Due to limitation of penetration therapy with first and second-generation photodynamic therapy (PDT) photosensitizers, an NIR II-guided photoactivatable complex was proposed via the self-assembly of the photosensitive polymer PTSQ and the electrostatic adsorption of siPD-L1 to enhance cancer immunotherapy.
The PTSQ/siRNA could trigger complex destructive effects by generating ROS with laser irradiation, facilitating endosomal escape of siPD-L1 and immunogenic cell death.
The spatiotemporal synergy between PDT and immune checkpoint blockade effectively overcome immunosuppression within tumor microenvironment, ultimately enhancing the efficacy of cancer immunotherapy.
Abstract:
Photodynamic therapy (PDT) triggers immunogenic cell death (ICD) within the tumor microenvironment, consequently enhancing tumor immunotherapy. However, the maximum absorption wavelengths of first and second-generation PDT photosensitizers limit the penetration depth of therapeutics, resulting in insufficient anti-tumor outcomes. This study reports a custom-designed polymer, PTSQ, which exhibits significant absorption in the near-infrared region (NIR) window and fluorescence emission spectra within the NIR II range, demonstrating excellent PDT efficiency. Additionally, PTSQ self-assembles into nanomicelles, exhibiting outstanding siRNA delivery. To further enhance tumor immunotherapy, we introduce an immune checkpoint blockade strategy and prepared PTSQ/siPD-L1 complexes. We present a novel approach to tumor treatment by combining NIR light-activated PDT and ICD to enhance siPD-L1 therapy. At the cellular level, PTSQ/siPD-L1 complexes exhibit potent induction of ICD while concurrently suppressing PD-L1 gene expression. In vivo, these complexes significantly impede the growth of CT26, 4T1, and patient-derived xenograft (PDX) tumors. This effect is achieved by promoting in situ ICD, which reverses tumor environment and activates immune cells in tumors and spleens, including T cells, dendritic cells (DCs), and macrophages. Overall, this study offers insights for the development of NIR II-guided cancer immunotherapy and underscores the efficacy of PDT in conjunction with checkpoint blockade for cancer treatment.
Author list:
Yuquan Zhang†, Jie Wang†, Tian Zhang, Dongsheng Tang, Haiyin Yang, Shuai Guo, Yuchuan Fan, Caixia Sun, Haihua Xiao, Yuanyu Huang*, Yuhua Weng*
How to cite:
Y. Zhang, J. Wang, T. Zhang, D. Tang, H. Yang, S. Guo, Y. Fan, C. Sun, H. Xiao, Y. Huang, Y. Weng, Exploration 2025, 20240047.
https://doi.org/10.1002/EXP.20240047