Smart-responsive lentinan-DMXAA conjugate for synergistic STING-mediated pancreatic cancer immunotherapy.

Pancreatic cancer is a highly aggressive malignancy with a poor prognosis, primarily due to its immunosuppressive tumor microenvironment (TME) and suboptimal efficacy of current immunotherapies. Herein, we developed a novel conjugate (LNT-DMXAA) by covalently grafting the STING agonist DMXAA onto the immunomodulatory polysaccharide (lentinan, LNT) via esterification and Schiff-base reactions, showing high drug loading (DMXAA, 9.91%; LNT, 90.09%) and enzyme/pH-responsive drug release. In vitro experiments revealed that LNT-DMXAA effectively elicited STING-dependent BMDC maturation via the TBK1-IRF3 axis, upregulating IFN-β and CXCL10, and exhibiting negligible cytotoxicity. Additionally, DMXAA synergized with LNT to enhance BMDC activation and OVA antigen presentation, with LNT-DMXAA demonstrating greater effectiveness. In Pan02 mice, LNT-DMXAA significantly inhibited tumor growth by activating dendritic cells for antigen presentation, promoting intratumoral CD8+/CD4+ T-cell infiltration, and performed better than DMXAA, LNT and physical mixtures. In addition, the conjugate exhibited excellent biocompatibility without notable organ toxicity or hemolysis, while enhancing DMXAA solubility. Collectively, LNT-DMXAA demonstrates potential as a pancreatic cancer immunotherapy agent by integrating LNT and DMXAA to synergistically address tumor immune evasion.