2. Academic Validation
  3. Local Exosome Inhibition Potentiates Mild Photothermal Immunotherapy Against Breast Cancer

Local Exosome Inhibition Potentiates Mild Photothermal Immunotherapy Against Breast Cancer

  • Adv Sci (Weinh). 2025 Jan;12(2):e2406328. doi: 10.1002/advs.202406328.
Qian Chen 1 2 3 4,  Yanan Li 5,  Jiameng Hu 6 7,  Zhenyu Xu 1 2 3,  Shengyi Wang 1 2 3,  Naicong Cai 1 2 3,  Mengjiao He 1 2 3,  Yifang Xiao 1 2 3,  Yuan Ding 8,  Mengjuan Sun 1 2 3,  Chunjiayu Li 1 2 3,  Yiyang Cao 1 2 3,  Zhongyuan Wang 1 6,  Fang Zhou 1 4,  Guangji Wang 1 4,  Chen Wang 1 6,  Jiasheng Tu 1 2 3,  Haiyang Hu 1 6 9,  Chunmeng Sun 1 2 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, China.
  • 2 Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, China.
  • 3 NMPA Key Laboratory for Research and Evaluation of Pharmaceutical Preparations and Excipients, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China.
  • 4 Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China.
  • 5 School of Food and Pharmaceutical Engineering, Nanjing Normal University, No. 1 Wenyuan Road, Nanjing, 210023, China.
  • 6 School of Life Science and Technology, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, China.
  • 7 Institute of Systems and Physical Biology, Shenzhen Bay Laboratory, Shenzhen, 518055, China.
  • 8 Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai, 201203, China.
  • 9 Central Laboratory, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, China.
PMID: 39574346 DOI: 10.1002/advs.202406328
Abstract

Limited immune infiltration within the tumor microenvironment (TME) hampers the efficacy of Immune Checkpoint blockade (ICB) therapy. To enhance immune infiltration, mild photothermal therapy (PTT) is often combined with immunotherapy. However, the impact of mild PTT on the TME remains unclear. The bioinformatics analyses reveal that mild PTT amplifies immune cell infiltration and stimulates T-cell activity. Notably, it accelerates the release of tumor cell-derived exosomes (TEX) and upregulates PD-L1 expression on both tumor cells and TEX. Consequently, it is proposed that locally inhibiting TEX release is crucial for overcoming the adverse effects of mild PTT, thereby enhancing ICB therapy. Thus, a multi-stage drug delivery system is designed that concurrently delivers photosensitizers (reduced graphene oxide nanosheets, NRGO), anti-PD-L1 Antibodies, and exosome inhibitors (sulfisoxazole). The system employs a temperature-sensitive lipid gel as the primary carrier, with NRGO serving as a secondary carrier that supports photothermal conversion and incorporation of sulfisoxazole. Importantly, controlled drug release is achieved using near-infrared radiation. The findings indicate that this local combination therapy remodels the immunosuppressive TME through exosome inhibition and enhanced immune cell infiltration, while also boosting T-cell activity to trigger systemic antitumor immunity, showcasing the remarkable efficacy of this combination strategy in eradicating cold tumors.

Keywords

combination immunotherapy; exosome inhibition; immune checkpoint blockade; mild photothermal therapy; multistage drug depot.

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