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 <i>Kras ^G12D/+</i> ( <i>Kras*</i> ) 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 <i>LSL-Kras ^G12D/+</i> ; <i>Trp53 ^R172H/+ ;Pdx1 ^Cre/+</i> ( <i>KPC</i> ) genetically engineered mouse model. Selective deletion of CREB ( <i>Creb ^fl/fl</i> ) in <i>KPC</i> ( <i>KPCC</i> ^-/- ) mice attenuates primary disease burden. Unbiased transcriptomic analysis and validation using diverse molecular, genetic and pharmacological approaches <i>in vitro</i> and <i>in vivo</i> identify CREB-mediated transcriptional regulation of leukemia inhibitory factor ( <i>Lif</i> ) 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.