New approaches for cryptococcosis treatment and prevention—a systematic review

Background: Cryptococcosis remains a life-threatening fungal infection with high mortality despite current antifungal therapy. The toxicity, limited accessibility, poor tissue penetration, and increasing resistance associated with conventional antifungals highlight the need for innovative preventive and therapeutic strategies. This systematic review summarises recent advances in cryptococcosis management and identifies priorities for future research and clinical translation.

Methods: PubMed, Embase, Web of Science, Cochrane Library, and ClinicalTrials.gov were systematically searched for studies published between January 2005 and December 2025. Data on study characteristics, therapeutic strategies, mechanisms, and outcomes were extracted. Because of substantial heterogeneity among clinical and preclinical studies, quantitative synthesis and certainty-of-evidence assessment were not performed.

Results: Eighty-six studies were included. Promising advances were identified in vaccines, immunotherapy, nanotechnology-based drug delivery, novel antifungal agents, drug repurposing, and non-pharmacological interventions. Vaccine candidates induced protective immunity in animal models but remain preclinical. Adjunctive interferon-γ is the only immunotherapy supported by clinical evidence, whereas programmed cell death protein 1 (PD-1) blockade, chimeric antigen receptor T-cell (CART) therapy, most of monoclonal antibodies, and other immunomodulators remain under preclinical investigation. MAT2203 demonstrated non-inferior efficacy with improved safety compared with intravenous amphotericin B. Several novel antifungal agents have entered clinical development, whereas repurposed drugs have shown limited clinical benefit. Most non-pharmacological approaches also remain experimental.

Conclusions: Emerging strategies are reshaping cryptococcosis management beyond conventional antifungal therapy. Although most remain at the preclinical or early clinical stage, advances in host-directed immunotherapy, nanomedicine, and novel antifungal development provide promising opportunities to improve treatment efficacy, safety, and accessibility. Well-designed clinical studies are needed to facilitate clinical translation.