A new approach to T-cell engineering may help overcome one of cancer immunotherapy’s greatest challenges: enabling immune cells to effectively target and destroy solid tumours. While T-cell-based therapies have already revolutionized treatment for blood cancers, their success has been limited in solid tumours due to the suppressive tumour microenvironment and the scarcity of suitable antigens.
Researchers have developed a new strategy that allows engineered T cells to recognize and respond to a single tumour antigen through two coordinated mechanisms. The key lies in combining a conventional T-cell receptor (TCR) with a specially designed chimeric costimulatory receptor (CCR) that also binds to the same antigen, creating a dual-targeting system that strengthens cell activation and function.
Dual Targeting of BTN3A
The team applied this strategy to the stress ligand BTN3A, a molecule widely found on many solid tumours. Using structural modelling, alanine scanning, and antibody screening, they identified a BTN3A-specific CCR, known as 103-4-1BB, that binds to a different part of BTN3A than the γ9δ2 T-cell receptor. This separation of binding sites allows both receptors to engage BTN3A simultaneously, triggering a stronger immune response.
Experiments showed that this dual engagement enhanced T-cell activation, proliferation, and tumour-killing ability. The extracellular portion of 103-4-1BB helped stabilize interactions between T cells and tumour cells, improving the sensitivity of the γ9δ2TCR, while its intracellular signalling domain promoted cell fitness and sustained tumour control in animal models.
Toward a Versatile Immunotherapy Platform
Interestingly, when the CCR bound to BTN3A on the engineered T cell itself, it enhanced survival even without tumour cells present. However, interaction with BTN3A on tumour cells was essential for infiltration, clearance, and long-term immune memory.
The researchers say this design provides a blueprint for developing new cis/trans-active CCRs that strengthen T-cell performance while maintaining specificity for a single tumour antigen. The approach could open the door to more effective, broadly applicable treatments for solid cancers that have so far resisted immune-based therapies.
Reference
Hernández-López P et al. Cis- and trans-binding chimeric costimulatory receptors enhance T-cell fitness and tumor control. Cellular & Molecular Immunology. 2025;
https://doi.org/10.1038/s41423-025-01373-9.
