Targeting KMT5C Suppresses Lung Cancer Progression and Enhances the Efficacy of Immunotherapy
Abstract The immune evasion is one major challenge for cancer immunotherapy. Despite considerable advancements in immune checkpoint blockade (ICB) therapies for the advanced non‐small cell lung cancer (NSCLC) patients, only a minority of patients receive long‐term survival benefit. Here, this work d...
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Wiley
2025-05-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202407575 |
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| author | Yunfeng Yuan Qianyu Li Guoquan Yan Yifei Qian Wenyun Guo Songling Li Fan Wang Wanjing Shang Zijun Zhu Di Ge Yanan Wang Yanfeng Liu |
| author_facet | Yunfeng Yuan Qianyu Li Guoquan Yan Yifei Qian Wenyun Guo Songling Li Fan Wang Wanjing Shang Zijun Zhu Di Ge Yanan Wang Yanfeng Liu |
| author_sort | Yunfeng Yuan |
| collection | DOAJ |
| description | Abstract The immune evasion is one major challenge for cancer immunotherapy. Despite considerable advancements in immune checkpoint blockade (ICB) therapies for the advanced non‐small cell lung cancer (NSCLC) patients, only a minority of patients receive long‐term survival benefit. Here, this work demonstrates that lysine methyltransferase 5C (KMT5C) is a crucial promoter of the NSCLC progression and immune evasion. This work first observes that upregulation of KMT5C in NSCLC correlated with cancer progression and poor patient prognosis. Notably, KMT5C knockdown in NSCLC cells suppress tumor growth and metastasis in mice. Mechanistically, this work demonstrates that KMT5C activated the DNA repair response to inhibit the STING‐IRF3 pathway, downstream type I IFN signaling, and CCL5 secretion, leading to the downregulation of CD8+ T cell infiltration and function in NSCLC, ultimately facilitating tumor immune evasion and tumor progression. Importantly, both the pharmacological inhibitor A196 and the genetic inhibition of KMT5C could synergize with anti‐PD‐1 therapy in the lung cancer mouse model. Clinically, high expression levels of KMT5C in patients with NSCLC are associated with a lower response rate and worse clinical outcomes to ICB therapy. Therefore, these findings identify a previously unknown functional link between KMT5C and tumor immune evasion, and demonstrate that targeting KMT5C may be a potential therapeutic approach for enhancing the efficacy of NSCLC patients to ICB therapy. |
| format | Article |
| id | doaj-art-24b39bc767154698bc76d47ef8937d74 |
| institution | OA Journals |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-24b39bc767154698bc76d47ef8937d742025-08-20T02:26:18ZengWileyAdvanced Science2198-38442025-05-011219n/an/a10.1002/advs.202407575Targeting KMT5C Suppresses Lung Cancer Progression and Enhances the Efficacy of ImmunotherapyYunfeng Yuan0Qianyu Li1Guoquan Yan2Yifei Qian3Wenyun Guo4Songling Li5Fan Wang6Wanjing Shang7Zijun Zhu8Di Ge9Yanan Wang10Yanfeng Liu11Department of Thoracic Surgery Zhongshan Hospital Fudan University Shanghai 200032 ChinaDepartment of Liver Surgery Clinical Stem Cell Research Center Ren Ji Hospital Shanghai Jiao Tong University School of Medicine Shanghai 200127 ChinaInstitute of Biomedical Sciences Shanghai Medical College Fudan University Shanghai 200032 ChinaDepartment of Liver Surgery Clinical Stem Cell Research Center Ren Ji Hospital Shanghai Jiao Tong University School of Medicine Shanghai 200127 ChinaDepartment of Liver Surgery Clinical Stem Cell Research Center Ren Ji Hospital Shanghai Jiao Tong University School of Medicine Shanghai 200127 ChinaDepartment of Liver Surgery Clinical Stem Cell Research Center Ren Ji Hospital Shanghai Jiao Tong University School of Medicine Shanghai 200127 ChinaDepartment of Liver Surgery Clinical Stem Cell Research Center Ren Ji Hospital Shanghai Jiao Tong University School of Medicine Shanghai 200127 ChinaLymphocyte Biology Section Laboratory of Immune System Biology National Institute of Allergy and infectious Diseases National Institutes of Health Bethesda MD 20814 USADepartment of Liver Surgery Clinical Stem Cell Research Center Ren Ji Hospital Shanghai Jiao Tong University School of Medicine Shanghai 200127 ChinaDepartment of Thoracic Surgery Zhongshan Hospital Fudan University Shanghai 200032 ChinaDepartment of Laboratory Medicine Ren Ji Hospital Shanghai Jiao Tong University School of Medicine Shanghai 200127 ChinaDepartment of Liver Surgery Clinical Stem Cell Research Center Ren Ji Hospital Shanghai Jiao Tong University School of Medicine Shanghai 200127 ChinaAbstract The immune evasion is one major challenge for cancer immunotherapy. Despite considerable advancements in immune checkpoint blockade (ICB) therapies for the advanced non‐small cell lung cancer (NSCLC) patients, only a minority of patients receive long‐term survival benefit. Here, this work demonstrates that lysine methyltransferase 5C (KMT5C) is a crucial promoter of the NSCLC progression and immune evasion. This work first observes that upregulation of KMT5C in NSCLC correlated with cancer progression and poor patient prognosis. Notably, KMT5C knockdown in NSCLC cells suppress tumor growth and metastasis in mice. Mechanistically, this work demonstrates that KMT5C activated the DNA repair response to inhibit the STING‐IRF3 pathway, downstream type I IFN signaling, and CCL5 secretion, leading to the downregulation of CD8+ T cell infiltration and function in NSCLC, ultimately facilitating tumor immune evasion and tumor progression. Importantly, both the pharmacological inhibitor A196 and the genetic inhibition of KMT5C could synergize with anti‐PD‐1 therapy in the lung cancer mouse model. Clinically, high expression levels of KMT5C in patients with NSCLC are associated with a lower response rate and worse clinical outcomes to ICB therapy. Therefore, these findings identify a previously unknown functional link between KMT5C and tumor immune evasion, and demonstrate that targeting KMT5C may be a potential therapeutic approach for enhancing the efficacy of NSCLC patients to ICB therapy.https://doi.org/10.1002/advs.202407575immune checkpoint blockade therapyimmune evasionlysine methyltransferase 5Cnon‐small cell lung cancerSTING‐IRF3 signaling |
| spellingShingle | Yunfeng Yuan Qianyu Li Guoquan Yan Yifei Qian Wenyun Guo Songling Li Fan Wang Wanjing Shang Zijun Zhu Di Ge Yanan Wang Yanfeng Liu Targeting KMT5C Suppresses Lung Cancer Progression and Enhances the Efficacy of Immunotherapy Advanced Science immune checkpoint blockade therapy immune evasion lysine methyltransferase 5C non‐small cell lung cancer STING‐IRF3 signaling |
| title | Targeting KMT5C Suppresses Lung Cancer Progression and Enhances the Efficacy of Immunotherapy |
| title_full | Targeting KMT5C Suppresses Lung Cancer Progression and Enhances the Efficacy of Immunotherapy |
| title_fullStr | Targeting KMT5C Suppresses Lung Cancer Progression and Enhances the Efficacy of Immunotherapy |
| title_full_unstemmed | Targeting KMT5C Suppresses Lung Cancer Progression and Enhances the Efficacy of Immunotherapy |
| title_short | Targeting KMT5C Suppresses Lung Cancer Progression and Enhances the Efficacy of Immunotherapy |
| title_sort | targeting kmt5c suppresses lung cancer progression and enhances the efficacy of immunotherapy |
| topic | immune checkpoint blockade therapy immune evasion lysine methyltransferase 5C non‐small cell lung cancer STING‐IRF3 signaling |
| url | https://doi.org/10.1002/advs.202407575 |
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