IFNα-induced BST2+ tumor-associated macrophages facilitate immunosuppression and tumor growth in pancreatic cancer by ERK-CXCL7 signaling

Pancreatic ductal adenocarcinoma (PDAC) features an immunosuppressive tumor microenvironment (TME) that resists immunotherapy. Tumor-associated macrophages, abundant in the TME, modulate T cell responses. Bone marrow stromal antigen 2-positive (BST2⁺) macrophages increase in Kras^G12D/+; Trp53^R172H/+; Pdx1-Cre mouse models during PDAC progression. However, their role in PDAC remains elusive. Our findings reveal a negative correlation between BST2⁺ macrophage levels and PDAC patient prognosis. Moreover, an increased ratio of exhausted CD8⁺ T cells is observed in tumors with up-regulated BST2⁺ macrophages. Mechanistically, BST2⁺ macrophages secrete CXCL7 through the ERK pathway and bind with CXCR2 to activate the AKT/mTOR pathway, promoting CD8⁺ T cell exhaustion. The combined blockade of CXCL7 and programmed death-ligand 1 successfully decelerates tumor growth. Additionally, cGAS-STING pathway activation in macrophages induces interferon (IFN)α synthesis leading to BST2 overexpression in the PDAC TME. This study provides insights into IFNα-induced BST2⁺ macrophages driving an immune-suppressive TME through ERK-CXCL7 signaling to regulate CD8⁺ T cell exhaustion in PDAC.