Regulating lactate-related immunometabolism and EMT reversal for colorectal cancer liver metastases using shikonin targeted delivery
Abstract Background There are few effective medications for treating colorectal cancer and liver metastases (CRLM). The interactions among glycolysis, epithelial-mesenchymal transition (EMT), and immune microenvironment contribute to the progression of CRLM. A main glycolytic enzyme pyruvate Kinase...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-05-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13046-023-02688-z |
| _version_ | 1797827239494025216 |
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| author | Li Long Wei Xiong Fenwang Lin Jiazhen Hou Guihua Chen Taoxing Peng Yihao He Rui Wang Qin Xu Yongzhuo Huang |
| author_facet | Li Long Wei Xiong Fenwang Lin Jiazhen Hou Guihua Chen Taoxing Peng Yihao He Rui Wang Qin Xu Yongzhuo Huang |
| author_sort | Li Long |
| collection | DOAJ |
| description | Abstract Background There are few effective medications for treating colorectal cancer and liver metastases (CRLM). The interactions among glycolysis, epithelial-mesenchymal transition (EMT), and immune microenvironment contribute to the progression of CRLM. A main glycolytic enzyme pyruvate Kinase M2 (PKM2) is highly expressed in colorectal cancer and CRLM, and thus can be a potential therapeutic target. Methods A therapeutic strategy was proposed and the shikonin-loaded and hyaluronic acid-modified MPDA nanoparticles (SHK@HA-MPDA) were designed for CRLM therapy via PKM2 inhibition for immunometabolic reprogramming. The treatment efficacy was evaluated in various murine models with liver metastasis of colorectal tumor. Results SHK@HA-MPDA achieved tumor-targeted delivery via hyaluronic acid-mediated binding with the tumor-associated CD44, and efficiently arrested colorectal tumor growth. The inhibition of PKM2 by SHK@HA-MPDA led to the remodeling of the tumor immune microenvironment and reversing EMT by lactate abatement and the suppression of TGFβ signaling; the amount of cytotoxic effector CD8+ T cells was increased while the immunosuppressive MDSCs decreased. Conclusion The work provided a promising targeted delivery strategy for CRLM treatment by regulating glycolysis, EMT, and anticancer immunity. Graphic abstract An immunometabolic strategy for treating colorectal cancer liver metastases using the shikonin-loaded, hyaluronic acid-modified mesoporous polydopamine nanoparticles (SHK@HA-MPDA) via glycolysis inhibition, anticancer immunity activation, and EMT reversal. SHK@HA-MPDA can inhibit cytoplasmic PKM2 and glycolysis of the tumor and reduce lactate flux, and then activate the DCs and remodel the tumor immune microenvironment. The reduced lactate flux can reduce MDSC migration and suppress EMT. |
| first_indexed | 2024-04-09T12:46:10Z |
| format | Article |
| id | doaj.art-5df9893b47a5426aa4ee84de278f5012 |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-04-09T12:46:10Z |
| publishDate | 2023-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-5df9893b47a5426aa4ee84de278f50122023-05-14T11:31:35ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662023-05-0142112010.1186/s13046-023-02688-zRegulating lactate-related immunometabolism and EMT reversal for colorectal cancer liver metastases using shikonin targeted deliveryLi Long0Wei Xiong1Fenwang Lin2Jiazhen Hou3Guihua Chen4Taoxing Peng5Yihao He6Rui Wang7Qin Xu8Yongzhuo Huang9Artemisinin Research Center, Guangzhou University of Chinese MedicineArtemisinin Research Center, Guangzhou University of Chinese MedicineDepartment of Kidney Transplantation, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua UniversitySchool of Chinese Materia Medica, Nanjing University of Chinese MedicineArtemisinin Research Center, Guangzhou University of Chinese MedicineState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesArtemisinin Research Center, Guangzhou University of Chinese MedicineArtemisinin Research Center, Guangzhou University of Chinese MedicineAbstract Background There are few effective medications for treating colorectal cancer and liver metastases (CRLM). The interactions among glycolysis, epithelial-mesenchymal transition (EMT), and immune microenvironment contribute to the progression of CRLM. A main glycolytic enzyme pyruvate Kinase M2 (PKM2) is highly expressed in colorectal cancer and CRLM, and thus can be a potential therapeutic target. Methods A therapeutic strategy was proposed and the shikonin-loaded and hyaluronic acid-modified MPDA nanoparticles (SHK@HA-MPDA) were designed for CRLM therapy via PKM2 inhibition for immunometabolic reprogramming. The treatment efficacy was evaluated in various murine models with liver metastasis of colorectal tumor. Results SHK@HA-MPDA achieved tumor-targeted delivery via hyaluronic acid-mediated binding with the tumor-associated CD44, and efficiently arrested colorectal tumor growth. The inhibition of PKM2 by SHK@HA-MPDA led to the remodeling of the tumor immune microenvironment and reversing EMT by lactate abatement and the suppression of TGFβ signaling; the amount of cytotoxic effector CD8+ T cells was increased while the immunosuppressive MDSCs decreased. Conclusion The work provided a promising targeted delivery strategy for CRLM treatment by regulating glycolysis, EMT, and anticancer immunity. Graphic abstract An immunometabolic strategy for treating colorectal cancer liver metastases using the shikonin-loaded, hyaluronic acid-modified mesoporous polydopamine nanoparticles (SHK@HA-MPDA) via glycolysis inhibition, anticancer immunity activation, and EMT reversal. SHK@HA-MPDA can inhibit cytoplasmic PKM2 and glycolysis of the tumor and reduce lactate flux, and then activate the DCs and remodel the tumor immune microenvironment. The reduced lactate flux can reduce MDSC migration and suppress EMT.https://doi.org/10.1186/s13046-023-02688-zShikoninColorectal cancer liver metastasisGlycolysisPyruvate kinase M2 (PKM2)Epithelial-mesenchymal transition (EMT)Immune microenvironment |
| spellingShingle | Li Long Wei Xiong Fenwang Lin Jiazhen Hou Guihua Chen Taoxing Peng Yihao He Rui Wang Qin Xu Yongzhuo Huang Regulating lactate-related immunometabolism and EMT reversal for colorectal cancer liver metastases using shikonin targeted delivery Journal of Experimental & Clinical Cancer Research Shikonin Colorectal cancer liver metastasis Glycolysis Pyruvate kinase M2 (PKM2) Epithelial-mesenchymal transition (EMT) Immune microenvironment |
| title | Regulating lactate-related immunometabolism and EMT reversal for colorectal cancer liver metastases using shikonin targeted delivery |
| title_full | Regulating lactate-related immunometabolism and EMT reversal for colorectal cancer liver metastases using shikonin targeted delivery |
| title_fullStr | Regulating lactate-related immunometabolism and EMT reversal for colorectal cancer liver metastases using shikonin targeted delivery |
| title_full_unstemmed | Regulating lactate-related immunometabolism and EMT reversal for colorectal cancer liver metastases using shikonin targeted delivery |
| title_short | Regulating lactate-related immunometabolism and EMT reversal for colorectal cancer liver metastases using shikonin targeted delivery |
| title_sort | regulating lactate related immunometabolism and emt reversal for colorectal cancer liver metastases using shikonin targeted delivery |
| topic | Shikonin Colorectal cancer liver metastasis Glycolysis Pyruvate kinase M2 (PKM2) Epithelial-mesenchymal transition (EMT) Immune microenvironment |
| url | https://doi.org/10.1186/s13046-023-02688-z |
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