therapy vectors needs careful evaluation and management, while the potential for gene therapy to deliver localized and sustained immunomodulation within the cochlea represents an exciting future direction.