Reprogramming the pancreatic ductal adenocarcinoma microenvironment: A novel integrin-targeted cytotoxin, ProAgio, potentiates chemotherapy [RNA-seq]

Pancreatic ductal adenocarcinoma (PDAC) growth and metastasis are influenced by the tumor microenvironment (TME), which includes immune cells, endothelial cells, macrophages, and cancer-associated fibroblasts (CAFs). Since the novel integrin-targeted cytotoxin ProAgio can modulate the TME, we investigated its combination with various conventional chemotherapies in genetically engineered (GEM) and murine models of PDAC. The combination of ProAgio plus chemotherapy significantly modulated TME, improving hypoxia, reducing tumor weight, and eliminating metastasis to the lung and liver. Notably, the combination therapy with gemcitabine also increased overall survival in GEM model animals compared to either treatment alone. Single-cell RNA sequencing (scRNA seq; acquired from GEM model animals), flow cytometry, immunofluorescence, and immunohistochemistry analyses suggested that ProAgio plus chemotherapy treatment reprogrammed the PDAC- TME by changing activated CAFs toward a qCAFs (quiescent CAFs), macrophages from protumor to proinflammatory polarization, and activating natural killer (NK) cells, CD4⁺, and CD8⁺ T cells. Combination therapy inhibited PDAC stemness. ProAgio-treated CAFs in vitro exhibited reduced secretion of glycine and cysteine, vital metabolites that support stemness and tumor progression. These results highlight the potential of ProAgio to potentiate the efficacy of chemotherapy through modulating the PDAC-ME and improving hypoxia.