Chemically inducible signaling complex (CISC) (CISC)

The Chemically inducible signaling complex (CISC) is a synthetic biological platform designed to allow external, pharmacological control over intracellular signaling pathways within engineered cell therapies (Cook et al., 2023) [1]. It typically consists of chimeric fusion proteins incorporating drug-binding domains, such as the FK506-binding protein (FKBP) and the FKBP-rapamycin binding (FRB) domain of mTOR, linked to specific receptor signaling subunits (Molecular Therapy, 2023) [4]. When a small-molecule inducer like rapamycin or its analogs is administered, it acts as a molecular bridge to dimerize these components and trigger a downstream signaling cascade, most commonly the IL-2/STAT5 pathway (ResearchGate, 2025) [2][5]. This technology is primarily used to provide critical survival and expansion signals to engineered regulatory T cells (EngTregs), enabling them to persist and function effectively without relying on endogenous cytokines (NIH/PMC, 2023) [3]. Currently, CISC-based therapies such as GNTI-122 are being investigated for the treatment of autoimmune diseases like Type 1 diabetes, where they promote immune tolerance by ensuring the stability of therapeutic cell populations (Uenishi et al., 2024) [11]. By utilizing low, sub-immunosuppressive doses of clinically approved drugs, the CISC offers a precise method for managing the behavior of advanced cellular products in vivo (Seattle Children's, 2023) [6].

Other names

IL-2 CISCChemically induced signaling complexHeterodimeric chemically inducible signaling complexIL-2 receptor chemically inducible signaling complex

The mechanism involves the drug-induced dimerization of two or more chimeric fusion proteins, such as those combining drug-binding domains (e.g., FKBP and FRB) with cytokine receptor subunits (e.g., IL-2 receptor beta and gamma chains). When a small-molecule inducer like rapamycin binds to these domains, it brings the receptor subunits into proximity, triggering the activation of downstream signaling pathways such as the JAK/STAT5 cascade (Cook et al., 2023) [1][4]. This allows the engineered cells to receive survival and expansion signals independently of endogenous ligands (NIH/PMC, 2023) [3].