{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:15:41Z","timestamp":1785413741742,"version":"3.56.0"},"posted":{"date-parts":[[2026,7,15]]},"group-title":"Cancer Biology","reference-count":57,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T00:00:00Z","timestamp":1784073600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["R01CA167426"],"award-info":[{"award-number":["R01CA167426"]}],"id":[{"id":"https:\/\/ror.org\/040gcmg81","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,15]]},"abstract":"<jats:p>\n                  Macrophages are innate immune cells of embryonic or adult origin with tissue specific roles in homeostasis, disease surveillance, and wound repair that can be co-opted to promote tumor growth and spread\n                  <jats:sup>1\u201311<\/jats:sup>\n                  . An understanding of the specific roles of macrophage subsets in lung tumor initiation and progression could promote new therapeutic approaches for this deadly disease. Here, we show that KRAS\n                  <jats:sup>G12D<\/jats:sup>\n                  mutations in lung epithelium drive proliferation of resident, embryonically-derived alveolar macrophages, which then promote tumor cell proliferation and protection from ferroptosis, leading to tumor progression. Using genetically engineered mouse models of mutant KRAS\n                  <jats:sup>G12D<\/jats:sup>\n                  non-small cell lung cancer\n                  <jats:sup>12,13<\/jats:sup>\n                  , we found that alveolar macrophages accumulate by proliferation in response to tumor cell-secreted IL-34, recapitulating events observed in late embryonic lung development. Tumor alveolar macrophages in turn drive IGF-1-dependent tumor cell proliferation. Neutralization or deletion of IL-34 suppresses IGF-1 expression, reduces macrophage and tumor cell proliferation and inhibits tumor progression. High\n                  <jats:italic>IL34<\/jats:italic>\n                  and\n                  <jats:italic>IGF1<\/jats:italic>\n                  correlate with poor survival in KRAS\n                  <jats:sup>G12D\/V<\/jats:sup>\n                  lung adenocarcinomas and in other solid tumors, indicating that bi-directional proliferative signaling between resident macrophages and tumor cells can drive human lung tumor progression. These studies identify resident macrophage-tumor cell interactions as key interception points for lung cancer therapy.\n                <\/jats:p>","DOI":"10.64898\/2026.07.14.738492","type":"posted-content","created":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T14:50:12Z","timestamp":1784127012000},"source":"Crossref","is-referenced-by-count":0,"title":["An IL-34\u2013IGF-1 inflammatory axis fuels KRAS-mutant lung cancer progression"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8135-856X","authenticated-orcid":false,"given":"Jaroslav","family":"Zak","sequence":"first","affiliation":[{"name":"Department of Radiation Oncology, and Department of Internal Medicine Division of Hematology and Hematologic Malignancies, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Chen","sequence":"additional","affiliation":[{"name":"Moores Cancer Center, University of California, San Diego, La Jolla, CA"},{"name":"Department of Pathology, University of California, San Diego, La Jolla, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erpei","family":"Wang","sequence":"additional","affiliation":[{"name":"Moores Cancer Center, University of California, San Diego, La Jolla, CA"},{"name":"Department of Pathology, University of California, San Diego, La Jolla, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Ozark","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, and Department of Internal Medicine Division of Hematology and Hematologic Malignancies, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuliana","family":"Mognol","sequence":"additional","affiliation":[{"name":"Moores Cancer Center, University of California, San Diego, La Jolla, CA"},{"name":"Department of Pathology, 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