GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE328nnn/GSE328683/primary200OKTranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE328683GEOGSEfalseProgrammable synthetic cytokine receptors polarize macrophages to user-defined functional statesMacrophage-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.2026/08/05GSE328683GSM9687160GSM9687161GSM9687162GSM9687151GSM9687163GSM9687152GSM9687164GSM9687153GSM9687165GSM9687154GSM9687166GSM9687155GSM9687167GSM9687156GSM9687157GSM9687168GSM9687158GSM968715934284328683Homo sapiens[42182394]