Immune evasion, dysregulation, and emerging immunotherapies for invasive fungal infections in the immunocompromised host.

Invasive fungal infections (IFIs) represent a persistent challenge to global health, particularly in immunocompromised individuals, among whom they remain a leading cause of morbidity and mortality. Conventional antifungal regimens face growing limitations due to the emergence of drug resistance, drug-associated toxicities, and suboptimal efficacy. This review synthesizes advances from 2015 to 2025 in understanding the dynamic interactions between major fungal pathogens-, , and -and the host immune system, emphasizing both conserved and species-specific immune evasion mechanisms. These sophisticated strategies include surface antigen masking, biofilm formation, metabolic adaptation, and the secretion of immunomodulatory effectors, which collectively facilitate fungal persistence and dissemination. In the immunocompromised host, these evasion tactics are compounded by profound immune dysregulation, characterized by aberrant activation of the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome, deficiencies in T helper type 1 (Th1) and type 17 (Th17) responses, T-cell exhaustion, and upregulation of inhibitory checkpoints such as programmed cell death protein 1 (PD-1). These disruptions not only compromise pathogen clearance but also exacerbate immunopathology and tissue damage. Advancing beyond conventional antifungal paradigms, we highlight a dual-track therapeutic framework that integrates direct antifungal activity with tailored immunomodulation. Promising therapeutic avenues encompass immune checkpoint inhibitors, cytokine therapies, prophylactic and therapeutic vaccines, monoclonal antibodies, and adoptive cellular therapies such as chimeric antigen receptor T (CAR-T) cells. We further discuss the integration of multi-omics profiling and personalized immune monitoring to guide precision immunotherapy. Finally, we outline critical translational challenges and future directions aimed at improving clinical outcomes for immunocompromised patients afflicted with IFIs.