Pancreatic ductal adenocarcinoma: integrating molecular insights for targeted interventions

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal and aggressive tumor types, with a dismal 5-year survival rate of less than 15%. Despite major advances in understanding PDAC biology, therapeutic progress has been limited. Numerous preclinical studies have provided encouraging evidence that immune-based therapies may be effective. However, the clinical translation of immunotherapies for PDAC treatment has proven difficult with a lack of favorable tumor responses outside of a very select group of patients such as patients with MSI high tumors. Immune checkpoint inhibitors, as well as combination strategies with targeted radiotherapy or chemotherapy, have largely failed to demonstrate meaningful survival benefits for the majority of PDAC patients. Increasing evidence indicates that PDAC harbors a uniquely complex and multifaceted immunosuppressive microenvironment, which plays a central role in shielding malignant cells from effective antitumor immunity. Overcoming this barrier requires the development of rational and effective combination regimens that simultaneously target both the tumor and its surrounding immune microenvironment. Novel strategies, including the use of natural killer cell-based therapies, reprogramming of cancer-associated fibroblasts, and integration of predictive or prognostic biomarkers, hold promise for enhancing therapeutic efficacy. This review summarizes recent progress in PDAC immunotherapy, highlights key challenges, and discusses emerging approaches designed to improve patient outcomes.