Cytotoxic T cells (CTLs) become dysfunctional in the tumor microenvironment (TME) for a variety of reasons. These include an abundance of inhibitory factors in the TME and a paucity of stimulatory ones, such as cytokines. Researchers led by Ludwig Lausanne’s Patrick Barth and Caroline Arber reported in an October publication in Nature Biomedical Engineering a computational platform that addresses these challenges through the design of co-stimulatory cell-surface receptors that can be engineered into T cells or CAR-T cells used for adoptive cell therapies to enhance their anti-tumor efficacy. Called T-SenSERs (for TME-sensing switch receptors), the synthetic receptors are built by mixing and matching functional protein domains so that they convert the signals transmitted by factors abundant in the TME into co-stimulatory signals known to boost T cell function. The researchers demonstrated the utility of their platform by engineering T-SenSERs that bind either vascular endothelial growth factor or colony-stimulating factor-1, which both promote tumor growth and are selectively enriched in a variety of tumors. CAR-T cells equipped with these engineered receptors, which transmit a signal that boosts T cell proliferation and cytotoxicity when activated, showed enhanced anti-tumor activity in models of lung cancer and multiple myeloma.
Computational design of synthetic receptors with programmable signalling activity for enhanced cancer T cell therapy
Nature Biomedical Engineering, 2025 October 28