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.