Chimeric antigen receptor therapy in infectious diseases: emerging applications with a focus on invasive fungal...

Infections remain a major cause of morbidity and mortality among immunocompromised patients, particularly in the context of invasive fungal infections (IFIs), where outcomes are strongly dependent on host immune status. Despite advances in antifungal therapy, mortality remains high, highlighting the need for novel immunotherapeutic strategies.

This review aims to summarize current evidence on chimeric antigen receptor (CAR)-based therapies for infectious diseases, with a particular focus on IFIs, and to discuss their potential role, limitations, and future perspectives.

A narrative review of the literature was conducted using PubMed, focusing on preclinical and clinical studies evaluating CAR-based approaches in fungal, viral, and selected bacterial infections. Relevant references were identified from database searches and cross-referencing of key articles.

CAR-engineered immune cells, particularly CAR-T cells, represent a promising strategy to restore pathogen-specific immunity in immunocompromised hosts. In IFIs, targeting conserved fungal cell wall components such as β-glucans and mannans has shown encouraging preclinical results, with different CAR constructs demonstrating enhanced antifungal activity and immune activation, particularly against Aspergillus and Candida species. Alternative platforms, including CAR-natural killer cells and CAR macrophages, may offer advantages such as reduced toxicity and off-the-shelf availability, and have shown preliminary clinical feasibility in a patient with IFI. Although CAR-based approaches have also demonstrated activity against viral and selected bacterial pathogens, their clinical application remains largely exploratory. Several challenges limit translation into clinical practice, including complex manufacturing, delayed availability, safety concerns, antigen heterogeneity, and limited clinical evidence.

CAR-based immunotherapy represents a novel and potentially transformative approach for the management of severe infections in immunocompromised patients, particularly those with refractory or multidrug-resistant disease. Advances in manufacturing, target selection, and combination strategies will be essential to overcome current limitations. Further clinical studies are needed to define their safety, efficacy, and positioning within existing therapeutic frameworks.