ÌìÃÀ´«Ã½

A new study has uncovered how a class of cancer drugs called immune engagers can boost the body’s defences.

shows how a promising class of cancer medicines, known as immune engagers, reorganise immune cells’ surface receptors at the tiniest scales to help it fight tumours more effectively.

"The most exciting part is that we can actually see, at the tiniest scale, how this new medicine restructures the immune cells' surface receptors to fight cancer more effectively. It opens the door to designing even more powerful treatments." Dr Khodor Hazime

The research, led by ' lab in Imperial’s Department of Life Sciences in collaboration with  (led by ), the and the used cutting-edge super-resolution microscopy to show how a next-generation engager brings two key receptors on natural killer (NK) cells into close proximity. This nanoscale restructuring acts like a “signal booster”, amplifying the cells’ ability to kill cancer, including in samples taken directly from patients with acute myeloid leukaemia (AML).

First author from the Department of Life Sciences, said: ‘For me, the most exciting part is that we can actually see, at the tiniest scale, how this new medicine restructures the immune cells' surface receptors to fight cancer more effectively. It’s a completely new way of understanding how these therapies work, and it opens the door to designing even more powerful treatments.’

Receptors at nanoscale

Immune engagers are antibody-based drugs designed to guide immune cells to tumours. Some next-generation engagers target not just one, but two activating receptors at once. Until now, it was unclear how this affected immune cell organisation and function.

The team used super-resolution microscopy (dSTORM) to visualise how engaging NK cell receptors CD16a and NKG2D with a single molecule caused them to cluster together tightly on the cell surface.

This nanoscale rearrangement triggered stronger activation signals inside NK cells, boosting their ability to secrete anti-cancer molecules, like cytokines, and destroy tumour cells.

Crucially, the researchers confirmed this effect not only in human cancer cell lines and NK cells from healthy donors, but also in NK cells taken directly from the blood and bone marrow of AML patients.

Importantly, when the same two receptors were engaged separately, this effect was not seen, instead the power-up only happened when both were pulled together by the same engager.

Towards better therapies

NK cells are critical for immune defence, but cancers like AML often evade or blunt their activity. By forcing NK cells into a “more potent” state, engager therapies could offer new hope for patients whose cancers resist standard treatments.

Dr Hazime said: ‘NK cells make decisions based on how their receptors are arranged, not just which ones are present. By changing the nanoscale organisation, this medicine effectively tunes the immune cell’s engine to run at higher power.’

lThe engager studied here (CC-96191) is part of Bristol Myers Squibb’s development pipeline, and the team’s mechanistic insights could help guide its optimisation toward patient trials. Their findings also suggest that future engagers could be deliberately designed to bring the most effective receptor pairs together on immune cells, offering a blueprint for even more powerful therapies.