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Published on: April 29, 2015
Chemically programmed STING-activating nano-liposomal vesicles improve anticancer immunity
Xiaona Chen1, Fanchao Meng1, Yiting Xu1
1The First Affiliated Hospital, NHC Key Laboratory of Combined Multi-Organ Transplantation, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, 310003, Hangzhou, Zhejiang Province, P. R. China.
Abstract:
The often immune-suppressive tumor microenvironment (TME) may hinder immune evasion and response to checkpoint blockade therapies. Pharmacological activation of the STING pathway does create an immunologically hot TME, however, systemic delivery might lead to undesired off-target inflammatory responses. Here, we generate a small panel of esterase-activatable pro-drugs based on the structure of the non-nucleotide STING agonist MSA-2 that are subsequently stably incorporated into a liposomal vesicle for intravenous administration. The pharmacokinetic properties and immune stimulatory capacity of pro-drugs delivered via liposomes (SAProsomes) are enhanced compared to the free drug form. By performing efficacy screening among the SAProsomes incorporating different pro-drugs in syngeneic mouse tumor models, we find that superior therapeutic performance relies on improved delivery to the desired tumor and lymphoid compartments. The best candidate, SAProsome-3, highly stimulates secretion of inflammatory cytokines and creates a tumoricidal immune landscape. Notably, upon application to breast cancer or melanoma mouse models, SAProsome-3 elicits durable remission of established tumors and postsurgical tumor-free survival while decreasing metastatic burden without significant systemic toxicity. In summary, our work establishes the proof of principle for a better targeted and more efficient and safe STING agonist therapy.
Insights
New liposomal STING agonists (SAProsomes) enhance anti-tumor immunity by targeting the tumor microenvironment (TME). This approach improves drug delivery, reduces toxicity, and promotes durable remission in mouse cancer models.
Area of Science:
- Immunology
- Drug Delivery
- Oncology
Background:
- The tumor microenvironment (TME) often suppresses immune responses, limiting the effectiveness of cancer immunotherapies like checkpoint blockade.
- Activating the STING pathway can enhance anti-tumor immunity but systemic delivery faces challenges with off-target inflammation.
Purpose of the Study:
- To develop novel, targeted STING agonist therapies to overcome TME-mediated immune suppression.
- To improve the delivery and safety profile of STING agonists for enhanced cancer treatment.
Main Methods:
- Generation of esterase-activatable pro-drugs based on the STING agonist MSA-2.
- Incorporation of pro-drugs into liposomal vesicles (SAProsomes) for intravenous administration.
- Efficacy screening of SAProsomes in syngeneic mouse tumor models, evaluating immune stimulation and therapeutic outcomes.
Main Results:
- Liposomal delivery (SAProsomes) improved pharmacokinetic properties and immune-stimulating capacity compared to free pro-drugs.
- Therapeutic success correlated with enhanced delivery to tumor and lymphoid compartments.
- The lead candidate, SAProsome-3, induced potent inflammatory cytokine secretion, a tumoricidal immune landscape, and durable tumor remission in breast cancer and melanoma models.
- SAProsome-3 reduced metastatic burden and demonstrated postsurgical tumor-free survival without significant systemic toxicity.
Conclusions:
- SAProsomes represent a proof-of-principle for targeted and safer STING agonist therapy.
- This liposomal delivery system enhances STING agonist efficacy by improving tumor targeting and reducing systemic side effects.
- The findings support the potential of SAProsomes as a novel immunotherapeutic strategy for various cancers.
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