Overcoming immunosuppression in pancreatic cancer: Efficacy of polyamine blockade and anti-PD-1 combinational therapy

Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive cancer with an 88% mortality rate. This high mortality rate is due to its dense microenvironment, late-stage diagnosis, and limited treatment options. Polyamines, small molecules essential for cell growth, play a critical role here because their dysregulation is linked to PDAC tumor growth, invasion, and metastasis. Polyamine accumulation also reinforces an immunologically “cold” tumor microenvironment by supporting the recruitment of immunosuppressive cell populations and promoting immune-evasion pathways such as PD-1 signaling. This study aims to explore the interaction between polyamines and the PDAC immune microenvironment, and to evaluate the effectiveness of combining Polyamine Blockade Therapy (PBT) with anti-PD-1 inhibitors as a novel immunotherapy strategy. Using an orthotopic mouse model of PDAC with syngeneic GFP-Luc2 cells, we assessed the impact of PBT, consisting of Difluoromethylornithine (DFMO) and the polyamine transport inhibitor (PTI) Trimer44NMe (Trimer PTI), in conjunction with anti-PD-1 therapy. Tumor progression was monitored via in vivo bioluminescence imaging, and immune cell populations were analyzed using both tumor multiplexing and flow cytometry of peripheral tissues. The combined PBT and anti-PD-1 treatment led to a significant reduction in tumor mass, increased infiltration of anti-tumor immune cells, and enhanced systemic anti-tumor immune responses. The combination of Polyamine Blockade Therapy with anti-PD-1 inhibition shows promise as an effective immunotherapy for PDAC, potentially improving patient outcomes by disrupting the polyamine-mediated immunosuppressive network while enhancing anti-tumor immunity.