A CSF-cytokine code predicts macrophage response polarity and tumor outcomes

A CSF-cytokine code predicts macrophage response polarity and tumor outcomes | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article A CSF-cytokine code predicts macrophage response polarity and tumor outcomes Florence Vallelian, Dominik Schaer, Nadja Schulthess-Lutz, Matthias Peterhans, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7346391/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 13 Mar, 2026 Read the published version in Communications Biology → Version 1 posted You are reading this latest preprint version Abstract Tumor-associated macrophages can either promote or suppress cancer, but current therapeutic approaches fail because we lack a predictive framework for macrophage function. The prevailing M1/M2 paradigm oversimplifies how macrophage developmental origin (ontogeny) and local cytokines interact to determine anti- versus pro-tumor responses. We systematically mapped eight reference macrophage states by differentiating mouse bone marrow cells with either M-CSF or GM-CSF, followed by polarization with four key cytokines (IFN‑γ, IL‑4, IL‑10, TGF‑β). Using integrated transcriptomics, 3D tumor spheroids, and experimental metastasis models, we discovered that macrophage ontogeny determines whether cytokines promote or suppress tumor growth. Most strikingly, IL-4 induced opposite effects: promoting tumor growth, invasion, and metastasis in M-CSF macrophages while suppressing these processes in GM-CSF macrophages. This ontogeny-dependent polarity switch also affected IL-10 responses, whereas IFN‑γ remained consistently anti-tumor and TGF‑β consistently pro-tumor across both lineages. These findings establish an "ontogeny‑cytokine code" that predicts macrophage function based on developmental origin and cytokine environment. By identifying ontogeny as a master determinant of cytokine responses, this work provides a new framework for precision cancer immunotherapy. Biological sciences/Immunology/Innate immune cells/Monocytes and macrophages/Phagocytes Biological sciences/Cancer/Tumour immunology/Immunosurveillance Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SchaeretalSuppCommBiol.pdf Supplementary Figures RS1255.pdf Reporting Summary Cite Share Download PDF Status: Published Journal Publication published 13 Mar, 2026 Read the published version in Communications Biology → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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