Host immunosuppression and antifungal pressure cooperatively shape fungal adaptation and pulmonary microenvironment in cryptococcosis.

Cryptococcus neoformans remains a major opportunistic pathogen causing life-threatening pulmonary and systemic infections in immunocompromised individuals. Effective disease control is challenged by limited therapeutic options and by the pathogen's remarkable ability to adapt under immune and pharmacological pressures. Corticosteroids, while indispensable for managing inflammatory and autoimmune conditions, can disrupt immune homeostasis and worsen fungal infections. To investigate how corticosteroid-induced immunosuppression interacts with antifungal therapy, we employed a murine model of pulmonary cryptococcosis. Dexamethasone treatment promoted fungal proliferation, decreased CD45+ leukocyte infiltration, and induced excessive neutrophilic activity, evidenced by enhanced MPO+ staining. It also upregulated the expression of mannose receptor, indicating macrophage polarization toward an alternatively activated M2-like phenotype, and caused laminin degradation, culminating in severe pulmonary injury. In contrast, fluconazole reduced fungal burden, preserved lung architecture, and partially restored immune and extracellular matrix balance, even in combination with dexamethasone. Yeasts recovered from bronchoalveolar lavage fluid and lung tissue exhibited distinct adaptive profiles depending on treatment and anatomical origin, including alterations in capsule size, titan cell formation, chitin remodeling, lipid accumulation, and polysaccharide secretion. Dexamethasone-driven reductions in viscosity and loss tangent at intermediate frequencies mechanically relax the alveolar lumen, potentially enabling more efficient fungal displacement and dissemination. Collectively, these findings demonstrate how immunosuppressive and antifungal pressures jointly influence fungal adaptation, immune dynamics, and pulmonary biomechanics, providing integrated insights into host-pathogen-drug interactions that are relevant for optimizing cryptococcosis therapy.