{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:20:37Z","timestamp":1792790437100,"version":"4.5.0"},"posted":{"date-parts":[[2026,10,2]]},"group-title":"Immunology","reference-count":57,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T00:00:00Z","timestamp":1790899200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIGMS","award":["T32 GM133364"],"award-info":[{"award-number":["T32 GM133364"]}],"id":[{"id":"https:\/\/ror.org\/04q48ey07","id-type":"ROR","asserted-by":"crossref"}]},{"name":"American Society of Hematology","id":[{"id":"https:\/\/ror.org\/02nw48b86","id-type":"ROR","asserted-by":"crossref"}]},{"name":"James and Jesse Millis Distinguished Professorship of Surgery"},{"name":"NCI","award":["R01CA236910"],"award-info":[{"award-number":["R01CA236910"]}]},{"name":"NCI","award":["R37CA251877"],"award-info":[{"award-number":["R37CA251877"]}]},{"name":"NCI","award":["P50CA257911"],"award-info":[{"award-number":["P50CA257911"]}]},{"name":"Pancreatic Cancer Action Network","award":["22-WG-DERB"],"award-info":[{"award-number":["22-WG-DERB"]}],"id":[{"id":"https:\/\/ror.org\/03t5n9b81","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Burroughs Wellcome Fund","award":["Career Award for Medical Scientists"],"award-info":[{"award-number":["Career Award for Medical Scientists"]}],"id":[{"id":"https:\/\/ror.org\/01d35cw23","id-type":"ROR","asserted-by":"crossref"}]},{"name":"NIH","award":["K08CA248960"],"award-info":[{"award-number":["K08CA248960"]}]},{"name":"V Foundation for Cancer Research","award":["V Scholar Award"],"award-info":[{"award-number":["V Scholar Award"]}],"id":[{"id":"https:\/\/ror.org\/00kbbk236","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Melanoma Research Alliance","award":["Young Investigator Award"],"award-info":[{"award-number":["Young Investigator Award"]}],"id":[{"id":"https:\/\/ror.org\/025ck6r46","id-type":"ROR","asserted-by":"crossref"}]},{"name":"University Cancer Research Fund"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,10,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Tumor-associated macrophages (TAMs) promote tumor growth, inhibit effector lymphocytes, and induce resistance to immune checkpoint inhibitors (ICI). Therapies designed to deplete TAMs have had little success in the clinic, and strategies aimed to repolarize immunosuppressive TAMs to pro-inflammatory states have struggled with systemic toxicity. We have identified that the combination of low folate in the tumor microenvironment and TAM dependency on the high affinity folate receptor beta (FR\u03b2) for folate uptake results in a unique metabolic dependency of TAMs necessary for their immunosuppressive function. FR\u03b2 (encoded by\n                  <jats:italic>Folr2<\/jats:italic>\n                  ) is uniquely expressed on myeloid cells and upregulated on TAMs. FR\u03b2+ TAMs exhibit an immunosuppressive phenotype in melanoma and are associated with worse clinical outcomes and resistance to ICI in melanoma patients. We generated a novel\n                  <jats:italic>\n                    Folr2\n                    <jats:sup>-\/-<\/jats:sup>\n                  <\/jats:italic>\n                  mouse model to study why TAMs express a unique folate receptor and showed that tumor growth was slowed in the absence of\n                  <jats:italic>Folr2<\/jats:italic>\n                  in a T-cell dependent manner. We observed a dramatic repolarization of\n                  <jats:italic>\n                    Folr2\n                    <jats:sup>-\/-<\/jats:sup>\n                  <\/jats:italic>\n                  TAMs\n                  <jats:italic>in vivo<\/jats:italic>\n                  to pro-inflammatory states, resulting in increased cytotoxic T cell and NK cell infiltration into tumors. Importantly, we show that folate is low in the tumor microenvironment by performing metabolomics on melanoma tumors and adjacent normal tissue from warm autopsy patient specimens, and that we could increase tumor growth in\n                  <jats:italic>\n                    Folr2\n                    <jats:sup>-\/-<\/jats:sup>\n                  <\/jats:italic>\n                  mice by increasing serum folate to supraphysiologic concentrations with a high folate diet. Integrated metabolomics and transcriptomic analysis demonstrated that\n                  <jats:italic>\n                    Folr2\n                    <jats:sup>-\/-<\/jats:sup>\n                  <\/jats:italic>\n                  macrophages have impaired folate uptake and 1C metabolism-based reduction of oxidized glutathione in low folate conditions, resulting in increased mitochondrial reactive oxygen species (ROS) in\n                  <jats:italic>\n                    Folr2\n                    <jats:sup>-\/-<\/jats:sup>\n                  <\/jats:italic>\n                  cells. Excess ROS results in leakage of mitochondrial DNA into the cytoplasm, activating cGAS-STING signaling and promoting pro-inflammatory macrophage polarization through TBK1 and NF-kB. Together, our data demonstrate that TAM expression of FR\u03b2 promotes their immunosuppressive functions by maintaining folate uptake in the low folate tumor microenvironment, suggesting that FR\u03b2 is a novel metabolic checkpoint on TAMs.\n                <\/jats:p>","DOI":"10.64898\/2026.09.29.755523","type":"posted-content","created":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T17:00:12Z","timestamp":1790960412000},"source":"Crossref","is-referenced-by-count":0,"title":["Folate metabolism in tumor-associated macrophages drives immunosuppressive function to promote tumor growth"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2979-9624","authenticated-orcid":false,"given":"Matthew P.","family":"Zimmerman","sequence":"first","affiliation":[{"name":"Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514"},{"name":"Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, 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