Looking Beyond Checkpoint Inhibitor Monotherapy: Uncovering New Frontiers for Pancreatic Cancer Immunotherapy.

Pancreatic ductal adenocarcinoma (PDAC) stands out as one of the most aggressive and challenging tumors, characterized by a bleak prognosis with a mere 11% survival rate over five years in the United States. Its formidable nature is primarily attributed to its highly aggressive behavior and poor response to existing therapies. PDAC, being notably resistant to immune interventions, presents a significant obstacle in treatment strategies. While immune checkpoint inhibitor therapies have revolutionized outcomes for various cancers, their efficacy in PDAC remains exceedingly low, benefiting less than 1% of patients. The consistent failure of these therapies in PDAC has prompted intensive investigation, particularly at the preclinical level, to unravel the intricate mechanisms of resistance inherent in this cancer type. This pursuit aims to pave the way for the development of novel immunotherapeutic strategies tailored to the distinct characteristics of PDAC. This review endeavors to provide a comprehensive exploration of these emerging immunotherapy approaches in PDAC, with a specific emphasis on elucidating their underlying immunological mechanisms. Additionally, it sheds light on recently identified factors driving resistance to immunotherapy and evasion of the immune system in PDAC, offering insights beyond the conventional drivers that have been extensively studied.