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.