Rethinking PDAC: from immunological silence to therapeutic opportunity

Abstract

Pancreatic ductal adenocarcinoma (PDAC) ranks among the deadliest malignancies, with only 13% of patients surviving five years after diagnosis. This poor prognosis stems from late detection, treatment resistance, spatial and phenotypic heterogeneity, and a highly immunosuppressive tumor microenvironment. Unlike immunogenic cancers, PDAC is an immunologically ‘cold’ tumor, marked by minimal immune cell infiltration, defective antigen-presentation machinery, and stromal barriers. While immune checkpoint blockade (ICB) has shown success against various cancers, it has proven largely ineffective when used alone in PDAC. However, emerging research has identified promising new approaches, including neoantigen-targeted vaccines, stromal modulation, and combination therapies such as ICB with chemotherapy, cytokine blockade, and kinase inhibitors. The development of personalized immunotherapy approaches is being refined by predictive biomarkers that assess factors such as T cell infiltration levels, antigen-presenting capacity, and the spatial immune cell landscape. Here, we review the immune landscape of PDAC, current and emerging immunotherapeutic strategies, and highlight the critical role of biomarkers and immune profiling in appropriately categorizing patients. Collectively, these insights provide a foundation for designing rational combination therapies to transform PDAC into a cancer that is more immunologically responsive and amenable to therapy.