Unlocking macrophage engineering and therapies with synthetic polarization circuits
Embargo Date
2026-06-08
OA Version
Citation
Abstract
Macrophages are versatile immune cells capable of diverse functions, enabled by unique cellular properties such as inflammation scavenging, phagocytosis capability, and perhaps most interesting, their unparallel phenotype plasticity. In response to extracellular signals, macrophages activate distinctive functional programs and differentiate into two general subtypes: classically activated macrophages (M1) and alternatively activated macrophages (M2). M1 macrophages promote inflammation and show anti-tumor activity in synergy with T cells, while M2 macrophages play a vital role in wound healing and treating anti-inflammatory diseases. While macrophage phenotypic plasticity is essential for maintaining tissue homeostasis, in pathological contexts such as cancer, microenvironmental signals often skew macrophages towards phenotypes that exacerbate disease progression. Therefore, the ability to precisely control macrophage activation states in vivo could unlock new therapeutic strategies to restore immune function and halt disease mechanisms.To leverage the diverse immune functions of macrophages—in both immune environments and pathological contexts, we developed a synthetic system for inducible macrophages polarization combining three synergistic innovations: (1) engineered STAT effector proteins that can robustly drive constitutive and sustained macrophage polarization to M1 or M2 state, independent of cytokine induction. (2) synZiFTRs 2.0, an optimized human gene regulation toolkit built upon our previous work, enabling drug-inducible and enhanced transgene expression with minimal basal activity; and (3) monocyte-targeting nanoparticles for cell-specific delivery of synZiFTR induction agents. Central to this advance is the discovery of the IWS1 TIMs domain as a potent transcriptional synergizer, which enhances human transcriptional activators like p65 through stimulating transcriptional elongation, without compromising safety or inducibility. This work establishes a generalizable framework for macrophage reprogramming with spatiotemporal precision, offering a tunable and clinically translatable approach for diverse applications. By decoupling polarization cues from local signals and integrating polarization effectors with synthetic gene regulation switches, our platform allows robust macrophage polarization against microenvironmental inferences while minimizing off-target effects. These advances not only provide new tools for macrophage-based therapies but also illuminate broader principles for engineering immune cell behavior in therapeutic contexts.
Description
2025