Transforming growth factor-beta receptor type II–4-1BB chimeric switch receptor (TGFβRII–4-1BB CSR)

The Transforming growth factor-beta receptor type II–4-1BB chimeric switch receptor (TGFβRII–4-1BB CSR) is a synthetic fusion protein engineered to enhance the potency and persistence of adoptive cell therapies, such as CAR-T and TIL therapies, within the immunosuppressive tumor microenvironment (TME) [1, 4]. In many solid tumors, TGF-beta is overexpressed and acts as a major barrier to immune cell infiltration and activity by inducing T-cell exhaustion and apoptosis [2, 4]. The TGFβRII–4-1BB CSR addresses this by coupling the extracellular ligand-binding domain of the TGF-beta receptor type II with the intracellular signaling domain of the 4-1BB (CD137) co-stimulatory molecule [1, 3]. Upon binding to TGF-beta, the receptor 'switches' the inhibitory signal into a stimulatory one, triggering 4-1BB pathways that promote T-cell metabolic fitness, survival, and effector function [3, 5]. This technology is currently being evaluated in clinical trials, notably in ROR1-targeted CAR-T cells (LYL797) and tumor-infiltrating lymphocytes (LYL845), to treat various solid malignancies [1, 6].

Other names

TGFβRII-4-1BB switch receptorTGFβRII:4-1BBTGFβ-4-1BB CSRTGFβR2-4-1BBTGFβRII-CD137 chimeric switch receptor

The receptor binds extracellular TGF-beta via its TGFβRII domain and converts the typically immunosuppressive signal into a co-stimulatory signal through its intracellular 4-1BB domain, enhancing T-cell activity and survival.