Remodelling of the tumour-lymph node immune microenvironment promotes T- and NK-cell comobilization for tumour immunotherapy

Abstract

Reversing the suppressive tumour immune microenvironment has become a crucial strategy to enhance immunotherapy. Moreover, the immune lymph node (LN) microenvironment significantly influences the efficacy of immune cells. However, the critical role of the LN immune microenvironment on the regulation of antitumour effects is often ignored. Here, we developed the pH/MMP2/temperature triple-sensitive immunomodulatory nanoinducer NIL-IM-Lip, which can be precisely delivered to tumours and directed to the LNs. NIL-IM-Lip relieved the immunosuppressive effects of regulatory T cells (Treg) while coactivating cytotoxic T lymphocytes and natural killer cells both in tumours and LNs to reshape the tumour-lymph node immune microenvironment (TLIME) and enhance antitumour immunotherapy. Furthermore, the combined application of NIL-IM-Lip and the PD-1 mAb significantly enhanced the antitumour effectiveness of CTLs and NK cells. Notably, combination treatment with NIL-IM-Lip and the PD-1 mAb greatly suppressed tumour growth in both hot tumours (B16F10 model) and cold tumours (CT26 model) with a 20% complete response in the B16F10 model. Our work highlights the critical role of the TLIME in immunotherapy, displaying encouraging prospects when combined with PD-1 mAb treatment to strengthen antitumour immune effects, offering a new strategy for clinical use.