Original: https://doi.org/10.1007/s00262-025-04096-y
Pancreatic ductal adenocarcinoma (PDAC) is a type of pancreatic cancer that often contains a high number of a specific immune cell called PMN-MDSCs, which suppress T-cell activity and help tumors evade the immune system. These cells use the JAK2/STAT3 pathway to control arginase activity, which inhibits T-cells.
Traditional approaches to block PMN-MDSCs systemically can cause serious side effects, like neutropenia (low neutrophil levels) and unwanted changes in blood cell production. To avoid these problems, the researchers developed a nanoengineering strategy to specifically target PMN-MDSCs without harming other cells.
By analyzing patient and mouse PDAC samples, they identified the surface receptor CXCR2 as a target unique to PMN-MDSCs. They modified a CXCR2 inhibitor drug (AZD5069) to make it water-soluble and attached it to nanoparticles that specifically home to CXCR2. These CXCR2-targeted nanoparticles were taken up almost exclusively by PMN-MDSCs, not by tumor cells, fibroblasts, or other immune cells.
They then loaded the nanoparticles with a JAK2/STAT3 inhibitor (Ruxolitinib) to create CXCR2-NPRuxo. This formulation more effectively blocked STAT3-regulated arginase activity in PMN-MDSCs and activated T-cells, compared with giving the drug freely. In mouse models of PDAC, treatment with CXCR2-NPRuxo reduced tumor size without causing significant neutropenia.
Overall, this study shows that delivering drugs specifically to PMN-MDSCs using CXCR2-targeted nanoparticles is a promising new way to overcome immune suppression and boost anti-tumor immunity in pancreatic cancer.