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.
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.
J Control Release. 2023 May;357:460-471. doi: 10.1016/j.jconrel.2023.04.027. Epub 2023 Apr 19.
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.
免疫检查点阻断（ICB）已显示出显著的临床疗效，但由于免疫抑制性肿瘤微环境，其反应可能有所不同。为了增强抗肿瘤免疫，将 ICB 治疗与肿瘤代谢重编程相结合可能是一种有前途的策略。在这项研究中，我们开发了一种名为 BVC 的光免疫刺激剂，旨在通过重编程谷氨酰胺代谢来增强免疫识别并防止免疫逃逸，以消除转移性肿瘤。BVC 是一种无载体自组装纳米颗粒，由光敏剂（氯乙酮）、ASCT2 抑制剂（V9302）和 PD1/PDL1 阻断剂（BMS-1）组成，具有良好的稳定性和增强的药物递送效率。BVC 的强大光动力疗法（PDT）能力归因于其对谷氨酰胺代谢的调节，这影响了肿瘤组织内的氧化还原微环境。通过靶向 ASCT2 介导的谷氨酰胺代谢，BVC 抑制谷氨酰胺转运和 GSH 合成，导致 Fas 和 PDL1 的上调。此外，BVC 介导的 PDT 诱导免疫原性细胞死亡，引发一连串的免疫反应。因此，BVC 不仅增强了 CD8 T 细胞与 Fas 过表达肿瘤细胞之间的免疫识别，而且通过 PD1/PDL1 阻断减少了肿瘤细胞的免疫逃逸，显著有益于转移性肿瘤的消除。这项研究为多协同肿瘤治疗开辟了一条新途径。
