Pietro Fontana Lab

Enlisting the immune system to fight disease is not a new concept. Especially in the last several years, advances in checkpoint blockade immunotherapy and chimeric antigen receptor (CAR) T-cell therapies have profoundly altered the way certain cancers are treated. However, these approaches have historically had limitations when treating solid tumors. There are myriad reasons for this: an impenetrable tumor microenvironment, treatment-related toxicity, antigen escape, among others. To overcome some of these issues, we employ a multidisciplinary approach to mechanistically understand innate immune proteins and harness that understanding to develop immunomodulators with therapeutic potential. 

Our integrated approach has already proven that an innate immune inflammatory programmed cell death protein called gasdermin D (GSDMD) provokes antitumor immunity in some cancer cells. Programmed cell death mechanisms, such as GSDMD-mediated pyroptosis, are activated when foreign or aberrant cellular material is detected. Pyroptotic cell death relies on the cleavage of GSDMD, which forms holes in the pores of the plasma membrane and releases inflammatory cytokines. Pyroptosis can cause a severe inflammatory response, but we identified a small molecule agonist that promotes antitumor immunity by activating a tumor’s GSDMD proteins (and pyroptotic cell death) without the cleavage event that causes the pro-inflammatory cytokine release. These results highlight a potentially impactful strategy for promoting tumor cell death without prolific inflammation.

Cytoplasmic DNA is the hallmark of cellular damage and/or infection and warrants a prompt immune response. Therefore, the innate immune system’s ability to detect and mount an appropriate response to this molecule is crucial for maintaining cellular homeostasis and health. Our laboratory integrates structural biology, biochemistry, cell biology, chemical biology, model systems and immunological approaches to explore the molecular mechanisms driving innate immune recognition of DNA and how these mechanisms may play a role in the development of diseases.

Dr. Fontana received master’s degrees in both molecular biology and biotechnology at the University of Palermo, followed by a DPhil degree in pathology from the University of Oxford. He then trained as a postdoctoral fellow at Harvard University, where he structurally characterized innate immune cell death protein complexes and a nuclear pore complex. Dr. Fontana then became an instructor of pediatrics at Harvard Medical School and staff scientist at Boston Children’s Hospital.

Dr. Fontana joined St. Jude in 2025 as an Assistant Member in the Department of Immunology. He is also a key contributor to the Center of Excellence in Pediatric Immuno-Oncology, where he utilizes his expertise in structural biology, biochemistry, biophysics, cell biology and innate immunity to advance the field of translational immuno-oncology. Dr. Fontana’s research focuses on innate immune signaling at a mechanistic level. By using a multidisciplinary approach, the Fontana lab is advancing our understanding of basic biology and identifying vulnerabilities in the immune system that can be targeted with small molecules.