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

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-β 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, α-SMA, TGF-β1, and CSF-1R expression relative to Pan02 tumors. In high fibrotic, CSF1RHigh 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 CSF1RLow 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.