🧬 The M1/M2 macrophage paradigm is no longer sufficient. What comes next? A new Immunity Perspective by Ginhoux, Mulder, Arcila-Barrera, and Amit proposes a major conceptual shift: Macrophages should be defined by combinations of functional gene programs—not binary polarization states or individual markers. 🔬 1. Macrophage identity is modular The authors propose eight recurring transcriptional programs: ① Homeostasis: LYVE1, TIMD4, MRC1 ② Scavenger/lipid handling: TREM2, APOE, GPNMB, SPP1 ③ Fibrosis/remodeling: SPP1, MMP9, TGFB1 ④ Immunosuppression: IL10, IDO1, CD274 ⑤ Antigen presentation: HLA-DRA, CD74, CIITA ⑥ Interferon response: CXCL9, CXCL10, STAT1 ⑦ Inflammation: NLRP3, IL1B, TNF ⑧ Monocyte recruitment/transition: CCR2, FCN1, S100A8 A ninth category accommodates previously unrecognized programs. Crucially, individual macrophages can activate several programs simultaneously. 🧠 2. The same marker can indicate opposite biological functions TREM2 illustrates this paradox. In Alzheimer's disease, TREM2-associated microglial programs may support lipid handling, debris clearance, and tissue protection. In obesity, related macrophage programs can contribute to metabolic adaptation. However, in tumors, TREM2/SPP1-associated macrophages may promote immunosuppression, fibrosis, and treatment resistance. TREM2 expression alone does not define macrophage function. ⚡ 3. Why macrophage-targeted therapies sometimes fail Clinical experience demonstrates the limitations of single-target approaches. • CSF1R inhibition has shown activity in tenosynovial giant cell tumors but limited efficacy in glioblastoma. • Anti-TREM2 antibody PY314 demonstrated minimal antitumor activity in a phase 1a ovarian cancer study. • Anti-CD47 antibody magrolimab failed to improve survival in phase 3 AML trials. These outcomes highlight the importance of compensatory immune programs and tissue-specific biology. 💊 4. From macrophage depletion to functional reprogramming The authors highlight emerging therapeutic strategies: TREM2-targeted immunocytokines: Combine macrophage targeting with tumor-localized activation of a masked IL-2 superkine. Armored CAR-T cells: Target suppressive TREM2⁺ or FOLR2⁺ macrophages while restricting IL-12 secretion to the tumor environment. CAR-macrophages: Engineer macrophages to enhance tumor phagocytosis and remodel local immunity. In vivo myeloid engineering: Use delivery platforms to introduce therapeutic programs into macrophages. These approaches aim to modify entire immune ecosystems rather than simply eliminate marker-positive cells. 🔍 5. A new framework for macrophage drug discovery The proposed therapeutic logic is: Single-cell profiling → Functional module scoring → Regulatory network identification → Surface-accessible targeting → Spatially restricted reprogramming This framework could be particularly valuable in cancer, fibrosis, obesity, and neurodegeneration. However, transcriptional modules remain working classifications, and experimental perturbation is necessary to establish causal functions. 💡 The broader implication Macrophage plasticity is both a therapeutic challenge and an opportunity. A macrophage population beneficial during acute tissue repair may become pathogenic when the same program persists chronically. Future therapies must therefore consider cellular origin, tissue location, disease stage, regulatory state, and treatment timing. The next frontier in immunotherapy is not simply targeting macrophages—it is programming the right macrophage functions, in the right tissue, at the right time. 📄 Ginhoux F, Mulder K, Arcila-Barrera S, Amit I. Embracing macrophage complexity for research and translation. Immunity. 2026. Perspective. DOI: doi.org/10.1016/j.immuni.202… #Macrophages #Immunology #Immunotherapy #TREM2 #SPP1 #TumorMicroenvironment #SingleCellRNAseq #CARMacrophages #SyntheticImmunology #CancerResearch #DrugDiscovery