Early immunotherapy aids in treating potentially fatal fungal pneumonias in preclinical models

MD Anderson Research News June 03, 2026

• Lung infections caused by opportunistic molds can “paralyze” the immune system 

• Researchers tested adding immunotherapy on top of standard antifungal treatments

• This approach reversed immune system paralysis, leading to better survival and less severe illness in lab models, especially when immunotherapy was administered early

• Study demonstrates a potentially clinically relevant strategy for deploying immunotherapies against fungal infections

A new study led by researchers at The University of Texas MD Anderson Cancer Center has shown that early administration of immunotherapy with standard antifungal treatment improved outcomes and largely alleviated immune system paralysis caused by fungal lung infections in preclinical models. 

These findings could herald new clinically relevant strategies for treating a variety of life-threatening invasive fungal pneumonias, which disproportionately affect immunocompromised cancer patients. 

The study, published in Proceedings of the National Academy of Sciences, was led by Sebastian Wurster, M.D., assistant professor, and Dimitrios P. Kontoyiannis, M.D., Ph.D., professor, both of Infectious Diseases, Infection Control and Employee Health.

“Despite an expanded arsenal of antifungal treatments, immune system dysfunction still is a major cause of failure when treating infections, with significantly high morbidity and mortality rates associated with pneumonias caused by opportunistic molds. There is an urgent need for adjunct immune-enhancing therapies to improve outcomes,” Kontoyiannis said. “Our research shows that adding an immune checkpoint inhibitor to antifungal treatments is helpful in experimental mold pneumonias, especially when given early.”

How could a therapy designed for cancer help treat fungal infections?

The immune system is made up of many different types of cells, including T cells, which attack and kill infected or cancerous cells. T cells have proteins that prevent them from attacking healthy cells, acting as a system of checks and balances. Immune checkpoint inhibitors block those proteins so that T cells are free to attack infected cells.

Immune checkpoint inhibitors commonly are used to allow T cells to more effectively eliminate cancer cells, but they are not currently standard treatment for fungal infections. 

Certain molds that can infect the lungs cause T cells to become exhausted and dysregulated – a condition known as immune paralysis – so they stop mounting a proper defense, enabling the infection to spread throughout the lungs. 

In this study, even with antifungal treatment, immune paralysis persisted unless anti-PD-L1 immune checkpoint inhibitors were administered. This essentially reenergizes T cells so they can do their job and eliminate infections. These findings are consistent with other studies from the Kontoyiannis Laboratory showing that immune checkpoint inhibitors can reverse T cell exhaustion associated with a fungal infection, similar to how they work in oncology.

Why is treatment timing so important?

Mold infections mostly affect immunocompromised people, including patients with cancer. Their already weakened immune system makes them more susceptible to fungal infections, which further suppress their immune response, allowing the infections to become life-threatening. 

For many, the immune system initially fights the infection, but it shuts down quickly. Researchers identified a window of opportunity to intervene early, while the immune system is still active, to prevent irreversible system shutdown and possibly prevent immune toxicity associated with high fungal overgrowth, seen typically in late manifestations of fungal infections.

One particularly noteworthy aspect of this study is that researchers tried to simulate clinically relevant timelines by starting treatment shortly after symptoms would manifest in patients. Researchers compared beginning immunotherapy treatment three days and five days after fungal exposure, noting significantly better outcomes with earlier administration. 

What’s next for this approach?

These findings reframe a mold infection as both an immune-dysregulation disease and a fungal overgrowth, indicating a need to treat it with a combination of antifungal and immune-based therapies. Further preclinical and clinical exploration of early immunotherapy interventions to treat potentially fatal mold pneumonias is needed to validate this approach. If successful, the framework could be expanded to investigate the effectiveness of different immunotherapies and treat a broader spectrum of clinically important mold pneumonias. 

“During our research, similar immune paralysis patterns could be seen across multiple mold types, meaning this approach may be generalized to change how we treat life-threatening fungal infections in immunocompromised patients,” Wurster said. “The better effectiveness of immune checkpoint inhibitors when given early in fungal pneumonias suggests that outcomes can be further improved with earlier diagnosis and immune profiling that identifies the most suitable candidates for such interventions.”

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This study was supported by Astellas Pharma Global Development, the National Institute of Allergy and Infectious Diseases (NIAID), the Cyrus Scholar Award, the Robert C. Hickey Chair Endowment, and the National Cancer Institute. For a full list of collaborating authors, disclosures and funding sources, see the full paper in Proceedings of the National Academy of Sciences.