Fluconazole tolerance and virulence adaptations of Candida albicansisolated from head and neck cancer patients

<i>Candida albicans</i> is the predominant opportunistic pathogen causing oral candidiasis in immunocompromised head and neck cancer (HNC) patients. Fluconazole (FLC) is commonly used for treatment and prophylaxis; however, persistent infections remain a clinical challenge during cancer therapy. We hypothesized that <i>C. albicans </i>survival under FLC exposure may be driven by the development of tolerance or resistance, accompanied by altered virulence traits. In this study, we characterized FLC susceptibility and virulence profiles of clinical C. albicans isolates obtained from HNC patients. Most isolates were susceptible to FLC, but two tolerant phenotypes, moderate (MT) and heavy tolerance (HT), were identified. FLC prophylaxis did not significantly affect tolerance prevalence or severity. Both tolerant isolates exhibited upregulation of key resistance genes, ERG11. Under FLC exposure, the MT isolate modestly increased expression of ALS1 and SAP6, while downregulating other virulence genes, correlating with reduced adhesion and biofilm formation. Conversely, the HT isolate upregulated ALS3, HWP1, and SAP6, enhancing adhesion and sustaining biofilm integrity. Despite SAP6 upregulation in both, host cell cytotoxicity was similar. These findings highlight adaptive mechanisms by which FLC-tolerant <i>C. albicans r</i>etain pathogenicity under antifungal stress, posing potential challenges for clinical management in HNC patients.