Stier, a physician-scientist with expertise in immune and metabolic dysfunction during critical illness, is affiliated with the Vanderbilt Center for Immunobiology and the Vanderbilt Institute for Infection, Immunology and Inflammation (VI4). He explains that sepsis involves an overwhelming release of inflammatory molecules, such as cytokines, which can cause severe tissue damage, septic shock, organ failure, and death if left uncontrolled. Despite decades of efforts to curb this cytokine storm, effective drug therapies for sepsis have remained elusive, suggesting that targeting inflammation alone is insufficient. While antibiotics and intensive supportive care help patients survive the acute phase, Stier notes that these measures often only buy time, relying on the body’s own ability to recover, which does not always succeed.

During critical illness such as sepsis, the body’s normal metabolic functions are disrupted, including immunometabolism the processes that supply energy to immune cells. As a result, the immune system’s protective capacity becomes exhausted, leading to acquired immunosuppression that increases the risk of secondary infections, ongoing organ dysfunction, recurrent hospitalizations, and death. While earlier studies have described metabolic and immune abnormalities, this research is among the first to investigate the underlying mechanisms linking immunometabolic dysfunction in sepsis to immunosuppression, or immunoparalysis. To do so, Stier and his team employed advanced techniques such as single-cell sequencing and flow cytometry to analyze immune cells from the blood of critically ill patients.

CD4+ T helper cells, which drive immune responses, and regulatory T (Treg) cells, which prevent excessive inflammation, are central to immune function. To examine how critical illness and sepsis affect these cells, the Vanderbilt Health team applied SCENITH, an advanced flow cytometry–based technique that allows single-cell analysis of energy metabolism. Using this approach, the researchers found that Treg cells undergo metabolic reprogramming during critical illness and sepsis, altering tryptophan metabolism and responses to oxidative stress in ways that enhance their immunosuppressive activity while disadvantaging CD4+ helper T cells. This metabolic shift appears to give Treg cells a survival and functional edge, contributing to the immunoparalysis seen in sepsis. Although the findings are preclinical, the study demonstrates the power of using ICU patient samples to uncover immunometabolic mechanisms and identify potential therapeutic targets for critical illness and sepsis.

Source: https://news.vumc.org/2026/01/15/immunometabolism-may-be-a-key-to-controlling-sepsis-study/