Self-reinforced photodynamic immunostimulator to downregulate and block PD-L1 for metastatic breast cancer treatment

• Published in: Biomaterials 2023-12, Vol.303, p.122392-122392, Article 122392
• Main Authors: Qiu, Ziwen, Lu, Zhenming, Huang, Jiaqi, Zhong, Yingtao, Yan, Ni, Kong, Renjiang, Cheng, Hong
• Format: Article
• Language: English
• Subjects: B7-H1 Antigen - metabolism; biocompatible materials; breast neoplasms; Breast Neoplasms - drug therapy; cancer therapy; Cell Line, Tumor; Female; Humans; immunity; immunostimulants; Immunotherapy; ligands; metastasis; oxidative stress; peptides; phosphorylation; Photochemotherapy; photosensitizing agents; Photosensitizing Agents - therapeutic use; programmed cell death; protoporphyrin; signal transduction; transactivators
• ISSN: 0142-9612; 1878-5905
• DOI: 10.1016/j.biomaterials.2023.122392

Tumor cells overexpress programmed cell death ligand 1 (PD-L1) to impede immune responses and escape immune elimination. Development of effective combination regimens to sensitize immunotherapy is promising but always challenging. Herein, a self-reinforced photodynamic immunostimulator (designated as PCS) is constructed for metastatic breast cancer treatment through simultaneous downregulation and blockade of PD-L1. Specifically, PCS is prepared by encapsulating signal transducer and activator of transcription 3 (STAT3) inhibitor (Stattic) into photosensitizer (protoporphyrin IX) modified PD-L1 blockade peptide (CVRARTR) through drug self-assembly. PCS can facilitate the targeted drug accumulation in PD-L1 overexpressed breast cancer cells to block PD-L1 and inhibit the phosphorylation of STAT3 to downregulate PD-L1. Moreover, PCS increases intracellular oxidative stress to show a robust anti-proliferation effect through photodynamic therapy (PDT), which also triggers an immunogenic cell death (ICD) to expose the immunostimulatory signals. Consequently, the efficient PD-L1 inhibition and robust PDT of PCS synergistically suppress the malignant growth of breast cancer, and concurrently activate the systemic anti-tumor immunity for metastatic inhibition with no obvious side effects. Such a photodynamic immunostimulator may provide an effective combination regimen for therapies activated immunotherapy against metastatic breast cancer.