Synthetic rapamycin-activated cytokine receptor (S-RACR) (S-RACR)

The Synthetic rapamycin-activated cytokine receptor (S-RACR) is an engineered signaling platform designed to provide precise, drug-inducible control over the survival and expansion of adoptive cell therapies, particularly iPSC-derived cytotoxic innate lymphoid cells (ILCs) and NK cells [1]. The receptor system typically utilizes a split-receptor design where the intracellular signaling domains of cytokine receptors, such as the IL-2 receptor beta chain and the common gamma chain, are fused to dimerization domains (FKBP and FRB) [2]. Upon administration of rapamycin, these domains are brought together, mimicking the natural assembly of a cytokine-receptor complex and activating the JAK/STAT5 pathway without the need for exogenous cytokines like IL-2 or IL-15 [3]. This approach addresses a major challenge in cell therapy: the rapid exhaustion or death of therapeutic cells in the nutrient-poor and cytokine-depleted tumor microenvironment [1]. By using a clinically approved small molecule like rapamycin as a switch, clinicians can potentially tune the persistence and potency of the engineered cells in vivo while avoiding the systemic toxicities associated with high-dose cytokine infusions [2][3].

Other names

Rapamycin-activated cytokine receptorRapamycin-inducible cytokine receptorS-RACRRapamycin-controlled cytokine signaling system

Rapamycin acts as a chemical inducer of dimerization (CID), bridging the FKBP and FRB domains of the synthetic receptor to trigger intracellular cytokine signaling (e.g., IL-2 or IL-15 pathways) via STAT5 phosphorylation [1][2].