Modulation of host lung immunity in Pneumocystis pneumonia: a review of current concepts and future prospects for novel adjunctive immune-based therapies

Abstract Pneumocystis jirovecii pneumonia remains a significant cause of mortality and morbidity in immunocompromised populations worldwide. Mortality rates range from 5% to 30% in HIV-positive individuals and 4% to 76% in those without HIV. Recognizing its public health impact, the World Health Organization (WHO) included Pneumocystis jirovecii in its 2022 “Fungal Priority Pathogens” list. In this review, we will summarize published findings over the last 14 years on the immunopathogenic mechanisms underlying Pneumocystis pneumonia–related lung injury and examine the potential for targeting these pathways in adjunctive immune modulation therapy. Notably, recent studies have identified promising immune-based interventions, including PD-1/PD-L1 blockade and IL-7 therapy, which may enhance pathogen clearance while controlling damaging inflammation. Additionally, small molecule inhibitors such as BRD5529 and ALW-II-41-27 have shown potential in reducing lung injury by modulating proinflammatory signaling pathways in Pneumocystis pneumonia.