Lysosome blockade induces divergent metabolic programs in macrophages and tumours for cancer immunotherapy

Ma，Jing1; Ma，Ruijuan1; Zeng，Xueke2; Zhang，Liming2; Liu，Jianing1; Zhang，Wei1; Li，Tao1; Niu，Hanjing1; Bao，Guochen3; Wang，Chaojie4; Wang，Peng George5; Wang，Jiajia2; Li，Xia2; Zou，Taotao6; Xie，Songqiang1

2023-12-01

10.1186/s13046-023-02768-0

Journal of Experimental and Clinical Cancer Research   Impact Factor & Quartile

1756-9966

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 Ca 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.

SCI

English

Others

Natural Science Foundation of Henan Province[212300410110];Science and Technology Innovation Talents in Universities of Henan Province[222102310216];Science and Technology Innovation Talents in Universities of Henan Province[222102310402];Key Scientific Research Project of Colleges and Universities in Henan Province[22A350002];Natural Science Foundation of Henan Province[232300420047];China Postdoctoral Science Foundation[Grant 2021M701089];

Oncology

Oncology

WOS:001042050200001

BMC

CLINICAL MEDICINE

2-s2.0-85166526359

Scopus

1.School 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 University,Kaifeng,Henan,475004,China
2.Joint National Laboratory for Antibody Drug Engineering,Henan University,Kaifeng, Henan,475004,China
3.Institute for Biomedical Materials and Devices (IBMD),Faculty of Science,University of Technology Sydney,Sydney,Australia
4.The Key Laboratory of Natural Medicine and Immuno-Engineering,Henan University,Kaifeng,475004,China
5.School of Medicine,The Southern University of Science and Technology,Shenzhen,Guangdong,518005,China
6.School of Pharmaceutical Sciences Sun Yat,Sen University,Guangzhou,Guangdong,510006,China

Ma，Jing,Ma，Ruijuan,Zeng，Xueke,et al. Lysosome blockade induces divergent metabolic programs in macrophages and tumours for cancer immunotherapy[J]. Journal of Experimental and Clinical Cancer Research,2023,42(1).

Ma，Jing.,Ma，Ruijuan.,Zeng，Xueke.,Zhang，Liming.,Liu，Jianing.,...&Xie，Songqiang.(2023).Lysosome blockade induces divergent metabolic programs in macrophages and tumours for cancer immunotherapy.Journal of Experimental and Clinical Cancer Research,42(1).

Ma，Jing,et al."Lysosome blockade induces divergent metabolic programs in macrophages and tumours for cancer immunotherapy".Journal of Experimental and Clinical Cancer Research 42.1(2023).