Transforming growth factor-beta chimeric receptor (TGFβ-CSR) (TGFβ-CSR)

The Transforming growth factor-beta (TGFβ) chimeric receptor module is a synthetic protein construct engineered to reprogram the immune system's response to TGFβ, a potent immunosuppressive cytokine prevalent in the tumor microenvironment. In many solid tumors, high levels of TGFβ typically inhibit T-cell activity and promote exhaustion by signaling through endogenous TGFβ receptors and activating the inhibitory SMAD pathway (Schlenker et al., 2022). The chimeric module, often referred to as a chimeric switch receptor (CSR), consists of the extracellular ligand-binding domain of a TGFβ receptor (most commonly TGFβRII) fused to the intracellular signaling domains of stimulatory molecules like 4-1BB, CD28, or cytokine receptors such as IL-7R or IL-12R (Golumba-Nagy et al., 2018). When this module binds to TGFβ, it triggers an activating signal instead of an inhibitory one, effectively "flipping the switch" to promote T-cell proliferation, survival, and effector function (Chang et al., 2018). This technology is primarily integrated into adoptive cell therapies, such as CAR-T or TCR-T cells, to enhance their performance against TGFβ-secreting solid tumors like glioblastoma and pancreatic cancer. Companies like Lyell Immunopharma are actively developing these modules (e.g., cTBR) to improve the durability and efficacy of cell therapies in hostile immune environments (Lyell, 2024).

Other names

Chimeric TGF-beta receptorcTBRTGF-beta chimeric switch receptorTGFβ-IL-7 receptor fusionTGFβ-4-1BB fusionTGFβ-IL-12 chimeric receptorTGFβ-dominant negative receptor module

Converts inhibitory TGF-beta signaling into stimulatory intracellular signals by fusing the extracellular ligand-binding domain of a TGF-beta receptor to stimulatory signaling endodomains such as 4-1BB, CD28, or cytokine receptor chains (e.g., IL-7R, IL-12R).