Improvement of the Anticancer Efficacy of PD‐1/PD‐L1 Blockade: Advances in Molecular Mechanisms and Therapeutic Strategies
ABSTRACT The clinical success of PD‐1/PD‐L1 blockade has revolutionized cancer immunotherapy. However, the issues of immune resistance have become increasingly prominent, representing a critical limitation in modern oncology. This phenomenon has prompted efforts to elucidate the mechanisms underlyin...
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| Format: | Article |
| Language: | English |
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Wiley
2025-08-01
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| Series: | MedComm |
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| Online Access: | https://doi.org/10.1002/mco2.70274 |
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| author | Peng Gao Xiao Li Zhenyu Duan Yang Wang Yinggang Li Jing Wang Kui Luo Jie Chen |
| author_facet | Peng Gao Xiao Li Zhenyu Duan Yang Wang Yinggang Li Jing Wang Kui Luo Jie Chen |
| author_sort | Peng Gao |
| collection | DOAJ |
| description | ABSTRACT The clinical success of PD‐1/PD‐L1 blockade has revolutionized cancer immunotherapy. However, the issues of immune resistance have become increasingly prominent, representing a critical limitation in modern oncology. This phenomenon has prompted efforts to elucidate the mechanisms underlying both types of resistance and to find breakthrough therapeutic strategies. This article provides a comprehensive overview of PD‐1/PD‐L1 blockade resistance mechanisms from both primary and acquired resistance perspectives, including tumor intrinsic factors, immune microenvironment components, and systemic factors. Building on this foundation, emerging research demonstrates that type I interferons (IFNs), particularly IFN‐α and IFN‐β, play crucial immunomodulatory roles in overcoming resistance to PD‐1/PD‐L1 blockade. We delineate six molecular mechanisms through which IFN‐α/β enhance PD‐1/PD‐L1 blockade efficacy, and innovative strategies are proposed to therapeutically boost IFN‐α/β production, including gene editing techniques, targeting the cGAS‐STING or TLR pathway and so on. Furthermore, insights into current challenges and future directions of the application of IFN‐α/β to improve PD‐1/PD‐L1 blockade are discussed. This review holds significant academic value by not only synthesizing current knowledge on PD‐1/PD‐L1 resistance mechanisms but also pioneering a framework for leveraging type I IFNs to overcome these barriers. |
| format | Article |
| id | doaj-art-8a10d547513b4ffc8006dee401c24f21 |
| institution | Kabale University |
| issn | 2688-2663 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | MedComm |
| spelling | doaj-art-8a10d547513b4ffc8006dee401c24f212025-08-20T03:46:33ZengWileyMedComm2688-26632025-08-0168n/an/a10.1002/mco2.70274Improvement of the Anticancer Efficacy of PD‐1/PD‐L1 Blockade: Advances in Molecular Mechanisms and Therapeutic StrategiesPeng Gao0Xiao Li1Zhenyu Duan2Yang Wang3Yinggang Li4Jing Wang5Kui Luo6Jie Chen7Department of General Surgery Breast Disease Center Department of Radiology Huaxi MR Research Center (HMRRC) Institution of Radiology and Medical Imaging Sichuan Engineering Research Center for Intelligent Diagnosis and Treatment of Breast Diseases Frontiers Science Center for Disease‐Related Molecular Network State Key Laboratory of Biotherapy West China Hospital Sichuan University Chengdu ChinaDepartment of Anus and Intestine Surgery First Affiliated Hospital of China Medical University Shenyang ChinaDepartment of General Surgery Breast Disease Center Department of Radiology Huaxi MR Research Center (HMRRC) Institution of Radiology and Medical Imaging Sichuan Engineering Research Center for Intelligent Diagnosis and Treatment of Breast Diseases Frontiers Science Center for Disease‐Related Molecular Network State Key Laboratory of Biotherapy West China Hospital Sichuan University Chengdu ChinaDepartment of Medical Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing ChinaDepartment of General Surgery Breast Disease Center Department of Radiology Huaxi MR Research Center (HMRRC) Institution of Radiology and Medical Imaging Sichuan Engineering Research Center for Intelligent Diagnosis and Treatment of Breast Diseases Frontiers Science Center for Disease‐Related Molecular Network State Key Laboratory of Biotherapy West China Hospital Sichuan University Chengdu ChinaDepartment of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing ChinaDepartment of General Surgery Breast Disease Center Department of Radiology Huaxi MR Research Center (HMRRC) Institution of Radiology and Medical Imaging Sichuan Engineering Research Center for Intelligent Diagnosis and Treatment of Breast Diseases Frontiers Science Center for Disease‐Related Molecular Network State Key Laboratory of Biotherapy West China Hospital Sichuan University Chengdu ChinaDepartment of General Surgery Breast Disease Center Department of Radiology Huaxi MR Research Center (HMRRC) Institution of Radiology and Medical Imaging Sichuan Engineering Research Center for Intelligent Diagnosis and Treatment of Breast Diseases Frontiers Science Center for Disease‐Related Molecular Network State Key Laboratory of Biotherapy West China Hospital Sichuan University Chengdu ChinaABSTRACT The clinical success of PD‐1/PD‐L1 blockade has revolutionized cancer immunotherapy. However, the issues of immune resistance have become increasingly prominent, representing a critical limitation in modern oncology. This phenomenon has prompted efforts to elucidate the mechanisms underlying both types of resistance and to find breakthrough therapeutic strategies. This article provides a comprehensive overview of PD‐1/PD‐L1 blockade resistance mechanisms from both primary and acquired resistance perspectives, including tumor intrinsic factors, immune microenvironment components, and systemic factors. Building on this foundation, emerging research demonstrates that type I interferons (IFNs), particularly IFN‐α and IFN‐β, play crucial immunomodulatory roles in overcoming resistance to PD‐1/PD‐L1 blockade. We delineate six molecular mechanisms through which IFN‐α/β enhance PD‐1/PD‐L1 blockade efficacy, and innovative strategies are proposed to therapeutically boost IFN‐α/β production, including gene editing techniques, targeting the cGAS‐STING or TLR pathway and so on. Furthermore, insights into current challenges and future directions of the application of IFN‐α/β to improve PD‐1/PD‐L1 blockade are discussed. This review holds significant academic value by not only synthesizing current knowledge on PD‐1/PD‐L1 resistance mechanisms but also pioneering a framework for leveraging type I IFNs to overcome these barriers.https://doi.org/10.1002/mco2.70274PD‐1/PD‐L1 blockade resistancecancer treatmenttype I interferonscGAS‐STING pathway |
| spellingShingle | Peng Gao Xiao Li Zhenyu Duan Yang Wang Yinggang Li Jing Wang Kui Luo Jie Chen Improvement of the Anticancer Efficacy of PD‐1/PD‐L1 Blockade: Advances in Molecular Mechanisms and Therapeutic Strategies MedComm PD‐1/PD‐L1 blockade resistance cancer treatment type I interferons cGAS‐STING pathway |
| title | Improvement of the Anticancer Efficacy of PD‐1/PD‐L1 Blockade: Advances in Molecular Mechanisms and Therapeutic Strategies |
| title_full | Improvement of the Anticancer Efficacy of PD‐1/PD‐L1 Blockade: Advances in Molecular Mechanisms and Therapeutic Strategies |
| title_fullStr | Improvement of the Anticancer Efficacy of PD‐1/PD‐L1 Blockade: Advances in Molecular Mechanisms and Therapeutic Strategies |
| title_full_unstemmed | Improvement of the Anticancer Efficacy of PD‐1/PD‐L1 Blockade: Advances in Molecular Mechanisms and Therapeutic Strategies |
| title_short | Improvement of the Anticancer Efficacy of PD‐1/PD‐L1 Blockade: Advances in Molecular Mechanisms and Therapeutic Strategies |
| title_sort | improvement of the anticancer efficacy of pd 1 pd l1 blockade advances in molecular mechanisms and therapeutic strategies |
| topic | PD‐1/PD‐L1 blockade resistance cancer treatment type I interferons cGAS‐STING pathway |
| url | https://doi.org/10.1002/mco2.70274 |
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