Lysosome blockade induces divergent metabolic programs in macrophages and tumours for cancer immunotherapy
Abstract Background Platinum-drugs based chemotherapy in clinic increases the potency of tumor cells to produce M2 macrophages, thus leading to poor anti-metastatic activity and immunosuppression. Lysosome metabolism is critical for cancer cell migration and invasion, but how it promotes antitumor i...
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2023-08-01
|
| Series: | Journal of Experimental & Clinical Cancer Research |
| Online Access: | https://doi.org/10.1186/s13046-023-02768-0 |
| _version_ | 1797451021468827648 |
|---|---|
| author | Jing Ma Ruijuan Ma Xueke Zeng Liming Zhang Jianing Liu Wei Zhang Tao Li Hanjing Niu Guochen Bao Chaojie Wang Peng George Wang Jiajia Wang Xia Li Taotao Zou Songqiang Xie |
| author_facet | Jing Ma Ruijuan Ma Xueke Zeng Liming Zhang Jianing Liu Wei Zhang Tao Li Hanjing Niu Guochen Bao Chaojie Wang Peng George Wang Jiajia Wang Xia Li Taotao Zou Songqiang Xie |
| author_sort | Jing Ma |
| collection | DOAJ |
| description | Abstract Background Platinum-drugs based chemotherapy in clinic increases the potency of tumor cells to produce M2 macrophages, thus leading to poor anti-metastatic activity and immunosuppression. Lysosome metabolism is critical for cancer cell migration and invasion, but how it promotes antitumor immunity in tumours and macrophages is poorly understood and the underlying mechanisms are elusive. The present study aimed to explore a synergistic strategy to dismantle the immunosuppressive microenvironment of tumours and metallodrugs discovery by using the herent metabolic plasticity. Methods Naphplatin was prepared by coordinating an active alkaline moiety to cisplatin, which can regulate the lysosomal functions. Colorectal carcinoma cells were selected to perform the in vivo biological assays. Blood, tumour and spleen tissues were collected and analyzed by flow cytometry to further explore the relationship between anti-tumour activity and immune cells. Transformations of bone marrow derived macrophage (BMDM) and M2-BMDM to the M1 phenotype was confirmed after treatment with naphplatin. The key mechanisms of lysosome-mediated mucolipin-1(Mcoln1) and mitogen-activated protein kinase (MAPK) activation in M2 macrophage polarization have been unveiled. RNA sequencing (RNA-seq) was used to further explore the key mechanism underlying high-mobility group box 1(HMGB1)-mediated Cathepsin L(CTSL)-lysosome function blockade. Results We demonstrated that naphplatin induces divergent lysosomal metabolic programs and reprograms macrophages in tumor cells to terminate the vicious tumour-associated macrophages (TAMs)-MDSCs-Treg triangle. Mechanistically, macrophages treated with naphplatin cause lysosome metabolic activation by triggering Ca2+ release via Mcoln1, which induces the activation of p38 and nuclear factor-κB (NF-κB) and finally results in polarizing M2 macrophages. In contrast, HMGB1-mediated lysosome metabolic blockade in cancer cells is strongly linked to antitumor effects by promoting cytoplasmic translocation of HMGB1. Conclusions This study reveals the crucial strategies of macrophage-based metallodrugs discovery that are able to treat both immunologically “hot” and “cold” cancers. Different from traditional platinum-based antitumour drugs by inhibition of DNAs, we also deliver a strong antitumour strategy by targeting lysosome to induce divergent metabolic programs in macrophages and tumours for cancer immunotherapy. |
| first_indexed | 2024-03-09T14:48:56Z |
| format | Article |
| id | doaj.art-002eb2bdab89473f94a351ef49dadf5c |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-03-09T14:48:56Z |
| publishDate | 2023-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-002eb2bdab89473f94a351ef49dadf5c2023-11-26T14:34:31ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662023-08-0142111510.1186/s13046-023-02768-0Lysosome blockade induces divergent metabolic programs in macrophages and tumours for cancer immunotherapyJing Ma0Ruijuan Ma1Xueke Zeng2Liming Zhang3Jianing Liu4Wei Zhang5Tao Li6Hanjing Niu7Guochen Bao8Chaojie Wang9Peng George Wang10Jiajia Wang11Xia Li12Taotao Zou13Songqiang Xie14School of Pharmacy, Institute of Chemical Biology, Henan Province Engineering Research Center of High Value Utilization to Natural Medical Resource in Yellow River Basin, State key Laboratory of Antiviral Drugs, School of Pharmacy, Henan UniversitySchool of Pharmacy, Institute of Chemical Biology, Henan Province Engineering Research Center of High Value Utilization to Natural Medical Resource in Yellow River Basin, State key Laboratory of Antiviral Drugs, School of Pharmacy, Henan UniversityJoint National Laboratory for Antibody Drug Engineering, Henan UniversityJoint National Laboratory for Antibody Drug Engineering, Henan UniversitySchool of Pharmacy, Institute of Chemical Biology, Henan Province Engineering Research Center of High Value Utilization to Natural Medical Resource in Yellow River Basin, State key Laboratory of Antiviral Drugs, School of Pharmacy, Henan UniversitySchool of Pharmacy, Institute of Chemical Biology, Henan Province Engineering Research Center of High Value Utilization to Natural Medical Resource in Yellow River Basin, State key Laboratory of Antiviral Drugs, School of Pharmacy, Henan UniversitySchool of Pharmacy, Institute of Chemical Biology, Henan Province Engineering Research Center of High Value Utilization to Natural Medical Resource in Yellow River Basin, State key Laboratory of Antiviral Drugs, School of Pharmacy, Henan UniversitySchool of Pharmacy, Institute of Chemical Biology, Henan Province Engineering Research Center of High Value Utilization to Natural Medical Resource in Yellow River Basin, State key Laboratory of Antiviral Drugs, School of Pharmacy, Henan UniversityInstitute for Biomedical Materials and Devices (IBMD), Faculty of Science, University of Technology SydneyThe Key Laboratory of Natural Medicine and Immuno-Engineering, Henan UniversitySchool of Medicine, The Southern University of Science and TechnologyJoint National Laboratory for Antibody Drug Engineering, Henan UniversityJoint National Laboratory for Antibody Drug Engineering, Henan UniversitySchool of Pharmaceutical Sciences Sun Yat, Sen UniversitySchool of Pharmacy, Institute of Chemical Biology, Henan Province Engineering Research Center of High Value Utilization to Natural Medical Resource in Yellow River Basin, State key Laboratory of Antiviral Drugs, School of Pharmacy, Henan UniversityAbstract Background Platinum-drugs based chemotherapy in clinic increases the potency of tumor cells to produce M2 macrophages, thus leading to poor anti-metastatic activity and immunosuppression. Lysosome metabolism is critical for cancer cell migration and invasion, but how it promotes antitumor immunity in tumours and macrophages is poorly understood and the underlying mechanisms are elusive. The present study aimed to explore a synergistic strategy to dismantle the immunosuppressive microenvironment of tumours and metallodrugs discovery by using the herent metabolic plasticity. Methods Naphplatin was prepared by coordinating an active alkaline moiety to cisplatin, which can regulate the lysosomal functions. Colorectal carcinoma cells were selected to perform the in vivo biological assays. Blood, tumour and spleen tissues were collected and analyzed by flow cytometry to further explore the relationship between anti-tumour activity and immune cells. Transformations of bone marrow derived macrophage (BMDM) and M2-BMDM to the M1 phenotype was confirmed after treatment with naphplatin. The key mechanisms of lysosome-mediated mucolipin-1(Mcoln1) and mitogen-activated protein kinase (MAPK) activation in M2 macrophage polarization have been unveiled. RNA sequencing (RNA-seq) was used to further explore the key mechanism underlying high-mobility group box 1(HMGB1)-mediated Cathepsin L(CTSL)-lysosome function blockade. Results We demonstrated that naphplatin induces divergent lysosomal metabolic programs and reprograms macrophages in tumor cells to terminate the vicious tumour-associated macrophages (TAMs)-MDSCs-Treg triangle. Mechanistically, macrophages treated with naphplatin cause lysosome metabolic activation by triggering Ca2+ release via Mcoln1, which induces the activation of p38 and nuclear factor-κB (NF-κB) and finally results in polarizing M2 macrophages. In contrast, HMGB1-mediated lysosome metabolic blockade in cancer cells is strongly linked to antitumor effects by promoting cytoplasmic translocation of HMGB1. Conclusions This study reveals the crucial strategies of macrophage-based metallodrugs discovery that are able to treat both immunologically “hot” and “cold” cancers. Different from traditional platinum-based antitumour drugs by inhibition of DNAs, we also deliver a strong antitumour strategy by targeting lysosome to induce divergent metabolic programs in macrophages and tumours for cancer immunotherapy.https://doi.org/10.1186/s13046-023-02768-0 |
| spellingShingle | Jing Ma Ruijuan Ma Xueke Zeng Liming Zhang Jianing Liu Wei Zhang Tao Li Hanjing Niu Guochen Bao Chaojie Wang Peng George Wang Jiajia Wang Xia Li Taotao Zou Songqiang Xie Lysosome blockade induces divergent metabolic programs in macrophages and tumours for cancer immunotherapy Journal of Experimental & Clinical Cancer Research |
| title | Lysosome blockade induces divergent metabolic programs in macrophages and tumours for cancer immunotherapy |
| title_full | Lysosome blockade induces divergent metabolic programs in macrophages and tumours for cancer immunotherapy |
| title_fullStr | Lysosome blockade induces divergent metabolic programs in macrophages and tumours for cancer immunotherapy |
| title_full_unstemmed | Lysosome blockade induces divergent metabolic programs in macrophages and tumours for cancer immunotherapy |
| title_short | Lysosome blockade induces divergent metabolic programs in macrophages and tumours for cancer immunotherapy |
| title_sort | lysosome blockade induces divergent metabolic programs in macrophages and tumours for cancer immunotherapy |
| url | https://doi.org/10.1186/s13046-023-02768-0 |
| work_keys_str_mv | AT jingma lysosomeblockadeinducesdivergentmetabolicprogramsinmacrophagesandtumoursforcancerimmunotherapy AT ruijuanma lysosomeblockadeinducesdivergentmetabolicprogramsinmacrophagesandtumoursforcancerimmunotherapy AT xuekezeng lysosomeblockadeinducesdivergentmetabolicprogramsinmacrophagesandtumoursforcancerimmunotherapy AT limingzhang lysosomeblockadeinducesdivergentmetabolicprogramsinmacrophagesandtumoursforcancerimmunotherapy AT jianingliu lysosomeblockadeinducesdivergentmetabolicprogramsinmacrophagesandtumoursforcancerimmunotherapy AT weizhang lysosomeblockadeinducesdivergentmetabolicprogramsinmacrophagesandtumoursforcancerimmunotherapy AT taoli lysosomeblockadeinducesdivergentmetabolicprogramsinmacrophagesandtumoursforcancerimmunotherapy AT hanjingniu lysosomeblockadeinducesdivergentmetabolicprogramsinmacrophagesandtumoursforcancerimmunotherapy AT guochenbao lysosomeblockadeinducesdivergentmetabolicprogramsinmacrophagesandtumoursforcancerimmunotherapy AT chaojiewang lysosomeblockadeinducesdivergentmetabolicprogramsinmacrophagesandtumoursforcancerimmunotherapy AT penggeorgewang lysosomeblockadeinducesdivergentmetabolicprogramsinmacrophagesandtumoursforcancerimmunotherapy AT jiajiawang lysosomeblockadeinducesdivergentmetabolicprogramsinmacrophagesandtumoursforcancerimmunotherapy AT xiali lysosomeblockadeinducesdivergentmetabolicprogramsinmacrophagesandtumoursforcancerimmunotherapy AT taotaozou lysosomeblockadeinducesdivergentmetabolicprogramsinmacrophagesandtumoursforcancerimmunotherapy AT songqiangxie lysosomeblockadeinducesdivergentmetabolicprogramsinmacrophagesandtumoursforcancerimmunotherapy |