Loss of Annexin A1 in macrophages restrains efferocytosis and remodels immune microenvironment in pancreatic cancer by activating the cGAS/STING pathway

Objective Pancreatic cancer is an incurable malignant disease with extremely poor prognosis and a complex tumor microenvironment. We sought to characterize the role of Annexin A1 (ANXA1) in pancreatic cancer, including its ability to promote efferocytosis and antitumor immune responses. Methods The tumor expression of ANXA1 and cleaved Caspase-3 (c-Casp3) and numbers of tumor-infiltrating CD68 + macrophages in 151 cases of pancreatic cancer were examined by immunohistochemistry and immunofluorescence. The role of ANXA1 in pancreatic cancer was investigated using myeloid-specific ANXA1-knockout mice. The changes in tumor-infiltrating immune cell populations induced by ANXA1 deficiency in macrophages were assessed by single-cell RNA sequencing and flow cytometry. Results ANXA1 expression in pancreatic cancer patient samples correlated with the number of CD68 + macrophages. The percentage of ANXA1 + tumor-infiltrating macrophages negatively correlated with c-Casp3 expression and was significantly associated with worse survival. In mice, myeloid-specific ANXA1 deficiency inhibited tumor growth and was accompanied by the accumulation of apoptotic cells in pancreatic tumor tissue caused by inhibition of macrophage efferocytosis, which was dependent on cGAS-STING pathway-induced type I interferon signaling. ANXA1 deficiency significantly remodeled the intratumoral lymphocyte and macrophage compartments in tumor-bearing mice by increasing the number of effector T cells and pro-inflammatory macrophages. Furthermore, combination therapy of ANXA1 knockdown with gemcitabine and anti-programmed cell death protein-1 antibody resulted in synergistic inhibition of pancreatic tumor growth. Conclusion This research uncovers a novel role of macrophage ANXA1 in pancreatic cancer. ANXA1-mediated regulation of efferocytosis by tumor-associated macrophages promotes antitumor immune response via STING signaling, suggesting potential treatment strategies for pancreatic cancer.

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