Environmental and Host Stress Adaptation in Nakaseomyces glabratus: Antifungal Tolerance, Persistence, and Potential Links to Resistance Evolution

Nakaseomyces glabratus (formerly Candida glabrata) is a high-priority fungal pathogen with marked stress adaptability and a well-documented capacity to acquire antifungal resistance. This critical narrative review examines how environmental and host-imposed stress responses intersect with antifungal tolerance, persistence, heteroresistance, and stable resistance. Literature was identified through targeted PubMed and publisher-site searches and citation tracking through 5 September 2026, prioritizing primary mechanistic and longitudinal studies. Hsp90–calcineurin signaling, MAPK/cell wall integrity pathways, Gcn2–eIF2α–Gcn4-mediated translational control, mitochondrial function, efflux regulation, genomic plasticity, and chromatin-associated regulation are considered. Experimental evidence shows that calcineurin regulates echinocandin tolerance and persistence, cell wall integrity-dependent tolerance can influence resistance emergence, and high echinocandin persistence is associated with preferential emergence of resistant populations under defined experimental and in vivo conditions. Heteroresistance is a distinct population state from which stable resistance can emerge experimentally. These findings support a framework in which stress-responsive survival may increase evolutionary opportunity without implying inevitable progression to resistance. A direct causal link between contemporary climate change and N. glabratus antifungal resistance remains unproven. Future studies should test whether realistic environmental or host stress histories reproducibly alter subsequent resistance trajectories across strains and clinical settings.