New research from Memorial Sloan Kettering Cancer Center (MSK) finds the TCA cycle’s waste-management function may present an opportunity against cancer; shows how microplastics impair immune ‘housekeeping’ functions; reveals the way the protein TOX plays different roles in different immune cells; and identifies a new combination approach for treating advanced kidney cancer after immunotherapy.
The tricarboxylic acid (TCA) cycle is best known for breaking down nutrients to generate energy and supplying building blocks for biosynthesis.
A new study from the lab of cell biologist Lydia Finley, PhD , at MSK’s Sloan Kettering Institute — led by medical student Abigail Xie, PhD, and postdoctoral fellow Julia Brunner, PhD — demonstrates that metabolite clearance is also an additional essential function of the TCA cycle.
One early product of the TCA cycle is citrate — which is useful for energy and other cellular processes. But if a cell makes more citrate than it can get rid of or use, citrate builds up inside mitochondria. When that happens, it triggers a stress response that slows protein production and cell growth.
Cancer cells are obsessed with growth, and require a high, carefully managed metabolism. The study suggests that some cancer cells may depend on parts of the TCA cycle to prevent citrate from building up — not just to produce energy.
This may present a weakness in cancer cells that could be exploited therapeutically, Dr. Finley says, as forcing citrate to build up inside them could trigger the stress response and slow tumor growth. Read more in Cell .
Microplastics can build up inside of immune cells, disrupting their key functions and potentially contributing to broader health problems, new research from an MSK-led team shows.
Scientists around the world are working to understand the impact of the tiny, ubiquitous plastic pieces that make their way into the human body. The MSK study — led by Ana Codo , a Weill Cornell Medicine graduate student working the lab of senior author Justin Perry, PhD at the Sloan Kettering Institute — focused on what happens when polystyrene microplastics are taken up by phagocytes, a type of immune cell that normally helps clean up tissues by engulfing harmful materials.
Using human cell and animal models, the researchers showed that after ingesting microplastics, phagocytes become less effective at clearing away dead and dying cells (an essential process called efferocytosis), as well as have a reduced ability for removing different infectious agents such as bacteria and fungi. Disruptions in these “housekeeping” functions could contribute to broader health problems, they note.
Inside phagocytes, microplastics caused a metabolic byproduct called methylglyoxal (MGO) to accumulate, gumming up the cells’ metabolism and suppressing efferocytosis, the study showed. Importantly, boosting the cell’s ability to get rid of MGO — by increasing levels of the MGO-detoxifying enzyme glyoxalase-1 — reversed the impact, pointing to a potential way to counteract microplastic-related dysfunction.
“Because the damage we’re seeing is tied to methylglyoxal, a key metabolite that forms advanced glycation end products, it raises a broader concern: microplastic exposure may connect to processes that lead to the development of diseases of aging and cancer — a link we are continuing to investigate,” Dr. Perry says.
Read more in Immunity .
Expression of a protein called TOX is associated with the exhaustion of cancer-fighting CD8+ T cells and poorer response to immunotherapy, but its role in CD4+ helper T cells has been unclear.
Now a new study from the lab of immunologist Andrea Schietinger, PhD, at the Sloan Kettering Institute reveals that TOX plays a strikingly different, positive role in CD4+ T cells. The work was led by first author Brianna Naizir , a Gerstner Sloan Kettering Graduate School student and member of the Schietinger Lab.
The researchers discovered that TOX is critical for CD4+ helper T cells to produce powerful molecules that help fight tumors, including interferon-gamma.
However, while having more TOX protein in CD4+ T cells is helpful in the context of cancer, TOX-expressing CD4+ T cells can also drive damaging autoimmune reactions, the team found in studies of autoimmune vasculitis and type 1 diabetes.
The findings suggest that TOX levels in CD4+ T cells could serve as a marker for doctors to predict which cancer patients will respond best to immunotherapy. And, by revealing TOX’s differing functions in CD8+ versus CD4+ T cells, the research provides new insights that could help improve the precision of immunotherapies.
Read more in Nature Immunology .
Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer. In about 20% of patients, the cancer has already spread outside the kidney by the time it’s found, and in about one-third of patients who have surgery, the cancer later spreads.
Immunotherapy drugs called checkpoint inhibitors are the standard first-line drug treatment for patients with ccRCC at this advanced stage, but for patients who don’t respond or who stop responding, there are no clear next steps. Now an international phase 3 clinical trial suggests a new approach targeting tumor blood vessel growth through two different pathways may offer benefit to many of these patients. The trial was led by MSK genitourinary medical oncologist Robert Motzer, MD .
The trial compared a combination of two drugs— belzutifan (Welireg®) and lenvatinib (Lenvima®) — to cabozantinib (Cabometyx®), a commonly used treatment. Belzutifan and lenvatinib are both targeted therapies that block the growth of blood vessels in tumors, but they work in different ways. Belzutifan is the first approved drug that acts on a pathway called HIF-2 alpha; lenvatinib acts on a pathway called VEGFR.
The study of 741 patients compared responses from patients receiving the new drug combination versus those given the older treatment. The combination was more effective and longer lasting: Almost half (47.2%) had their tumors shrink substantially, versus just over one-third (39.1%) in the control group. After two years, about half of the patients in the experimental group were still responding (49.5%), versus only about one-quarter of the control group (25.5%). There were no unexpected side effects in either group. It is still too early to determine if the new combination improved overall survival, and many of the patients are still being followed.
Dr. Motzer presented the results from the study at the American Society of Clinical Oncology’s Genitourinary Cancers Symposium on February 28, 2026. Read the conference abstract .