Abstract
C. auris is an emerging multidrug-resistant (MDR) fungal pathogen that poses an urgent threat to global public health. It is characterized by rapid nosocomial transmission, persistent environmental survival, and extensive cross-resistance to conventional antifungal therapies. This comprehensive narrative review bridges the fundamental molecular mechanisms of intrinsic and acquired antifungal resistance with host adaptation strategies and emerging clinical interventions. C. auris resistance is driven by a highly sophisticated network of genetic mutations and metabolic reprogramming distributed across six geographically distinct clades (I-VI), including the newly identified Clade VI from the Indomalayan zone. Azole resistance primarily relies on clade-specific point mutations in the target gene ERG11, synergistically amplified by TAC1b-driven transcriptional upregulation of the CDR1 efflux pump. Echinocandin resistance is predominantly mediated by conformational reshaping across three distinct hotspot regions of the FKS1 gene, bolstered by Hsp90-mediated stress compensatory networks. For polyenes, while clinical resistance is frequently overestimated by commercial assays, true tolerance mechanisms involved the depletion of target ergosterol and profound non-sterol-dependent sphingolipid remodeling. Beyond genomic modifications, C. auris exhibits significant phenotypic plasticity, forming robust, polysaccharide-rich biofilms on indwelling medical devices that confer profound physical drug tolerance. Clinically, the fungus demonstrates a strong cutaneous tropism-predominantly colonizing the axilla and groin-which acts as the primary reservoir for hospital outbreaks. Furthermore, experimental models reveal that C. auris actively exploits host immune deficiencies, specifically subverting the IL-17A/neutrophil/S100A8 axis, to evade immune clearance and establish persistent colonization. To overcome these formidable MDR bottlenecks, therapeutic paradigms are rapidly evolving. The integration of next-generation antifungals such as the long-acting echinocandin rezafungin, fosmanogepix, and ibrexafungerp, synergistic combination therapies, quorum-sensing inhibitors such as farnesol, and experimental nanocarrier delivery systems could represent promising frontiers to effectively dismantle the complex defense networks of C. auris.