Combination therapy for fungal diseases: the role of immunotherapy in the present and the future.

PURPOSE OF REVIEW: Invasive fungal infections remain associated with high morbidity and mortality despite advances in antifungal therapy. Current treatments are largely pathogen-directed and fail to address the dysregulated host immune responses that drive severe disease. Together with expanding at-risk populations and environmental changes that promote fungal adaptation, spread, and emergence resistance of fungal pathogens, this underscores the need for complementary immunotherapy.

RECENT FINDINGS: Disease outcome in invasive fungal infections is determined not only by fungal burden but also by host immune dysfunction. Improved understanding of antifungal immunity has led to a growing range of adjunctive immunotherapies. These include both immune-enhancing and immune-restraining approaches, such as cytokine-based therapies, pattern-recognition receptor agonists, immune checkpoint blockade, monoclonal antibodies, vaccines, cellular therapies, small-molecule immunomodulators, and corticosteroids. Accumulating evidence indicates that their efficacy depends on timing and the patient's immune status, underscoring the need for a balanced, context-specific personalized immunomodulation.

SUMMARY: Antifungal therapy remains the cornerstone of treatment for invasive fungal diseases, but outcomes depend on drug efficacy and host immunity. Combining antifungals with tailored immunomodulation, whether immune restraining, enhancing, or both, offers a promising way to improve outcomes. Future progress will rely on personalized, immune-guided therapies that restore antifungal immunity while limiting immunopathology.