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  3. Targeting glutamine metabolism with photodynamic immunotherapy for metastatic tumor eradication

Targeting glutamine metabolism with photodynamic immunotherapy for metastatic tumor eradication

  • J Control Release. 2023 Apr 19;357:460-471. doi: 10.1016/j.jconrel.2023.04.027.
Linping Zhao 1,  Xiaona Rao 2,  Rongrong Zheng 2,  Chuyu Huang 2,  Renjiang Kong 3,  Xiyong Yu 4,  Hong Cheng 5,  Shiying Li 6
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, PR China; Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou 510700, PR China.
  • 2 Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, PR China.
  • 3 Biomaterials Research Center, School of Biomedical Engineering, Southern Medical University, Guangzhou 510515, PR China.
  • 4 Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, PR China. Electronic address: yuxycn@aliyun.com.
  • 5 Biomaterials Research Center, School of Biomedical Engineering, Southern Medical University, Guangzhou 510515, PR China. Electronic address: chengh@smu.edu.cn.
  • 6 Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, PR China. Electronic address: lisy-sci@gzhmu.edu.cn.
PMID: 37068523 DOI: 10.1016/j.jconrel.2023.04.027
Abstract

Immune Checkpoint blockade (ICB) has shown significant clinical success, yet its responses can vary due to immunosuppressive tumor microenvironments. To enhance antitumor immunity, combining ICB therapy with tumor metabolism reprogramming may be a promising strategy. In this study, we developed a photodynamic immunostimulant called BVC aiming to boost immune recognition and prevent immune escape for metastatic tumor eradication by reprogramming glutamine metabolism. BVC, a carrier free self-assembled nanoparticle, comprises a photosensitizer (chlorin e6), an ASCT2 Inhibitor (V9302) and a PD1/PDL1 blocker (BMS-1), offering favorable stability and enhanced drug delivery efficiency. The potent photodynamic therapy (PDT) capability of BVC is attributed to its regulation of glutamine metabolism, which influences the redox microenvironment within tumor tissues. By targeting ASCT2-mediated glutamine metabolism, BVC inhibits glutamine transport and GSH synthesis, leading to the upregulation of Fas and PDL1. Additionally, BVC-mediated PDT induces immunogenic cell death, triggering a cascade of immune responses. Consequently, BVC not only enhances immune recognition between CD8+ T cells and Fas-overexpressing tumor cells but also reduces tumor cell immune escape through PD1/PDL1 blockade, significantly benefiting metastatic tumor eradication. This study paves a novel approach for multi-synergistic tumor treatment.

Keywords

Glutamine metabolism; Immune checkpoint blockade; Immunogenic cell death; Photodynamic therapy; Self-delivery.

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