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Programmable synthetic cytokine receptors polarize macrophages to user-defined functional states

ABSTRACT: Macrophage-based immunotherapies hold promise for cancer and other diseases, but lack of methods to precisely control macrophage polarization limits both mechanistic understanding and therapeutic applications. Here, we use a programmable synthetic cytokine receptor (SCR) platform to control primary human macrophage polarization. SCRs containing signaling motifs from the interferon-gamma (IFN-γ) or Interleukin-10 (IL-10) receptors are sufficient to mimic pro-inflammatory or anti-inflammatory polarization, respectively. Combinatorial assembly of nine distinct signaling motifs within the SCR signaling domain generates a diverse landscape of synthetic macrophage states with varied expression of inflammatory markers (CD80, CD40, PDL1), anti-inflammatory markers (CD163, CD206) and phagocytic capacity. SCRs programmed with multiple YxxQ motifs drive macrophage phagocytosis of E. coli and chimeric antigen receptor (CAR)-macrophage phagocytosis of cancer cells in mice, reducing tumor burden by 30-fold. Quantitative analysis reveals that motif-dependent polarization follows a two-state equilibrium model, enabling rational prediction of macrophage polarization state from SCR composition. Leveraging this framework, we design SCRs that simultaneously enhance phagocytosis and maintain pro-inflammatory function. Together, these findings establish a framework to synthetically program macrophage polarization states with potential applications in cancer immunotherapy and other disease contexts.

ORGANISM(S): Homo sapiens

PROVIDER: GSE328683 | GEO | 2026/08/05

REPOSITORIES: GEO

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Project description:Osteonecrosis (ON) of the femoral head (ONFH) is a devastating bone disease affecting over 20 million people worldwide. ONFH is caused by a disruption of blood supply, leading to necrotic cell death and increased inflammation. Macrophages are the key cells mediating the inflamma-tory responses in ON. It is unclear what are the dynamic phenotypes of macrophages, and what mechanisms may affect macrophage polarization and therefore the healing process. In our pre-liminary study, we found that there is an invasion of macrophages in the repair tissue during ON healing. Interestingly, in both ONFH patient and the mouse ON model, fat was co-labeled within macrophages using immunofluorescence staining, indicating phagocytosis of fat by mac-rophages. To study the effects of fat phagocytosis on macrophage phenotype, we set up an in vitro macrophage and fat co-culture system. We found that fat phagocytosis significantly de-creased M1 markers expression such as IL1β and iNOS in macrophages. Whereas the expression of M2 marker Arg1 was significantly increased with fat phagocytosis. To investigate if the polar-ization change is indeed mediated by phagocytosis, we treated the cells with Latrunculin A (LA, a phagocytosis inhibitor). LA supplement significantly reversed the polarization marker gene changes induced by fat phagocytosis. To provide an unbiased transcriptional gene analysis, we submitted the RNA for bulk RNA sequencing. Differential gene expression (DGE) analysis re-vealed top up-regulated genes were related to anti-inflammatory responses, while pro-inflammatory genes were significantly downregulated. Additionally, using the pathway en-richment and network analyses (Metascape), we confirmed that gene enriched categories related to pro-inflammatory responses were significantly downregulated in macrophages with fat phagocytosis. Finally, we validated the similar macrophage phenotype changes in vivo. To sum-marize, we discovered that fat phagocytosis occurs in both ONFH patients and the mouse ON model, which inhibits pro-inflammatory responses with increased anabolic gene expressions of macrophages. This fat phagocytosis induced macrophage phenotype is consistent with the in vivo changes shown in the ON mice model. Our study reveals a novel phagocytosis mediated macro-phage polarization mechanism in ON, which fills in our knowledge gaps of macrophage func-tions and provides new concepts in macrophage immunomodulation as a promising treatment for ON.

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Programmable synthetic cytokine receptors polarize macrophages to user-defined functional states

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