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Research Article: Dual inhibition of CSF-1R and IDO modulates the fibrotic and immunosuppressive tumor microenvironment in pancreatic ductal adenocarcinoma

Date Published: 2026-07-15

Abstract:
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-? 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, ?-SMA, TGF-?1, and CSF-1R expression relative to Pan02 tumors. In high fibrotic, CSF1R High KPC4662.5 tumors, dual targeting of CSF-1R and the immunosuppressive molecule indoleamine 2,3-dioxygenase (IDO), via PLX3397 and IDO-targeting Salmonella , respectively, significantly reduced tumor burden but showed no combination advantage in CSF1R Low 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.

Introduction:
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies among solid tumors with a current 5-year survival rate of ~13%. It constitutes 90% of all pancreatic tumors and is projected to become the second leading cause of cancer-related death by 2030 ( 1 ). PDAC is characterized by a desmoplastic (or fibrotic) stroma which negatively affects prognosis. The fibrotic stroma, which can account for up to 90% of the tumor volume, is primarily composed of extracellular matrix (ECM) rich in…

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