Carbon ion irradiation induces DNA damage in melanoma and optimizes the tumor microenvironment based on the cGAS–STING pathway

Guo, Junming; Shen, Rong; Wang, Fang; Wang, Yutong; Xia, Peng; Wu, Rile; Liu, Xiangwen; Ye, Weichun; Tian, Yingxia; Wang, Degui

doi:10.1007/s00432-023-04577-6

Cited by 8 publications

(9 citation statements)

References 45 publications

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“…Overall, the low-LET X-ray and high-LET C-ion radiations exhibit different physical properties and biological effects. Other studies also exhibited that C ions induced stronger cell cycle arrest (48) and immune responses activating effects than X rays (7,49). It is anticipated that further research will uncover additional biological properties of C ions.…”

Section: Carbon Ions Inhibited Lung Metastasis In Melanomamentioning

confidence: 97%

Carbon Ions Suppress Angiogenesis and Lung Metastases in Melanoma by Targeting CXCL10

Li,

Zhang,

Luo

et al. 2023

Radiation Research

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Carbon-ion radiotherapy (CIRT) enhanced local control in patients with malignant melanoma. In several in vitro studies, carbon ions (C ions) have been also shown to decrease the metastatic potential of melanoma cells. CXC motif 10 (CXCL10) has been shown to play a crucial role in regulating tumor metastasis and it significantly increase in human embryonic kidney cells after heavy ion irradiations. This study sought to explore the regulatory effect of C ions on melanoma metastasis, emphasizing the role of CXCL10 in this process. To explore the potential regulatory effect of C ions on tumor metastasis in vivo, we developed a lung metastasis mouse model by injecting B16F10 cells into the footpad and subjected all mice to treatment with X rays and C ions. Subsequently, a series of assays, including histopathological analysis, enzyme-linked immunosorbent assay, real-time PCR, and western blotting, were conducted to assess the regulatory effects of C ions on melanoma. Our results showed that mice treated with C ions exhibited significantly less tumor vascularity, enhanced tumor necrosis, alleviated lung metastasis, and experienced longer survival than X-ray irradiated mice. Moreover, VEGF expression in B16F10 cells was significantly reduced by C-ion treatment, which could be alleviated by CXCL10 knockdown in vitro. Further investigations revealed that co-culturing with HUVECs resulted in a significant inhibition of proliferation, migration, and tube formation ability in the C-ion treated group, while the opposite effect was observed in the C-ion treated with si-CXCL10 group. In conclusion, our findings demonstrate that treatment with carbon-ion radiation can suppress angiogenesis and lung metastases in melanoma by specifically targeting CXCL10. These results suggest the potential utility of carbon ions in treating melanoma.

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Section: Carbon Ions Inhibited Lung Metastasis In Melanomamentioning

confidence: 97%

Carbon Ions Suppress Angiogenesis and Lung Metastases in Melanoma by Targeting CXCL10

Li,

Zhang,

Luo

et al. 2023

Radiation Research

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“…Lastly, pre-clinical evidence suggests that carbon ion irradiation of cancer cells produce similar immune responses through the STING pathway relative to x-rays ( Du et al, 2021 ). However, the signaling may be stronger with carbon ions ( Guo et al, 2023 ), possibly related to their enhanced radiobiological effectiveness ( Schlaff et al, 2014 ). Ultimately, the radiobiology of these novel radiation modalities and delivery techniques is still under investigation, and the effect of these on tumor control and immune activation are active research questions, complicating studies using these techniques in combination with pharmacological immune activators.…”

Section: Considerations For Clinical Trials Of Radiation Therapy With...mentioning

confidence: 99%

Harnessing the cGAS-STING pathway to potentiate radiation therapy: current approaches and future directions

Colangelo,

Gerber,

Vatner

et al. 2024

Front. Pharmacol.

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In this review, we cover the current understanding of how radiation therapy, which uses ionizing radiation to kill cancer cells, mediates an anti-tumor immune response through the cGAS-STING pathway, and how STING agonists might potentiate this. We examine how cGAS-STING signaling mediates the release of inflammatory cytokines in response to nuclear and mitochondrial DNA entering the cytoplasm. The significance of this in the context of cancer is explored, such as in response to cell-damaging therapies and genomic instability. The contribution of the immune and non-immune cells in the tumor microenvironment is considered. This review also discusses the burgeoning understanding of STING signaling that is independent of inflammatory cytokine release and the various mechanisms by which cancer cells can evade STING signaling. We review the available data on how ionizing radiation stimulates cGAS-STING signaling as well as how STING agonists may potentiate the anti-tumor immune response induced by ionizing radiation. There is also discussion of how novel radiation modalities may affect cGAS-STING signaling. We conclude with a discussion of ongoing and planned clinical trials combining radiation therapy with STING agonists, and provide insights to consider when planning future clinical trials combining these treatments.

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“…Since heavy-ion irradiation does not impair healthy tissues beneath cancer due to its unique property named spread-out Bragg peak, as described above, it is plausible that the immune system remains healthy in response to the cancer fragments or particles generated by CIRT. Indeed, ICRT-irradiated cancer cells harbor robust cytotoxic lymphocytes such as CD8 + T cells and NK cells, which are rarely observed in non-irradiated cancer cells [ 63 , 64 ]. However, the underlying mechanisms are not fully understood.…”

Section: Cirt Activation Of Anti-cancer Immunitymentioning

confidence: 99%

“…As mentioned above, CIRT-induced DNA damage in cancer cells results in the release of clustered DNA breaks from the compartmentalized nuclei and mitochondria into the cytosol. These cytoplasmic dsDNAs are recognized by DNA sensors, namely, cGAS, which eventually activates the STING pathway [ 63 , 67 , 68 , 69 , 70 ]. Secondary messengers of the cGAS-STING-mediated pathways are highly conserved in the Kingdom of Life [ 71 ].…”

Section: Cirt Activation Of Anti-cancer Immunitymentioning

confidence: 99%

“…Dying cancer cells induced by CIRT are the major source of DNA. After the internalization or phagocytosis of DNA or dying cells, the cGAS-STING pathway is activated in the cytosol of phagocytes [ 63 , 67 , 68 , 69 , 70 ]. In line with the cancer cells, phagocytes in the vicinity of the cancer cells likely also secrete IFN-I.…”

Section: Cirt Activation Of Anti-cancer Immunitymentioning

confidence: 99%

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Carbon Ion Irradiation Activates Anti-Cancer Immunity

Sudo,

Tsutsui,

Fujimoto

2024

IJMS

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Carbon ion beams have the unique property of higher linear energy transfer, which causes clustered damage of DNA, impacting the cell repair system. This sometimes triggers apoptosis and the release in the cytoplasm of damaged DNA, leading to type I interferon (IFN) secretion via the activation of the cyclic GMP–AMP synthase-stimulator of interferon genes pathway. Dendritic cells phagocytize dead cancer cells and damaged DNA derived from injured cancer cells, which together activate dendritic cells to present cancer-derived antigens to antigen-specific T cells in the lymph nodes. Thus, carbon ion radiation therapy (CIRT) activates anti-cancer immunity. However, cancer is protected by the tumor microenvironment (TME), which consists of pro-cancerous immune cells, such as regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages. The TME is too robust to be destroyed by the CIRT-mediated anti-cancer immunity. Various modalities targeting regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages have been developed. Preclinical studies have shown that CIRT-mediated anti-cancer immunity exerts its effects in the presence of these modalities. In this review article, we provide an overview of CIRT-mediated anti-cancer immunity, with a particular focus on recently identified means of targeting the TME.

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Carbon ion irradiation induces DNA damage in melanoma and optimizes the tumor microenvironment based on the cGAS–STING pathway

Cited by 8 publications

References 45 publications

Carbon Ions Suppress Angiogenesis and Lung Metastases in Melanoma by Targeting CXCL10

Carbon Ions Suppress Angiogenesis and Lung Metastases in Melanoma by Targeting CXCL10

Harnessing the cGAS-STING pathway to potentiate radiation therapy: current approaches and future directions

Carbon Ion Irradiation Activates Anti-Cancer Immunity

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