Fas and TRAIL death receptor signaling system (Fas/TRAIL-DR)

The interaction between Fas ligand (FasL) and TRAIL on cytokine-induced killer (CIK) cells with their respective receptors (Fas, DR4, and DR5) on tumor cells represents a critical mechanism of the extrinsic apoptosis pathway (Schmidt-Wolf et al., 2011; PMID: 21833595). CIK cells are a heterogeneous population of effector lymphocytes, primarily CD3+CD56+ T cells, that exhibit potent non-MHC-restricted cytotoxicity against various malignancies (Jakob et al., 2003; PMID: 12692730). Upon binding, these ligands induce the trimerization of death receptors on the target cell surface, recruiting adapter proteins like FADD to form the death-inducing signaling complex (DISC) (UniProt P25445). This process triggers a proteolytic cascade involving Caspase-8 and Caspase-3, ultimately leading to programmed cell death of the tumor cell (Pitti et al., 1996; PMID: 8646770). While therapeutically promising, targeting this system faces challenges such as tumor-acquired resistance through decoy receptors or intracellular inhibitors like c-FLIP, and historical concerns regarding systemic toxicity (Thorburn, 2004; PMID: 15155836). CIK cell therapy aims to harness this pathway to provide a targeted yet broad-spectrum anti-tumor response, often in combination with other treatments to overcome resistance mechanisms.

Other names

Extrinsic apoptosis pathwayDeath receptor pathwayFasL-Fas/TRAIL-DR4/DR5 axisCIK cell cytotoxic pathwayApo2L/TRAIL signaling

Activation of the extrinsic apoptotic pathway via ligand-induced trimerization of death receptors (Fas, DR4, DR5), leading to the formation of the death-inducing signaling complex (DISC) and subsequent caspase activation (Thorburn, 2004; PMID: 15155836).