CAR T-cell therapy may work better if cancer cells are made stiffer

In mice with deadly melanoma, making tumours stiffer boosted CAR T-cell–style immunotherapy, shrinking or eliminating tumours in some animals.

A promising boost to CAR T-cell–style immunotherapy is emerging from an unexpected angle: not changing the immune system first, but changing the physical properties of the cancer cells it is meant to attack.

Researchers say that stiffening tumour cells helped tumour-targeting T-cells connect more effectively and deliver lethal payloads. The work, carried out in mice with melanoma, offers a potential new route to make immunotherapies that are already transforming cancer care even more powerful.

Cancer cells are often softer than healthy cells, and that difference may matter.. T-cells have a built-in ability to sense the stiffness of their environment. which can influence how well they respond to disease.. Scientists involved in the study were therefore interested in a mechanical explanation for how tumours may slip past immune attack.

“They were very curious about whether the softness of cancer cells may help them evade the immune system. and how T-cells’ mechanical sensing may influence their response to cancer. ” Li Tang of the Swiss Federal Institute of Technology Lausanne said at a conference in London on 11 May. Biophysical immunoengineering: from insight to clinical application.

To understand what makes cancer cells softer, the team compared the membranes of cancer cells with those of healthy cells. In both mouse and human cancer cells, they found the same pattern: the membranes contained more cholesterol.

With that clue in hand, the researchers moved to animal experiments.. They established tumours in 24 mice by injecting melanoma cells. described as the deadliest form of skin cancer. near one of the thighs.. Nine days later. the animals received an infusion of T-cells engineered to recognise the tumours. mirroring CAR T-cell therapy. an approach already approved for cancers including acute lymphoblastic leukaemia and B-cell lymphoma.

The treatment was paired with IL-15, a protein known to boost the cancer-killing ability of tumour-specific T-cells. Each mouse was given three IL-15 infusions over five days.

But the key variable was cholesterol.. Only half of the mice received a third intervention: methyl β-cyclodextrin, known as meβCD, injected directly into the tumours.. The compound reduces cholesterol levels in cell membranes and was administered daily between days 9 and 18 after the melanoma cells were injected.. The remaining mice received saline injections instead.

The difference in outcomes was stark. About a month later, all 12 mice that did not receive meβCD had died as tumours grew rapidly. In the meβCD group, seven mice died, while five experienced complete tumour disappearance.

“The numbers are great; it’s quite impressive,” said Lance Kam of Columbia University in New York.

Further analysis pointed to what changed at the cellular level.. By stiffening tumour cells, meβCD appeared to help tumour-specific T-cells latch on more strongly.. With improved attachment. the engineered T-cells were then able to deliver toxic molecules such as perforin. which destroys cancer cells by puncturing holes in them. more efficiently.

For Yi Sui at Queen Mary University of London, who was not involved in the work, the concept stands out because it treats cancer as more than a target for biology alone.

“It’s a completely new concept,” Sui said. “It’s really tackling a medical problem from a physical point of view. I think it’s highly promising.”

The researchers now plan to test the approach across a wider range of tumour types in mice. Tang said the next challenge is translation to humans.

“Then the big challenge is always going to be getting it into people,” Kam said.. Drugs that successfully target immune proteins in mice often fail in clinical settings because of differences in immune systems between species.. But he suggested that physically altering cancer cells’ stiffness could offer a more reliable starting point. since cancer cells tend to be softer in both people and mice.

The team is also working toward practicality. Alongside tumour injections of meβCD, it is developing drugs designed to produce a similar cholesterol-reducing, stiffness-altering effect, with the goal of delivering them in a single injection.

If further studies hold up, the strategy could reshape how CAR T-cell–based treatments are paired with other interventions, combining engineering of immune cells with a deliberate manipulation of the tumour’s physical landscape.

CAR T-cell therapy melanoma immunotherapy tumor stiffness IL-15 cholesterol meβCD