Downregulation of cGAS/STING expression in tumor cells by cancer-associated fibroblasts in colorectal cancer
Abstract The tumor cell-intrinsic cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway is critical for activating anti-tumor immunity and enhancing immune checkpoint blockade therapy in colorectal cancer (CRC). Cancer-associated fibroblasts (CAFs), key components of the CRC...
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Nature Portfolio
2025-06-01
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| Series: | Scientific Reports |
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| Online Access: | https://doi.org/10.1038/s41598-025-03924-6 |
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| author | Ryo Kanoda Shotaro Nakajima Hirokazu Okayama Akinao Kaneta Shun Chida Takuro Matsumoto Katsuharu Saito Tomohiro Kikuchi Yuya Maruyama Hiroya Suzuki Kosaku Mimura Motonobu Saito Hiroyuki Hanayama Wataru Sakamoto Tomoyuki Momma Zenichiro Saze Koji Kono |
| author_facet | Ryo Kanoda Shotaro Nakajima Hirokazu Okayama Akinao Kaneta Shun Chida Takuro Matsumoto Katsuharu Saito Tomohiro Kikuchi Yuya Maruyama Hiroya Suzuki Kosaku Mimura Motonobu Saito Hiroyuki Hanayama Wataru Sakamoto Tomoyuki Momma Zenichiro Saze Koji Kono |
| author_sort | Ryo Kanoda |
| collection | DOAJ |
| description | Abstract The tumor cell-intrinsic cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway is critical for activating anti-tumor immunity and enhancing immune checkpoint blockade therapy in colorectal cancer (CRC). Cancer-associated fibroblasts (CAFs), key components of the CRC tumor microenvironment, negatively regulate the anti-tumor immune response. However, their impact on tumor cell-intrinsic cGAS–STING expression remains unclear. In the present study, we investigated whether CAFs can downregulate cGAS–STING expression in CRC. We found that cGAS–STING expression in tumor cells inversely correlated with stromal expression of versican (VCAN), an immunosuppressive CAF marker, in CRC tissues. Co-culture experiments using primary human CAFs derived from CRC tissues revealed that CAFs downregulated cGAS and/or STING expression in CRC cell lines (WiDr, LoVo, HCT116). Furthermore, CAFs expressing VCAN and fibronectin 1 appeared to mediate this suppression. These findings suggest that immunosuppressive CAFs contribute to the downregulation of tumor cell-intrinsic cGAS–STING expression in CRC. Therefore, targeting CAFs to restore cGAS–STING expression may represent a promising strategy to enhance the efficacy of CRC treatment. |
| format | Article |
| id | doaj-art-5c68dd2a61da4df8aa11ca3bb726463a |
| institution | DOAJ |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-5c68dd2a61da4df8aa11ca3bb726463a2025-08-20T03:10:38ZengNature PortfolioScientific Reports2045-23222025-06-0115111110.1038/s41598-025-03924-6Downregulation of cGAS/STING expression in tumor cells by cancer-associated fibroblasts in colorectal cancerRyo Kanoda0Shotaro Nakajima1Hirokazu Okayama2Akinao Kaneta3Shun Chida4Takuro Matsumoto5Katsuharu Saito6Tomohiro Kikuchi7Yuya Maruyama8Hiroya Suzuki9Kosaku Mimura10Motonobu Saito11Hiroyuki Hanayama12Wataru Sakamoto13Tomoyuki Momma14Zenichiro Saze15Koji Kono16Department of Gastrointestinal Tract Surgery, School of Medicine, Fukushima Medical UniversityDepartment of Gastrointestinal Tract Surgery, School of Medicine, Fukushima Medical UniversityDepartment of Gastrointestinal Tract Surgery, School of Medicine, Fukushima Medical UniversityDepartment of Gastrointestinal Tract Surgery, School of Medicine, Fukushima Medical UniversityDepartment of Gastrointestinal Tract Surgery, School of Medicine, Fukushima Medical UniversityDepartment of Gastrointestinal Tract Surgery, School of Medicine, Fukushima Medical UniversityDepartment of Gastrointestinal Tract Surgery, School of Medicine, Fukushima Medical UniversityDepartment of Gastrointestinal Tract Surgery, School of Medicine, Fukushima Medical UniversityDepartment of Gastrointestinal Tract Surgery, School of Medicine, Fukushima Medical UniversityDepartment of Gastrointestinal Tract Surgery, School of Medicine, Fukushima Medical UniversityDepartment of Gastrointestinal Tract Surgery, School of Medicine, Fukushima Medical UniversityDepartment of Gastrointestinal Tract Surgery, School of Medicine, Fukushima Medical UniversityDepartment of Gastrointestinal Tract Surgery, School of Medicine, Fukushima Medical UniversityDepartment of Gastrointestinal Tract Surgery, School of Medicine, Fukushima Medical UniversityDepartment of Gastrointestinal Tract Surgery, School of Medicine, Fukushima Medical UniversityDepartment of Gastrointestinal Tract Surgery, School of Medicine, Fukushima Medical UniversityDepartment of Gastrointestinal Tract Surgery, School of Medicine, Fukushima Medical UniversityAbstract The tumor cell-intrinsic cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway is critical for activating anti-tumor immunity and enhancing immune checkpoint blockade therapy in colorectal cancer (CRC). Cancer-associated fibroblasts (CAFs), key components of the CRC tumor microenvironment, negatively regulate the anti-tumor immune response. However, their impact on tumor cell-intrinsic cGAS–STING expression remains unclear. In the present study, we investigated whether CAFs can downregulate cGAS–STING expression in CRC. We found that cGAS–STING expression in tumor cells inversely correlated with stromal expression of versican (VCAN), an immunosuppressive CAF marker, in CRC tissues. Co-culture experiments using primary human CAFs derived from CRC tissues revealed that CAFs downregulated cGAS and/or STING expression in CRC cell lines (WiDr, LoVo, HCT116). Furthermore, CAFs expressing VCAN and fibronectin 1 appeared to mediate this suppression. These findings suggest that immunosuppressive CAFs contribute to the downregulation of tumor cell-intrinsic cGAS–STING expression in CRC. Therefore, targeting CAFs to restore cGAS–STING expression may represent a promising strategy to enhance the efficacy of CRC treatment.https://doi.org/10.1038/s41598-025-03924-6Colorectal cancerCancer-associated fibroblastVersicanTumor cell-intrinsic cGAS–STING |
| spellingShingle | Ryo Kanoda Shotaro Nakajima Hirokazu Okayama Akinao Kaneta Shun Chida Takuro Matsumoto Katsuharu Saito Tomohiro Kikuchi Yuya Maruyama Hiroya Suzuki Kosaku Mimura Motonobu Saito Hiroyuki Hanayama Wataru Sakamoto Tomoyuki Momma Zenichiro Saze Koji Kono Downregulation of cGAS/STING expression in tumor cells by cancer-associated fibroblasts in colorectal cancer Scientific Reports Colorectal cancer Cancer-associated fibroblast Versican Tumor cell-intrinsic cGAS–STING |
| title | Downregulation of cGAS/STING expression in tumor cells by cancer-associated fibroblasts in colorectal cancer |
| title_full | Downregulation of cGAS/STING expression in tumor cells by cancer-associated fibroblasts in colorectal cancer |
| title_fullStr | Downregulation of cGAS/STING expression in tumor cells by cancer-associated fibroblasts in colorectal cancer |
| title_full_unstemmed | Downregulation of cGAS/STING expression in tumor cells by cancer-associated fibroblasts in colorectal cancer |
| title_short | Downregulation of cGAS/STING expression in tumor cells by cancer-associated fibroblasts in colorectal cancer |
| title_sort | downregulation of cgas sting expression in tumor cells by cancer associated fibroblasts in colorectal cancer |
| topic | Colorectal cancer Cancer-associated fibroblast Versican Tumor cell-intrinsic cGAS–STING |
| url | https://doi.org/10.1038/s41598-025-03924-6 |
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