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Smart-responsive lentinan-DMXAA conjugate for synergistic STING-mediated pancreatic cancer immunotherapy
Zhengxian Zhang1, Xin Zhu1, Jingru Cui1
1Academy of Chinese Medicine Sciences & School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, China.
Abstract:
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.
Insights
A new pancreatic cancer immunotherapy, LNT-DMXAA, combines lentinan (LNT) and a STING agonist (DMXAA) to overcome immune evasion. This conjugate effectively activates immune cells and inhibits tumor growth in mice.
Area of Science:
- Immunology
- Oncology
- Bioconjugation Chemistry
Background:
- Pancreatic cancer is aggressive with poor prognosis due to an immunosuppressive tumor microenvironment.
- Current immunotherapies show suboptimal efficacy against pancreatic cancer.
Purpose of the Study:
- To develop a novel conjugate, LNT-DMXAA, by linking lentinan (LNT) and DMXAA to enhance pancreatic cancer immunotherapy.
- To evaluate the efficacy and biocompatibility of LNT-DMXAA in vitro and in vivo.
Main Methods:
- Synthesized LNT-DMXAA via esterification and Schiff-base reactions, achieving high drug loading.
- Assessed STING pathway activation, BMDC maturation, and antigen presentation in vitro.
- Evaluated tumor growth inhibition, immune cell infiltration, and biocompatibility in Pan02 mouse models.
Main Results:
- LNT-DMXAA demonstrated enzyme/pH-responsive drug release and enhanced BMDC maturation via the STING-TBK1-IRF3 axis.
- The conjugate significantly inhibited tumor growth in mice by activating dendritic cells and promoting T-cell infiltration.
- LNT-DMXAA showed superior performance compared to individual components and exhibited excellent biocompatibility.
Conclusions:
- LNT-DMXAA effectively addresses tumor immune evasion by synergistically combining LNT and DMXAA.
- This novel conjugate holds significant potential as a pancreatic cancer immunotherapy agent.
