{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T07:05:37Z","timestamp":1784099137335,"version":"3.55.0"},"reference-count":51,"publisher":"Frontiers Media SA","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:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Pancreatic ductal adenocarcinoma (PDAC), one of the most aggressive forms of solid tumors, is characterized by extensive fibrosis and an immunosuppressive tumor microenvironment (TME) that limits therapeutic efficacy. Tumor-associated macrophages (TAMs), especially those with a pro-tumor, M2-like phenotype, contribute to immune evasion and fibrosis via TGF-\u03b2 signaling and CSF-1R-mediated recruitment. Using two orthotopic PDAC models that differ in stromal composition and baseline CSF-1R expression (KPC4662.5 and Pan02), we evaluated whether therapeutic response to macrophage-targeting strategies is context dependent. Consistent with established studies, highly fibrotic KPC4662.5 tumors exhibited elevated Arg1, \u03b1-SMA, TGF-\u03b21, and CSF-1R expression relative to Pan02 tumors. In high fibrotic, CSF1R\n                    <jats:sup>High<\/jats:sup>\n                    KPC4662.5 tumors, dual targeting of CSF-1R and the immunosuppressive molecule indoleamine 2,3-dioxygenase (IDO), via PLX3397 and IDO-targeting\n                    <jats:italic>Salmonella<\/jats:italic>\n                    , respectively, significantly reduced tumor burden but showed no combination advantage in CSF1R\n                    <jats:sup>Low<\/jats:sup>\n                    tumors. The lack of therapeutic efficacy with CSF-1R inhibitor monotherapy in PDAC models has previously been attributed to polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) infiltration following treatment. This combination therapy altered intratumoral immune cell composition by decreasing PMN-MDSCs and increasing effector T cell subsets. These findings identify tumor fibrosis and CSF-1R expression as potential biomarkers of response to combined CSF-1R and IDO inhibition and support biomarker-guided immunotherapeutic strategies in PDAC.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1792483","type":"journal-article","created":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T06:10:37Z","timestamp":1784095837000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Dual inhibition of CSF-1R and IDO modulates the fibrotic and immunosuppressive tumor microenvironment in pancreatic ductal adenocarcinoma"],"prefix":"10.3389","volume":"17","author":[{"given":"Lara C.","family":"Avsharian","sequence":"first","affiliation":[{"name":"Department of Immuno-Oncology, Beckman Research Institute of City of Hope","place":["Duarte, CA, United States"]},{"name":"Irell and Manella Graduate School of Biological Sciences, City of Hope","place":["Duarte, CA, 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