Enhanced antitumor immunity of VNP20009-CCL2-CXCL9 via the cGAS/STING axis in osteosarcoma lung metastasis
Background Osteosarcoma (OS) with pulmonary metastasis remains challenging due to limited treatment options and the immunosuppressive nature of the tumor microenvironment (TME). Bacteria-mediated cancer therapy has emerged as a promising strategy for solid tumors but often suffers from limited effic...
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2025-07-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/13/7/e012269.full |
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| author | Yuming Wang Qi Liu Chong Zhao Zhusheng Zhang Weibin Zhang Paul Castillo Tianyi Liu Elizabeth Ogando-Rivas Haipeng Tao Ruixuan Liu |
| author_facet | Yuming Wang Qi Liu Chong Zhao Zhusheng Zhang Weibin Zhang Paul Castillo Tianyi Liu Elizabeth Ogando-Rivas Haipeng Tao Ruixuan Liu |
| author_sort | Yuming Wang |
| collection | DOAJ |
| description | Background Osteosarcoma (OS) with pulmonary metastasis remains challenging due to limited treatment options and the immunosuppressive nature of the tumor microenvironment (TME). Bacteria-mediated cancer therapy has emerged as a promising strategy for solid tumors but often suffers from limited efficacy due to the immunosuppressive TME, which restricts the intensity and durability of the antitumor immune response. To overcome these challenges, we engineered a novel Salmonella strain, VNP20009-CCL2-CXCL9 (VNP-C-C), leveraging the intrinsic tumor tropism of Salmonella typhimurium VNP20009 (VNP) and improving immune modulation through the recruitment of effector immune cells into the TME by the chemokines CCL2 and CXCL9.Methods VNP-C-C was genetically engineered through electroporation of Plac-CCL2-CXCL9 plasmid and validated in vitro. Its antitumor efficacy, immune regulation capacity and immunomodulatory mechanisms were evaluated in vitro by using OS cell lines and immune cells (dendritic cells (DCs) and macrophages (Mφs)) and in vivo by using both immunocompromised and immunocompetent mouse models of OS lung metastasis.Results VNP-C-C effectively accumulated within tumors, triggering immunogenic cell death and subsequently activating the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway, thereby robustly promoting type I interferon secretion. The chemokines CCL2 and CXCL9 amplified the immune response by recruiting DCs, Mφs, and T cells to the TME. This orchestrated immune modulation reprogrammed tumor-associated macrophages to an antitumor phenotype, induced DCs maturation, significantly increased T-cell infiltration and activation within tumors, and promoted systemic T-cell memory formation in peripheral lymphoid organs. These effects collectively inhibited OS lung metastasis progression and provided survival benefits in mouse models.Conclusion The engineered bacterial strain VNP-C-C effectively converts the OS lung metastatic TME into a pro-inflammatory milieu, thereby stimulating robust innate and adaptive immune responses. This offers a highly promising therapeutic avenue for OS lung metastasis with considerable translational potential in cancer immunotherapy. |
| format | Article |
| id | doaj-art-5379f882a1c046bfafd6b02fafaadd63 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-5379f882a1c046bfafd6b02fafaadd632025-08-20T03:28:41ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262025-07-0113710.1136/jitc-2025-012269Enhanced antitumor immunity of VNP20009-CCL2-CXCL9 via the cGAS/STING axis in osteosarcoma lung metastasisYuming Wang0Qi Liu1Chong Zhao2Zhusheng Zhang3Weibin Zhang4Paul Castillo5Tianyi Liu6Elizabeth Ogando-Rivas7Haipeng Tao8Ruixuan Liu92 Shanghai Chest Hospital of Shanghai Jiao Tong University School of Medicine, Shanghai, Shanghai, China1 Orthopedics, Ruijin Hospital, Shanghai, Shanghai, China4 Neurosurgery, University of Florida, Gainesville, Florida, USA1 Orthopedics, Ruijin Hospital, Shanghai, Shanghai, China1 Orthopedics, Ruijin Hospital, Shanghai, Shanghai, China5 Pediatrics, University of Florida, Gainesville, Florida, USA3 Neurology, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China4 Neurosurgery, University of Florida, Gainesville, Florida, USA4 Neurosurgery, University of Florida, Gainesville, Florida, USA1 Orthopedics, Ruijin Hospital, Shanghai, Shanghai, ChinaBackground Osteosarcoma (OS) with pulmonary metastasis remains challenging due to limited treatment options and the immunosuppressive nature of the tumor microenvironment (TME). Bacteria-mediated cancer therapy has emerged as a promising strategy for solid tumors but often suffers from limited efficacy due to the immunosuppressive TME, which restricts the intensity and durability of the antitumor immune response. To overcome these challenges, we engineered a novel Salmonella strain, VNP20009-CCL2-CXCL9 (VNP-C-C), leveraging the intrinsic tumor tropism of Salmonella typhimurium VNP20009 (VNP) and improving immune modulation through the recruitment of effector immune cells into the TME by the chemokines CCL2 and CXCL9.Methods VNP-C-C was genetically engineered through electroporation of Plac-CCL2-CXCL9 plasmid and validated in vitro. Its antitumor efficacy, immune regulation capacity and immunomodulatory mechanisms were evaluated in vitro by using OS cell lines and immune cells (dendritic cells (DCs) and macrophages (Mφs)) and in vivo by using both immunocompromised and immunocompetent mouse models of OS lung metastasis.Results VNP-C-C effectively accumulated within tumors, triggering immunogenic cell death and subsequently activating the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway, thereby robustly promoting type I interferon secretion. The chemokines CCL2 and CXCL9 amplified the immune response by recruiting DCs, Mφs, and T cells to the TME. This orchestrated immune modulation reprogrammed tumor-associated macrophages to an antitumor phenotype, induced DCs maturation, significantly increased T-cell infiltration and activation within tumors, and promoted systemic T-cell memory formation in peripheral lymphoid organs. These effects collectively inhibited OS lung metastasis progression and provided survival benefits in mouse models.Conclusion The engineered bacterial strain VNP-C-C effectively converts the OS lung metastatic TME into a pro-inflammatory milieu, thereby stimulating robust innate and adaptive immune responses. This offers a highly promising therapeutic avenue for OS lung metastasis with considerable translational potential in cancer immunotherapy.https://jitc.bmj.com/content/13/7/e012269.full |
| spellingShingle | Yuming Wang Qi Liu Chong Zhao Zhusheng Zhang Weibin Zhang Paul Castillo Tianyi Liu Elizabeth Ogando-Rivas Haipeng Tao Ruixuan Liu Enhanced antitumor immunity of VNP20009-CCL2-CXCL9 via the cGAS/STING axis in osteosarcoma lung metastasis Journal for ImmunoTherapy of Cancer |
| title | Enhanced antitumor immunity of VNP20009-CCL2-CXCL9 via the cGAS/STING axis in osteosarcoma lung metastasis |
| title_full | Enhanced antitumor immunity of VNP20009-CCL2-CXCL9 via the cGAS/STING axis in osteosarcoma lung metastasis |
| title_fullStr | Enhanced antitumor immunity of VNP20009-CCL2-CXCL9 via the cGAS/STING axis in osteosarcoma lung metastasis |
| title_full_unstemmed | Enhanced antitumor immunity of VNP20009-CCL2-CXCL9 via the cGAS/STING axis in osteosarcoma lung metastasis |
| title_short | Enhanced antitumor immunity of VNP20009-CCL2-CXCL9 via the cGAS/STING axis in osteosarcoma lung metastasis |
| title_sort | enhanced antitumor immunity of vnp20009 ccl2 cxcl9 via the cgas sting axis in osteosarcoma lung metastasis |
| url | https://jitc.bmj.com/content/13/7/e012269.full |
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