A team of scientists from Johns Hopkins, spanning the Kimmel Cancer Center, the Bloomberg~Kimmel Institute for Cancer Immunotherapy, and the Bloomberg School of Public Health, has unveiled a critical metabolic balancing act within our immune system’s most formidable cancer fighters: CD8+ T cells. Their research, published online in the March 31, 2026, edition of Cell, reveals how the amino acid cysteine is partitioned within T-cells to control two essential, yet competing, functions—proliferation (the ability to multiply) and effector function (the ability to attack and kill cancer cells).[1][2]
The Double Life of Cysteine in T-Cells
Amino acids are well known as the building blocks of proteins, but many play additional roles in cellular metabolism, signaling, and maintaining redox homeostasis. Among these, cysteine stands out for its versatility. While traditionally classified as a ‘nonessential’ amino acid—meaning the body can synthesize it—the study shows that, under certain conditions, such as a robust immune response, cysteine becomes conditionally essential. T-cells, in particular, must import cysteine from their environment to meet the heightened demands of activation and proliferation.
“Once cysteine enters the cell, it can take on different fates. Understanding where it goes, and when, turns out to be essential for determining how T cells behave,” explained Erika Pearce, Ph.D, senior author and Bloomberg Distinguished Professor at Johns Hopkins.
Within CD8+ T cells, cysteine is not simply a generic fuel source. Instead, it is channeled into two distinct metabolic pathways, each supporting a different aspect of T-cell function:
- Glutathione Synthesis: Cysteine is a key substrate for the antioxidant glutathione (GSH), which helps regulate the cell’s redox state and modulates effector functions—such as the production of immune-signaling molecules that aid in attacking cancer cells.
- Iron-Sulfur Cluster Formation: Cysteine also donates its sulfur atom for the synthesis of iron-sulfur (FeS) clusters, a process orchestrated by the enzyme NFS1. These FeS clusters are essential for mitochondrial respiration and energy production, which underpin T-cell proliferation and sustained activity.
The Metabolic Trade-Off: Proliferation vs. Effector Function
Using laboratory and animal models, the Johns Hopkins team meticulously traced the fate of cysteine within T-cells. They discovered a crucial trade-off: When T-cells are starved of cysteine, they become hyperactive—producing more of the molecules needed to kill cancer cells—but they lose the ability to proliferate. Conversely, when the FeS cluster synthesis pathway is impaired (for example, by deleting NFS1), T-cells not only fail to multiply but also show signs of exhaustion and diminished anti-tumor immunity.
First author Beth Kelly Ph.D., summarizes the implications: “Since cysteine works through various cell pathways to support different immune functions, our study points to the possibility of selectively modulating how cysteine is used inside a T cell. The goal would be to preserve beneficial function and prevent CD8+ T-cell exhaustion.”
Experimental Evidence: Tumor Immunity in Action
In mouse models of melanoma, T-cells lacking NFS1—therefore unable to efficiently form FeS clusters—displayed reduced tumor control and signs of exhaustion, a state where T-cells become ineffective after prolonged stimulation. On the other hand, boosting NFS1 activity promoted T-cell proliferation and enhanced tumor control. Interestingly, blocking glutathione production after the initial activation of T-cells also led to stronger anti-tumor responses, suggesting that carefully manipulating these metabolic pathways can tip the balance in favor of effective cancer immunity.
These results are not limited to mouse models. Data from human hepatocellular carcinoma indicate that disrupted FeS metabolism in T cells is associated with exhaustion, further supporting the relevance of these findings in human disease.
The Broader Context: Nutrient Partitioning and Immune Cell Fate
This work adds a valuable layer of understanding to the field of immunometabolism, which explores how nutrients and metabolism shape immune responses. Most previous studies have focused on nutrient supply or early breakdown, but this research highlights that a single nutrient—cysteine—can be routed into multiple intracellular pathways, each with distinct, sometimes opposing effects on immune cell function.
The idea that ‘nonessential’ amino acids can become essential in specific physiological contexts, such as during robust immune activation, is gaining traction. When cellular demand for a nutrient outpaces the body’s synthetic capacity, immune cells must compete for extracellular supplies. The precise routing of these nutrients within cells becomes a determinant of immune function and fate.
The study’s findings echo earlier work in simpler organisms, such as the slime mold Dictyostelium, where cysteine allocation between antioxidant defense and proliferation dictated whether the organism would continue to grow or transition to a nonproliferative, multicellular state. The conservation of sulfur metabolic pathways across evolution highlights the fundamental importance of this process.
Therapeutic Opportunities: Fine-Tuning T-Cell Responses
By delineating how cysteine is split between glutathione synthesis and FeS cluster formation, the researchers have uncovered new opportunities to fine-tune T-cell responses in cancer and potentially other diseases. For example, selectively enhancing cysteine flux toward FeS cluster synthesis may boost T-cell proliferation and persistence, while transiently limiting glutathione production could amplify anti-tumor activity.
The implications for immunotherapy are significant. T-cell exhaustion remains a major obstacle in the fight against cancer, as exhausted T cells are less effective at controlling tumors. By understanding and manipulating the metabolic switches that govern exhaustion and effector function, scientists might design new strategies to reinvigorate T-cell activity. This could involve drugs that target specific enzymes (like NFS1) or metabolic pathways, or dietary interventions designed to modulate cysteine availability.
“Understanding how these pathways work gives us new opportunities to fine-tune T-cell responses in cancer and other diseases. While we illustrate this concept for cysteine, it is likely to apply to other metabolites relevant for immune cell function,” noted Pearce, emphasizing the broader significance and possible impact of the study outcomes.
Looking Ahead: Open Questions and Future Directions
While this study marks a major advance, the authors note that many questions remain. For instance, how do other nutrients interact with cysteine metabolism in T-cells? Are there specific tumor environments where cysteine limitation or rerouting is particularly pronounced? Can these findings be translated into effective therapies for patients?
Future research will also need to address the potential risks of manipulating cysteine pathways, as improper modulation could lead to unwanted side effects, such as impaired immune responses or toxicity in other tissues.
What’s next
The discovery of how cysteine is partitioned within T-cells to balance proliferation and cancer-killing activity opens a promising new chapter in cancer immunotherapy research. By mapping the metabolic circuits that underlie immune cell function, scientists are moving closer to custom-tailored interventions that can unleash the full power of the immune system against cancer and beyond.
The collaboration—featuring researchers Minsun Cha, Tatjana Gremelspacher, Jacob Martin, Massimo Andreis, Isha Maloo, Gustavo Carrizo, Mia Gidley, Michal Stanczak, Petya Apostolova, Joseph Longo, Lisa DeCamp, Eric Ma, Ryan Sheldon, Russell Jones, David Sanin, and Ananya Majumdar—was supported by prominent institutions and fellowships, including the Van Andel Institute, the Paul G. Allen Frontiers Group, the Chan Zuckerberg Initiative, and several NIH awards.
As the field of immunometabolism evolves, the nuanced control of intracellular nutrient routing—epitomized by the fate of cysteine in CD8+ T-cells—will remain a frontier with profound implications for health, disease, and the future of medicine.
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Reference
[1] Kelly B, Cha M, Gremelspacher T, Martin JL, Andreis M, Carrizo GE, Gidley M, Stanczak MA, Apostolova P, Sanin DE, Majumdar A, Pearce EL. Distinct control of T cell proliferation and effector function by partitioning of intracellular sulfur from cysteine. bioRxiv [Preprint]. 2026 Jan 29:2026.01.27.702014. doi: 10.64898/2026.01.27.702014. PMID: 41659672; PMCID: PMC12873821.
[2] Kelly B, Cha M, Gremelspacher T, Martin JL, Andreis M, Carrizo GE, Gidley M, Stanczak MA, Apostolova P, Sanin DE, Majumdar A, Pearce EL. Sulfur partitioning from cysteine controls T cell proliferation and effector function. DOI: 10.1016/j.cell.2026.03.012
Featured image: Milton S. Eisenhower Library and the Beach/Johns Hopkins. Photo courtesy: © 2026 Johns Hopkins University. Used with permission.
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