PTP1B deficiency in myeloid cells increases susceptibility to Candida albicans systemic infection by modulating antifungal immunity

Invasive candidiasis, primarily caused by Candida albicans, poses a significant threat to immunocompromised patients, with high mortality rates. Understanding how immune responses to Candida albicans is mounted and controlled is fundamental to developing new therapeutic strategies. Protein tyrosine phosphatase 1B (PTP1B) is a regulator of immunoreceptor signalling and downstream inflammatory and metabolic responses and a pharmaceutical target. Here we reveal a critical role for myeloid cell-intrinsic PTP1B in antifungal immunity. Mice lacking PTP1B in myeloid cells (LysM PTP1B⁻/⁻) were significantly more susceptible to systemic C. albicans infection, exhibiting lower survival, greater weight loss, and elevated fungal burdens in the kidney, liver, and brain. These mice also showed heightened proinflammatory mRNA expression in organs and increased kidney tubular inflammation, with increased leukocyte infiltration and chemokine production, contributing to immunopathology. Neutrophils from LysM PTP1B⁻/⁻ mice displayed impaired maturation in infected kidneys and reduced reactive oxygen species production in vitro. Proteomic profiling of infected bone marrow-derived macrophages (BMDMs) revealed significant enrichment of type I interferon-regulated proteins in the absence of PTP1B. These BMDMs showed impaired phagocytosis, reduced killing capacity, and lower viability during infection, phenotypes recapitulated in human macrophages treated with a pharmacological PTP1B inhibitor. Collectively, our findings highlight PTP1B as a key modulator of innate immune responses to C. albicans, balancing antifungal activity and systemic toxicity with inflammation and metabolic fitness. Boosting specific PTP1B-dependent pathways may offer new strategies for enhancing host defence while minimizing fungal-induced immunopathology.