While we have focused on transcription factors (TFs) in the development of mononuclear phagocytes, especially dendritic cells, this time I will present our new findings regarding tumor-associated macrophages in pancreatic ductal adenocarcinoma (PDAC).

PDAC remains one of the most intractable cancers with an extremely poor prognosis.  Specifically, an abundance of immunosuppressive TAM subsets is strongly associated with poor outcomes across various cancers, including PDAC. Consequently, reprogramming TAM phenotypes has emerged as a promising therapeutic strategy.

Recently, we identified a key TF highly expressed in immunosuppressive TAMs in both human and mouse PDAC. Myeloid-specific deletion of this TF in PDAC mouse models markedly inhibited tumor progression. TAMs lacking this TF acquired anti-tumor properties, enhancing effector functions of intratumoral CD8⁺ T cells while attenuating their exhaustion. We also found that this TF induces an immune checkpoint gene, and myeloid-specific deletion of this gene similarly inhibited PDAC growth.

Supporting its clinical relevance, the TF–immune checkpoint axis correlated with exhausted CD8⁺ T cell signatures and poor prognosis in patients with PDAC. These findings demonstrate that this TF drives the tumor-promoting functions of TAMs, highlighting it as a potential therapeutic target for PDAC.