Blockade of LIF and PD-L1 Enhances Chemotherapy in Preclinical PDAC Models.

: Pancreatic ductal adenocarcinoma (PDAC), expecting to be the second leading cause of cancer deaths by 2030, resists immune checkpoint therapies due to its immunosuppressive tumor microenvironment (TME). Leukemia inhibitory factor (LIF) is a key target in PDAC, promoting stemness, epithelial-mesenchymal transition (EMT), and therapy resistance. Phase 1 clinical trials showed anti-LIF therapy is safe but with limited efficacy, suggesting better outcomes when combined with chemotherapy, radiotherapy, or immunotherapy. : We assessed the combination of chemotherapy (gemcitabine/nab-paclitaxel) and dual blockade of LIF and PD-L1 on tumor growth and survival in orthotopic and spontaneous PDAC models. Flow cytometry and scRNA-seq were utilized to monitor the antitumor immune response. The role of key immune cells was further confirmed by depleting these immune cells, including CD4, CD8, or inflammatory monocytes. : Sequential treatment with chemotherapy (gemcitabine/nab-paclitaxel) and dual blockade of LIF and PD-L1 significantly improved antitumor efficacy compared to monotherapy or dual combinations of these therapies. This chemo/anti-LIF/anti-PD-L1 approach reduced EMT in tumor cells and enhanced the antitumor immune response, primarily through CD8 T cells, as depleting CD8 cells largely abrogated the effect of treatment. This combination therapy also shifted macrophages and dendritic cells towards an antitumor phenotype. : The combination of chemotherapy, anti-LIF, and anti-PD-L1 not only targeted tumor cells but also augmented the anti-tumor immune response. These findings strongly support advancing chemo/anti-LIF/anti-PD-L1 combination therapy to clinical trials in PDAC.