Targeting glutamine metabolism with photodynamic immunotherapy for metastatic tumor eradication

• Published in: Journal of controlled release 2023-05, Vol.357, p.460-471
• Main Authors: Zhao, Linping, Rao, Xiaona, Zheng, Rongrong, Huang, Chuyu, Kong, Renjiang, Yu, Xiyong, Cheng, Hong, Li, Shiying
• Format: Article
• Language: English
• Subjects: CD8-Positive T-Lymphocytes; Cell Line, Tumor; Glutamine; Glutamine metabolism; Immune checkpoint blockade; Immunogenic cell death; Immunotherapy; Photochemotherapy; Photodynamic therapy; Photosensitizing Agents - therapeutic use; Self-delivery; Tumor Microenvironment
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2023.04.027

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. Photodynamic immunostimulant (BVC) is developed through the self-assembly of photosensitizer (Ce6), ASCT2 inhibitor (V9302) and PD1/PDL1 blocker (BMS). Tumor metabolism reprogramming capacity of BVC can inhibit alanine-serine-cysteine transporter 2 (ASCT2) to transport glutamine and synthesize glutathione, contributing to improving the immune recognition by T cells and blocking the immune escape of tumor cells for metastatic tumor eradication. [Display omitted]