Temperature sensitive liposome based cancer nanomedicine enables tumour lymph node immune microenvironment remodelling

• Published in: Nature communications 2023-04, Vol.14 (1), p.2248-17, Article 2248
• Main Authors: Fu, Shunli, Chang, Lili, Liu, Shujun, Gao, Tong, Sang, Xiao, Zhang, Zipeng, Mu, Weiwei, Liu, Xiaoqing, Liang, Shuang, Yang, Han, Yang, Huizhen, Ma, Qingping, Liu, Yongjun, Zhang, Na
• Format: Article
• Language: English
• Subjects: 13/31; 631/250/251; 631/250/2520; 631/61/350/354; 631/67/1059; 64/60; Cancer; Cancer immunotherapy; Cell death; Cytotoxicity; Gelatinase A; Humanities and Social Sciences; Humans; Immune checkpoint inhibitors; Immunogenicity; Immunoregulation; Immunotherapy; Interleukin 15; Liposomes; Lymph nodes; Lymph Nodes - pathology; Lymphatic system; Lymphocytes; Lymphocytes T; Microenvironments; multidisciplinary; Nanomedicine; Nanoparticles; Nanotechnology; Neoplasms - pathology; Neoplasms - therapy; PD-1 protein; pH effects; Science; Science (multidisciplinary); Temperature; Tumor Microenvironment; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-38014-6

Targeting tumour immunosuppressive microenvironment is a crucial strategy in immunotherapy. However, the critical role of the tumour lymph node (LN) immune microenvironment (TLIME) in the tumour immune homoeostasis is often ignored. Here, we present a nanoinducer, NIL-IM-Lip, that remodels the suppressed TLIME via simultaneously mobilizing T and NK cells. The temperature-sensitive NIL-IM-Lip is firstly delivered to tumours, then directed to the LNs following pH-sensitive shedding of NGR motif and MMP2-responsive release of IL-15. IR780 and 1-MT induces immunogenic cell death and suppress regulatory T cells simultaneously during photo-thermal stimulation. We demonstrate that combining NIL-IM-Lip with anti-PD-1 significantly enhances the effectiveness of T and NK cells, leading to greatly suppressed tumour growth in both hot and cold tumour models, with complete response in some instances. Our work thus highlights the critical role of TLIME in immunotherapy and provides proof of principle to combine LN targeting with immune checkpoint blockade in cancer immunotherapy. The tumour lymph node microenvironment is an important contributor to the immune suppressiveness of tumours. Here authors target the tumours and the lymph node simultaneously via a pH and photothermal therapy targeted nanoparticle, and show mobilisation of anti-tumour cytotoxic T cells and NK cells and synergistic therapeutic effect with immune checkpoint blockade.