Emerging evidence for anti-PD-1 and IFN-γ as adjunctive immunotherapy in invasive mold infections.

Invasive mold diseases (IMDs) such as mucormycosis and aspergillosis carry high mortality despite optimal antifungal therapy. Adjunctive immunomodulation, including anti-PD-1 antibodies and interferon-γ, may help restore antifungal immunity in severely ill patients. We implemented multidisciplinary team meetings in France to assess and validate the use of adjunctive anti-PD-1 monoclonal antibodies and interferon-γ in combination with antifungal therapy for patients with life-threatening IMDs. Here, we report the characteristics and outcomes of the treated patients. Twelve cases were reviewed, and eight patients ultimately received adjunctive therapy. All presented with particularly severe IMDs, including seven mucormycosis (three cerebral, three intra-abdominal, and one extensive fasciitis) and one pulmonary aspergillosis. PD-1 expression on T cells was elevated in all patients. Following adjunctive treatment, six of the eight patients survived. Therapy was generally well tolerated; serious adverse events included one episode of cutaneous toxicity and two cases of acute respiratory distress syndrome, possibly related to immunotherapy. All resolved after treatment discontinuation. In our experience, adjunctive immunotherapy combined with antifungals was mostly associated with favorable outcomes in severe, refractory IMDs. These findings support further investigation of host-directed strategies as potential adjuncts in managing life-threatening fungal diseases. IMPORTANCE: This study provides preliminary evidence supporting the clinical relevance of host-directed immunotherapy as an adjunct to antifungal treatment in severe invasive mold diseases (IMDs), which remain associated with high mortality despite optimized antifungal regimens. By targeting immune dysfunction, particularly T-cell exhaustion mediated through the PD-1 pathway, the combined use of anti-PD-1 monoclonal antibodies and interferon-γ aims to restore effective antifungal immune responses. The observed survival benefit in this small cohort supports the biological rationale that reversing immune paralysis can enhance pathogen clearance in patients with IMDs. Although limited by sample size, this work provides encouraging evidence supporting the feasibility, tolerability, and potential efficacy of combined immunomodulatory strategies, thereby contributing to the evolving paradigm of personalized and immune-guided management in IMDs. Future work should focus on biomarker-guided patient selection, rigorous monitoring, and determining the optimal timing for therapy initiation. Integrating immunological profiling into patient assessment may enable more precise, stratified therapeutic approaches.