Chemotherapy‐Enabled Colorectal Cancer Immunotherapy of Self‐Delivery Nano‐PROTACs by Inhibiting Tumor Glycolysis and Avoiding Adaptive Immune Resistance
Abstract The chemo‐regulation abilities of chemotherapeutic medications are appealing to address the low immunogenicity, immunosuppressive lactate microenvironment, and adaptive immune resistance of colorectal cancer. In this work, the proteolysis targeting chimera (PROTAC) of BRD4 (dBET57) is found...
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| Format: | Article |
| Language: | English |
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Wiley
2024-04-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202309204 |
| _version_ | 1827233432536612864 |
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| author | Lin‐Ping Zhao Rong‐Rong Zheng Xiao‐Na Rao Chu‐Yu Huang Hang‐Yu Zhou Xi‐Yong Yu Xue‐Yan Jiang Shi‐Ying Li |
| author_facet | Lin‐Ping Zhao Rong‐Rong Zheng Xiao‐Na Rao Chu‐Yu Huang Hang‐Yu Zhou Xi‐Yong Yu Xue‐Yan Jiang Shi‐Ying Li |
| author_sort | Lin‐Ping Zhao |
| collection | DOAJ |
| description | Abstract The chemo‐regulation abilities of chemotherapeutic medications are appealing to address the low immunogenicity, immunosuppressive lactate microenvironment, and adaptive immune resistance of colorectal cancer. In this work, the proteolysis targeting chimera (PROTAC) of BRD4 (dBET57) is found to downregulate colorectal cancer glycolysis through the transcription inhibition of c‐Myc, which also inhibits the expression of programmed death ligand 1 (PD‐L1) to reverse immune evasion and avoid adaptive immune resistance. Based on this, self‐delivery nano‐PROTACs (designated as DdLD NPs) are further fabricated by the self‐assembly of doxorubicin (DOX) and dBET57 with the assistance of DSPE‐PEG2000. DdLD NPs can improve the stability, intracellular delivery, and tumor targeting accumulation of DOX and dBET57. Meanwhile, the chemotherapeutic effect of DdLD NPs can efficiently destroy colorectal cancer cells to trigger a robust immunogenic cell death (ICD). More importantly, the chemo‐regulation effects of DdLD NPs can inhibit colorectal cancer glycolysis to reduce the lactate production, and downregulate the PD‐L1 expression through BRD4 degradation. Taking advantages of the chemotherapy and chemo‐regulation ability, DdLD NPs systemically activated the antitumor immunity to suppress the primary and metastatic colorectal cancer progression without inducing any systemic side effects. Such self‐delivery nano‐PROTACs may provide a new insight for chemotherapy‐enabled tumor immunotherapy. |
| first_indexed | 2024-04-24T08:04:54Z |
| format | Article |
| id | doaj.art-5ef7f403debb46febbbad265cd7bd424 |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2025-03-21T19:33:14Z |
| publishDate | 2024-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-5ef7f403debb46febbbad265cd7bd4242024-06-03T14:05:50ZengWileyAdvanced Science2198-38442024-04-011115n/an/a10.1002/advs.202309204Chemotherapy‐Enabled Colorectal Cancer Immunotherapy of Self‐Delivery Nano‐PROTACs by Inhibiting Tumor Glycolysis and Avoiding Adaptive Immune ResistanceLin‐Ping Zhao0Rong‐Rong Zheng1Xiao‐Na Rao2Chu‐Yu Huang3Hang‐Yu Zhou4Xi‐Yong Yu5Xue‐Yan Jiang6Shi‐Ying Li7Key Laboratory of Biological Targeting Diagnosis Therapy and Rehabilitation of Guangdong Higher Education Institutes The Fifth Affiliated Hospital Guangzhou Medical University Guangzhou 510700 P. R. ChinaThe Fifth Affiliated Hospital Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology the NMPA and State Key Laboratory of Respiratory Disease the School of Pharmaceutical Sciences Guangzhou Medical University Guangzhou 511436 P. R. ChinaThe Fifth Affiliated Hospital Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology the NMPA and State Key Laboratory of Respiratory Disease the School of Pharmaceutical Sciences Guangzhou Medical University Guangzhou 511436 P. R. ChinaThe Fifth Affiliated Hospital Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology the NMPA and State Key Laboratory of Respiratory Disease the School of Pharmaceutical Sciences Guangzhou Medical University Guangzhou 511436 P. R. ChinaKey Laboratory of Biological Targeting Diagnosis Therapy and Rehabilitation of Guangdong Higher Education Institutes The Fifth Affiliated Hospital Guangzhou Medical University Guangzhou 510700 P. R. ChinaThe Fifth Affiliated Hospital Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology the NMPA and State Key Laboratory of Respiratory Disease the School of Pharmaceutical Sciences Guangzhou Medical University Guangzhou 511436 P. R. ChinaThe Fifth Affiliated Hospital Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology the NMPA and State Key Laboratory of Respiratory Disease the School of Pharmaceutical Sciences Guangzhou Medical University Guangzhou 511436 P. R. ChinaThe Fifth Affiliated Hospital Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology the NMPA and State Key Laboratory of Respiratory Disease the School of Pharmaceutical Sciences Guangzhou Medical University Guangzhou 511436 P. R. ChinaAbstract The chemo‐regulation abilities of chemotherapeutic medications are appealing to address the low immunogenicity, immunosuppressive lactate microenvironment, and adaptive immune resistance of colorectal cancer. In this work, the proteolysis targeting chimera (PROTAC) of BRD4 (dBET57) is found to downregulate colorectal cancer glycolysis through the transcription inhibition of c‐Myc, which also inhibits the expression of programmed death ligand 1 (PD‐L1) to reverse immune evasion and avoid adaptive immune resistance. Based on this, self‐delivery nano‐PROTACs (designated as DdLD NPs) are further fabricated by the self‐assembly of doxorubicin (DOX) and dBET57 with the assistance of DSPE‐PEG2000. DdLD NPs can improve the stability, intracellular delivery, and tumor targeting accumulation of DOX and dBET57. Meanwhile, the chemotherapeutic effect of DdLD NPs can efficiently destroy colorectal cancer cells to trigger a robust immunogenic cell death (ICD). More importantly, the chemo‐regulation effects of DdLD NPs can inhibit colorectal cancer glycolysis to reduce the lactate production, and downregulate the PD‐L1 expression through BRD4 degradation. Taking advantages of the chemotherapy and chemo‐regulation ability, DdLD NPs systemically activated the antitumor immunity to suppress the primary and metastatic colorectal cancer progression without inducing any systemic side effects. Such self‐delivery nano‐PROTACs may provide a new insight for chemotherapy‐enabled tumor immunotherapy.https://doi.org/10.1002/advs.202309204chemotherapycolorectal cancerimmunotherapynano‐PROTACsself‐delivery |
| spellingShingle | Lin‐Ping Zhao Rong‐Rong Zheng Xiao‐Na Rao Chu‐Yu Huang Hang‐Yu Zhou Xi‐Yong Yu Xue‐Yan Jiang Shi‐Ying Li Chemotherapy‐Enabled Colorectal Cancer Immunotherapy of Self‐Delivery Nano‐PROTACs by Inhibiting Tumor Glycolysis and Avoiding Adaptive Immune Resistance Advanced Science chemotherapy colorectal cancer immunotherapy nano‐PROTACs self‐delivery |
| title | Chemotherapy‐Enabled Colorectal Cancer Immunotherapy of Self‐Delivery Nano‐PROTACs by Inhibiting Tumor Glycolysis and Avoiding Adaptive Immune Resistance |
| title_full | Chemotherapy‐Enabled Colorectal Cancer Immunotherapy of Self‐Delivery Nano‐PROTACs by Inhibiting Tumor Glycolysis and Avoiding Adaptive Immune Resistance |
| title_fullStr | Chemotherapy‐Enabled Colorectal Cancer Immunotherapy of Self‐Delivery Nano‐PROTACs by Inhibiting Tumor Glycolysis and Avoiding Adaptive Immune Resistance |
| title_full_unstemmed | Chemotherapy‐Enabled Colorectal Cancer Immunotherapy of Self‐Delivery Nano‐PROTACs by Inhibiting Tumor Glycolysis and Avoiding Adaptive Immune Resistance |
| title_short | Chemotherapy‐Enabled Colorectal Cancer Immunotherapy of Self‐Delivery Nano‐PROTACs by Inhibiting Tumor Glycolysis and Avoiding Adaptive Immune Resistance |
| title_sort | chemotherapy enabled colorectal cancer immunotherapy of self delivery nano protacs by inhibiting tumor glycolysis and avoiding adaptive immune resistance |
| topic | chemotherapy colorectal cancer immunotherapy nano‐PROTACs self‐delivery |
| url | https://doi.org/10.1002/advs.202309204 |
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