Fungal Esophagitis: Molecular Insights Into Pathogenesis and Emerging Antifungal Strategies

Fungal esophagitis, predominantly caused by Candida species, remains the leading form of infectious esophagitis worldwide. Although historically linked to human immunodeficiency virus infection, its epidemiology has shifted over recent decades, with a growing incidence among oncology patients receiving immune checkpoint inhibitors, individuals with eosinophilic esophagitis on oral corticosteroids, and solid-organ transplant recipients. Increasing evidence highlights that disease pathogenesis extends beyond simple fungal overgrowth and involves intricate host-pathogen interactions. Pathogenic mechanisms such as adhesion, hyphal transition, and biofilm formation enhance fungal virulence, while mucosal immune dysfunction, particularly impaired T helper 17/interleukin 17 signaling and reduced antimicrobial peptide activity, predisposes to persistent infection. Antifungal resistance represents an emerging challenge, driven by efflux pump overexpression, ERG11 mutations conferring azole resistance, and mutations of FKS genes leading to reduced echinocandin susceptibility. These molecular mechanisms underscore the complexity of treatment and have important implications for antifungal selection and clinical management. While fluconazole remains the first-line agent for most cases, the increasing prevalence of non-albicans Candida species and drug resistance underscore the importance of alternative medications with different molecular targets. Agents such as the recently approved rezafungin as well as compounds such as ibrexafungerp and fosmanogepix, represent promising options for the treatment of refractory disease. This review synthesizes current advances in the molecular pathogenesis of fungal esophagitis, with particular emphasis on host-fungal interactions, antifungal resistance mechanisms, and novel treatment strategies. A deeper understanding of these processes is essential to improve management and to guide the development of innovative immunomodulatory and antifungal therapies.