The administration of anti-inflammatory macrophages has been proposed as an approach to reduce tissue injury in response to inflammation; however, this approach is limited by the instability of macrophages and their potential to switch to a pro-inflammatory phenotype. To overcome these limitations, researchers have now developed a chimeric antigen receptor (CAR) macrophage (CAR-M) that demonstrates anti-inflammatory functions in response to a pro-inflammatory stimulus. “Our approach demonstrates the potential to improve the therapeutic efficacy of immune cells while maintaining a stable and desired phenotype within the inflammatory microenvironment,” states lead author, Qi Cao.

Cao and colleagues engineered their CAR construct with an extracellular, anti-TNF single-chain fragment variable (scFv) linked to the intracellular domain of IL-4Rα, such that binding of the anti-TNF scFv to TNF triggered a signal switch to initiate an anti-inflammatory response. “A key innovation of our CAR methodology is the development of a novel chimeric signalling switch receptor (CSSR), which is designed to harness pro-inflammatory signals to drive an anti-inflammatory phenotype within the therapeutic cell,” explains Cao. “Our CSSR approach fundamentally differs from traditional CARs in two critical ways. First, conventional CARs typically augment the existing function of a cell, whereas our CSSR actively switches the cell’s functional output. Secondly, conventional CARs are predominantly used to enhance immune responses, whereas our CSSR is specifically designed to suppress them.”