The story so far: The Nobel Prize season for 2025 began with the announcement of the Physiology or Medicine Prize on October 6. The three awardees — U.S.-based researchers, Mary E. Brunkow and Fred Ramsdell, and Japan’s Shimon Sakaguchi — were chosen for their “discoveries concerning peripheral immune tolerance.” Their discovery enabled a fundamental understanding of how the immune system works — how it is regulated and kept in check. This has led to the evolution of several new potential treatment options, currently being tested, including for cancer.

What does their discovery mean?

Unless the body’s immune system is kept in check, it can attack its own organs. In that case, why do most people not develop autoimmune conditions where the body turns on itself? U.S. and Japanese scientists, working independently, arrived at an explanation for how the immune system is kept in check. It is for their work in making discoveries concerning what prevents the immune system from attacking the body that the Nobel was awarded. The laureates identified the immune system’s regulatory T cells which perform the precise task of preventing immune cells from launching an attack on the body.

Literally every day the immune system, a formidable army, is on guard, battling pathogens that try to invade the body. The question here is how do these cells “know what they should attack and what they should defend”, as the Nobel Committee pointed out. “Their discoveries have been decisive for our understanding of how the immune system functions and why we do not all develop serious autoimmune diseases,” said Olle Kämpe, chair of the Nobel Committee.

What are regulatory T cells?

The story goes back to Sakaguchi when he was working at the Aichi Cancer Centre Research Institute, Japan, some four decades ago. All T cells have special proteins called T-cell receptors on their surface. These receptors can be likened to a type of sensor. Using them, T cells can scan other cells to discover whether the body is under attack. There are a vast number of T cells with different receptors that can detect invaders, including new viruses. But they also have receptors that can attach to human tissues. But then, intuitively, is there a switch mechanism that warns the T cells off body cells?

In the 1980s, scientists realised that when T cells mature in the thymus, a small gland located in the upper chest behind the breastbone and in front of the heart that plays a crucial role in the immune system, they are taught to recognise and eliminate the body’s own proteins in a process called central tolerance. By the time Sakaguchi began his research into trying to understand this mechanism, his colleagues had already reportedly performed an experiment on newborn mice. They hypothesised that the mice would develop fewer T cells and have a weaker immune system if they removed the thymus. Instead, the immune system went into overdrive and ran amok, with the little mice developing several autoimmune conditions. This experiment might not have satisfied its primary goal, but in it was the idea for a Nobel that would come about 30 years later. Sakaguchi took off from where the experiment stopped. He injected these mice with T cells and it appeared that the T cells could protect the mice from autoimmune diseases.

Veering off from the current scientific wisdom of the time, Sakaguchi was convinced that the immune system must have some form of security guard — one that calms down T cells and keeps them in check; in this case, protecting the mice from the autoimmune condition. It took him over a decade, but in 1995, he presented to the world, a new class of T cells to the world, those that carried an extra protein called CD25 on their surface. This was called the regulatory T cell. But other researchers were not convinced yet of this idea.

It would take a second act, and efforts from Brunkow and Ramsdell, to concretely prove the experiment. A new set of mice, being studied since the Manhattan Project in fact, stood up to the occasion. In this instance, half of all the male mice were sickly and died in a few weeks, while the females thrived. It turned out the male’s organs were being attacked by T cells that destroyed the tissues. The Nobel-winning pair, who were then working at a biotech company Celltech Chiroscience in the U.S., realised that the mice could provide important clues in their work. After years of study, at an age when molecular biology was at best infantile, with a great deal of patience, they narrowed down on the faulty, mutant gene and named it Foxp3. They finally had an explanation for why a specific mouse strain was particularly vulnerable to autoimmune diseases. They also showed that mutations in the human equivalent of this gene cause a serious autoimmune disease, IPEX.

Two years later, Sakaguchi and others could prove, this time, convincingly, that the Foxp3 gene controls the development of the regulatory T cells, being able to prevent other T cells from mistakenly attacking the body’s own tissue, in a process that is called peripheral immune tolerance. Regulatory T cells also ensure that the immune system calms down after it has attacked invaders, answering Sakaguchi’s initial question.

What are the specific uses in medicine?

While specific therapies are yet to hit the market, over 200 studies involving regulatory T cells are currently in progress, said Thomas Perlmann, secretary-general of the Nobel Assembly, while making the announcement of the prize on October 6. These stand testimony to the potential slew of new treatment modalities to address various conditions.

This includes work on cancer — dismantling the regulatory T cells so that the immune system can access the tumours and set to work on them; and on autoimmune disorders where researchers are trying to promote the growth of more regulatory T cells, inside the body, but also outside of it, in order to make sure that the immune system does not attack its own body.

It is also believed that this research will have far-reaching implications for organ transplantation by regulating organ acceptance. Clinical studies are afoot to test many of these pathbreaking treatment modalities.

Published – October 12, 2025 02:37 am IST

New York:

Cancer cells rarely begin stealthily. Quite the contrary, they alert the immune system to their presence by displaying chemical red flags on their membranes. When detected, the body’s defences can swoop in and destroy renegade cells before they can do significant damage. Lipids, fatty molecules traditionally thought to be largely a fuel supply for developing tumours, are at the heart of this early detection system.

However, a new study in Nature shows that one specific lipid type is essential for cancer immune evasion — so much so that certain cancer cells cannot reproduce without it. The findings validate long-held assumptions that not only is this lipid a crucial factor in cancer biology (and thus a key therapeutic target).

“Cancer cells are altering how this lipid is metabolized, which in turn distorts the ‘eat me’ signals that malignant cells usually produce,” says first author Mariluz Soula, a former graduate student in the laboratory of Kivanc Birsoy, and now a scientist Lime Therapeutics. “This paints a very different picture of the role lipids play in cancer growth.”

Scientists have long known that cancer cells alter lipid metabolism, but it was generally assumed that cancer cells were gobbling up these lipids for energy–consuming the fatty molecules to help the tumor grow and spread far beyond that of healthy cells.

“We knew from the literature that elevated lipid levels correlate with severity of cancer growth and metastasis, but it was unclear how,” Soula says. The Birsoy lab, in conjunction with the laboratory of Gabriel D. Victoria, set out to answer this question by screening the genes involved in this process. They then implanted a series of cancer cells, each missing a different such gene, into mice with and without immune systems–thereby revealing which lipids a cancer cannot live without.

The result: so-called “sphingolipids.” Discovered in the late 1800s by German chemist Johann Ludwig Wilhelm Thudichum, sphingolipids were named after the enigmatic Sphinx of Greek lore because of their puzzling structure and function. Two centuries later, sphingolipids are less of a mystery. “We know that sphingolipids aren’t really used for energy,” Soula says. “They’re mainly in the cell membrane to create scaffolding for signaling proteins.”

This finding raised an intriguing possibility. Was lipid metabolism in cancer cells really just the story of hungry cells trying to consume more energy? Or was it a key part of the cancer cell’s efforts to subtly manipulate cell signaling and dodge the immune system?

To test how sphingolipids were driving cancer growth, the team turned to an FDA-approved drug used to treat Gaucher disease–a genetic disorder characterized by an impaired ability to break down lipids. The drug essentially blocks glycosphingolipid synthesis, and the team found that this impaired tumor growth in pancreatic, lung, and colorectal cancer models.

They also found that depleting glycosphingolipids prevented the formation of the “lipid nanodomains” that bunch signalizing molecules together on the membrane, impacting the cell’s surface receptors on the cell surface in a way that made them more sensitive to an immune response. These findings suggest that cancer cells hoard glycosphingolipids in order to obscure inflammatory signals, and that disrupting glycosphingolipid production can leave cancer cells vulnerable to the immune system.

“Everyone thought of elevated lipid levels as an energy source for cancer cells to consume,” Soula says. “We discovered that it’s far more nuanced. Lipids are not just fuel, but a protection mechanism for cancer cells that modulates how they communicate with the immune system.”

Future work will determine whether this holds true for multiple cancers. The team tested a variety of types, but found this mechanism at work in KRAS-dependent cancers (so named for the mutated oncogene that drives them). Still, the initial results could have significant clinical impact, given how aggressive many KRAS-dependent cancers, such as pancreatic cancer, tend to be. Based on their findings, the team suggests that drug and dietary interventions that stunt sphingolipid production may help increase the efficacy of existing immunotherapies.

“Diets may impact many aspects of cancer biology,” Birsoy says. “We believe modulating dietary lipids may be an interesting avenue to target cancer cells’ ability to evade immune cells.”

(Except for the headline, this story has not been edited by NDTV staff and is published from a syndicated feed.)