Bacteria and tumor debris induced pancreatic cancer progression via the NF-κB signaling pathway.

The tumor microenvironment (TME) of metastatic pancreatic ductal adenocarcinoma (PDAC) is characterized by significant cellular and spatial heterogeneity, and long-term hypoxia, leading to micronecrotic regions. PDAC clinical specimens were employed to investigate micronecrosis and we identified that bacteria and lipopolysaccharide (LPS) co-existed in PDAC tissue. Tumor-associated macrophages (TAMs) polarized by these complex components exhibit a distinct pro-inflammatory effect and correlate with drug resistance in pancreatic cancer. Single-cell data from the GEO database were used to identify differentially enrichment pathways between normal and cancer tissues. We explored the molecular mechanism of PDAC progression via macrophage-induced inflammation and immune evacuation. The bacterial components, in conjunction with PDAC debris, induced epithelial-mesenchyme transition in pancreatic cancer cells by activating nuclear factor kappa B (NF-κB) signaling and increasing programmed cell death ligand 1 (PD-L1) expression in TAMs, thus facilitating tumor progression. We then identified that CBL0137 significantly decreased PD-L1 expression by inhibiting NF-κB signaling and therapeutic efficacy was evaluated through systematic in vivo and in vitro drug experiments, Additionally, CBL0137 could synergize with gemcitabine to enhance its anti-tumor effect. Our results demonstrated the impact of necrosis and inflammation on tumor progression via TAMs and potential therapy strategies, suggesting that CBL0137 may be represented as a promising therapeutic candidate for PDAC.