Immunotherapy for invasive Candida infections: Translating host-directed strategies into clinical practice

Candida infections are a leading cause of invasive fungal disease (IFD), especially among critically ill and immunocompromised patients. Despite available pathogen-directed antifungal therapies, outcomes remain unsatisfactory with high associated morbidity and mortality rates. Increasing recognition of immune dysregulation of the host, including immunoparalysis and impaired antifungal effector responses, has driven interest in immunotherapeutic strategies as adjuncts to conventional treatment.

To provide a comprehensive overview of emerging immunotherapeutic approaches for invasive Candida infections and evaluate their mechanistic rationale, current evidence, and potential for clinical translation.

Relevant literature was identified through a focused search of PubMed/MEDLINE, Embase, and ClinicalTrials.gov, supplemented by the authors' personal collection of key studies and reference screening.

Immunotherapeutic strategies targeting invasive Candida infections encompass both non-cellular and cellular approaches. Cytokine-based therapies, including interferon-gamma and granulocyte/macrophage colony-stimulating factors, aim to restore impaired innate immunity and have demonstrated preliminary clinical benefits in selected populations. Immune checkpoint inhibitors represent a novel strategy to reverse T-cell exhaustion, supported by preclinical data but with limited clinical evidence to date in IFD. Cellular therapies, such as granulocyte transfusions, adoptive T-cell transfer, and engineered CAR T and CAR NK cells, offer innovative means to augment antifungal immunity, though their use remains largely preclinical. Preventive and therapeutic strategies involving vaccines and monoclonal antibodies are advancing, with several candidates showing promising immunogenicity and antifungal activity in preclinical and early clinical studies.

Immunotherapy has the potential to transform the management of invasive candidiasis by complementing antifungal therapy with host-directed interventions. Successful clinical translation will require real-time biomarker-driven patient stratification and rigorous safety evaluations to account for the heterogeneity of patients according to their immune status. Future research should prioritize adaptive, mechanism-based trial designs to enable precision immunotherapy and improve outcomes in high-risk populations.