MicroRNA-based strategies to overcome the immunotherapy barrier in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy that continues to pose a major clinical challenge, primarily due to the difficulty of early detection and the limited efficacy of existing therapeutic approaches. Immunotherapy, which has revolutionized the treatment of many other cancers, has shown limited success in PDAC, largely because of the complex and immunosuppressive features of its tumor microenvironment (TME). Consequently, strategies aimed at remodeling or modulating the TME have emerged as promising avenues for enhancing the therapeutical potential of immunotherapy in PDAC. MicroRNAs (miRNAs), a class of small non-coding RNAs, have emerged as key regulators of gene expression with multi-target capabilities and relatively low toxicity. Increasing evidence demonstrates that miRNAs play critical roles in regulating immune responses and shaping the TME across diverse tumor types, highlighting their considerable potential in improving immunotherapeutic outcomes in PDAC. In this review, we summarize the functional roles of miRNAs in PDAC and discuss the advantages of miRNA-based therapeutics compared with conventional treatments. We further examine current immunotherapeutic strategies for PDAC and highlight how miRNAs regulate immune activity and TME dynamics, providing mechanistic insights into miRNA-mediated immunotherapy. Finally, we discuss the major challenges limiting clinical translation, including off-target effects, toxicity, and delivery barriers and outline emerging delivery platforms that may enhance therapeutic efficacy. Besides, we explore how emerging technologies, such as artificial intelligence (AI), miniature soft robotics, and advanced 3D imaging ecosystems can be integrated into miRNA-based therapeutic strategies. Together, these innovations may pave the way for more effective, personalized, and patient-centered miRNA-based immunotherapies for PDAC.