Enhancing anti-tumor immunity through liposomal oxaliplatin and localized immunotherapy via STING activation
Zili Gu1, Yang Hao2, Timo Schomann3
1Department of Radiology, Leiden University Medical Center, the Netherlands.
Abstract:
The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is a promising approach for anti-cancer immunotherapy by bridging innate and adaptive immunity. Recent evidence suggests that chemotherapy-induced DNA damage can directly induce dendritic cell (DC) maturation and recruitment, which synergizes with STING activation to enhance anti-tumor effects. As an immunogenic cell death (ICD) inducer, oxaliplatin generates massive double-stranded DNA (dsDNA) crosslinks, release of tumor-associated antigens and promoting the "eat me" signal. STING activation improves antigen immunogenicity, which can promote T cell activation and infiltration. In this study, we developed liposomes encapsulating oxaliplatin and combine this formulation with a STING agonist (ADU-S100) for treating colorectal cancer. The liposomes efficiently inhibited the proliferation of tumor cells while induced ICD in CT26 colorectal cancer cells, which enhanced dendritic cell maturation and phagocytosis in vitro. The liposome-based immunochemotherapy exhibited the strongest efficacy, resulting in complete remission upon tumor inoculation. Mechanistic studies showed this potent anti-cancer effect was related to the significant recruitment of infiltrating CD8 and CD4 T cells, reduction of suppressive Treg cells, and a shift in the phenotype of tumor-associated suppressive macrophages that promote cancer to immune stimulating macrophages. Thus, our study demonstrated the potential of combining oxaliplatin-loaded liposomes with a STING agonist to reduce tumor growth by regulating the immunosuppressive state in the tumor.
Insights
Combining oxaliplatin liposomes with a STING agonist effectively treats colorectal cancer. This immunotherapy combination induces cancer cell death, enhances immune cell activity, and promotes tumor remission by reprogramming the tumor microenvironment.
Area of Science:
- Immunology
- Oncology
- Nanotechnology
Background:
- The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is crucial for bridging innate and adaptive immunity in anti-cancer immunotherapy.
- Chemotherapy-induced DNA damage can mature dendritic cells (DCs), synergizing with STING activation for enhanced anti-tumor effects.
- Oxaliplatin, an immunogenic cell death (ICD) inducer, generates double-stranded DNA (dsDNA) and promotes antigen release, while STING activation boosts antigen immunogenicity.
Purpose of the Study:
- To develop and evaluate liposomes encapsulating oxaliplatin combined with a STING agonist (ADU-S100) for colorectal cancer treatment.
- To investigate the synergistic effects of this combination therapy on tumor cell proliferation, ICD induction, and immune cell modulation.
- To elucidate the underlying mechanisms responsible for the anti-cancer efficacy of the liposome-based immunochemotherapy.
Main Methods:
- Development of liposomes encapsulating oxaliplatin.
- In vitro assessment of liposome efficacy on colorectal cancer cell proliferation and ICD induction.
- In vitro evaluation of dendritic cell maturation and phagocytosis.
- In vivo administration of liposomal oxaliplatin combined with a STING agonist in a colorectal cancer model.
- Mechanistic studies analyzing immune cell infiltration (CD8+, CD4+ T cells, Treg cells) and macrophage phenotype shifts.
Main Results:
- Liposomes efficiently inhibited tumor cell proliferation and induced ICD in CT26 colorectal cancer cells.
- The combination therapy resulted in enhanced dendritic cell maturation and phagocytosis in vitro.
- Liposome-based immunochemotherapy achieved complete tumor remission in vivo.
- Significant recruitment of CD8 and CD4 T cells, reduction of suppressive Treg cells, and reprogramming of tumor-associated macrophages were observed.
Conclusions:
- Combining oxaliplatin-loaded liposomes with a STING agonist demonstrates potent anti-cancer efficacy against colorectal cancer.
- This combination therapy effectively regulates the immunosuppressive tumor microenvironment, promoting an anti-tumor immune response.
- The developed liposome-based immunochemotherapy holds significant potential for advancing colorectal cancer treatment strategies.
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