Targeting CREB remodels the immune microenvironment to enhance immunotherapy responses in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) remains a challenging disease in need of improved treatments. Cyclic adenosine monophosphate response element binding protein 1 (CREB) is an emerging therapeutic target whose oncogenic effects in PDAC have been largely attributed to a key molecular interplay between oncogenic Kras G12D/+ ( Kras* ) and chronic inflammation driving irreversible acinar to ductal reprogramming. Here, we demonstrate that CREB activation fosters tumor associated macrophage (TAM) mediated immunosuppression and promotes PDAC growth in an aggressive LSL-Kras G12D/+ ; Trp53 R172H/+ ;Pdx1 Cre/+ ( KPC ) genetically engineered mouse model. Selective deletion of CREB ( Creb fl/fl ) in KPC ( KPCC -/- ) mice attenuates primary disease burden. Unbiased transcriptomic analysis and validation using diverse molecular, genetic and pharmacological approaches in vitro and in vivo identify CREB-mediated transcriptional regulation of leukemia inhibitory factor ( Lif ) as one of the potential mediators of tumor cell-macrophage crosstalk promoting a pro-tumor polarization of TAMs, thereby attenuating the infiltration of effector T cells. Mechanistically, cancer cell derived LIF facilitates an immunosuppressive, pro-tumorigenic state. Importantly, pharmacological targeting of the CREB-LIF signaling axis between cancer cells and macrophages, using a CREB-specific inhibitor (CREBi), significantly suppresses tumor growth and sensitizes PDAC to immunotherapy, highlighting the therapeutic potential of this treatment combination to improve outcomes in this aggressive disease.