Smart drug delivery platforms reprogramming cancer immune cycle to mitigate immune resistance of pancreatic tumors.

Immunotherapy has emerged as a promising strategy for pancreatic ductal adenocarcinoma (PDAC) therapy, yet its clinical efficacy suffers from the immunosuppressive tumor microenvironment (ITM). This ITM contributes to immune resistance by impeding the cancer immune (CI) cycle at multiple stages, including impaired antigen release and presentation, inadequate T cell priming and activation, restricted T cell infiltration, and compromised T cell cytotoxicity within the tumor. To address these challenges, smart drug delivery systems have emerged as a transformative strategy to precisely modulate the CI cycle, thereby reversing the ITM and restoring the anti-tumor immunity. In this review, we systematically dissect the clinical landscape of PDAC immunotherapy, outline key mechanisms of impaired CI cycle to drive immunotherapy resistance, and explore smart drug delivery platforms for reinitiating CI cycle. We further discuss the latest preclinical advances of precisely engineered drug delivery systems, and provide a perspective on their potential to harness the CI cycle and overcome immunotherapy resistance in PDAC. This review not only summarizes current progress but also provides a forward-looking perspective on next-generation immunotherapies, emphasizing the role of neuro-immune interactions and the rational design of spatiotemporally tunable, circadian rhythm-adaptable drug delivery systems.