Researchers Discover New Way To Wake Up Cancer-Killing T Cells

A new multi-pronged antibody design could help immune cells receive stronger activation signals against cancer.

Researchers at the University of Southampton have identified a new strategy that could strengthen how the immune system responds to cancer.

Reporting their findings in Nature Communications, the scientists describe the use of specially engineered antibodies designed to more effectively switch on T cells that are capable of destroying cancer cells.

These antibodies act by ‘grabbing’ and ‘clustering’ several immune cell receptors at once, increasing the strength of the signal that instructs T cells to attack tumors.

The work was led by a team at the University of Southampton’s Centre for Cancer Immunology and focused on an immune receptor known as CD27. To activate T cells, CD27 requires a specific matching key (ligand). This ligand is naturally produced during infections, but it is largely absent in cancer. Without this signal, T cells are only weakly activated and struggle to mount an effective response against cancer cells.

Limits of Conventional Antibodies

Antibodies can function like a master key by binding to immune receptors, but most antibodies used in current treatments have a Y-shaped structure with only two binding points. This limits them to engaging just two receptors at the same time.

Although antibody therapies have transformed cancer care, they are not effective for all patients. In many cases, T cells fail to receive the full set of activation signals needed to become fully functional.

To address this, the researchers created antibodies with four binding points, enabling them to attach to a greater number of receptors. These antibodies also recruit a second cell, which forces the bound CD27 receptors to cluster together. This process strengthens the activation signal and closely replicates how CD27 is triggered naturally within the body.

Professor Aymen Al‑Shamkhani at the University of Southampton, who led the study, explains: “We already understood how the body’s natural CD27 signal switches on T cells, but turning that knowledge into a medicine was the real challenge. Antibodies are reliable molecules that make excellent drugs. However, the natural antibody format was not powerful enough, so we had to create a more effective version.”

Stronger Anti-Tumor Responses

In lab studies using mice as well as human immune cells, the new antibodies were more effective in switching on CD8⁺ T cells – the ‘special forces’ of the immune system, than standard Y-shaped antibodies, delivering a more robust antitumor response.

By making CD27 more responsive to therapeutic targeting, the findings provide a blueprint for developing next‑generation immunotherapies that harness the immune system to fight cancer more effectively.

Professor Al‑Shamkhani said: “This approach could help improve future cancer treatments by allowing the immune system to work closer to its full potential.”

Reference: “Harnessing multivalency and FcγRIIB engagement to augment anti-CD27 immunotherapy” by Marcus A. Widdess, Anastasia Pakidi, Hannah J. Metcalfe, H. T. Claude Chan, Tatyana Inzhelevskaya, Chris A. Penfold, C. Ian Mockridge, Steven G. Booth, Sonya James, Sean H. Lim, Stephen A. Beers, Mark S. Cragg and Aymen Al-Shamkhani, 20 December 2025, Nature Communications.
DOI: 10.1038/s41467-025-67882-3

The research was funded by Cancer Research UK and highlights the Centre for Cancer Immunology’s role in advancing innovative cancer immunotherapies.

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