Overcoming T Cell Exhaustion in Tumor Microenvironment via Immune Checkpoint Modulation with Nano-Delivery Systems for Enhanced Immunotherapy.

Immune checkpoint blockade (ICB) therapy for tumors has arisen in growing interest. However, the low response rate of tumors to ICB is mainly attributed to the inhibitory infiltration of immune cells in the tumor microenvironment (TME). Despite the promising benefits of ICB, the therapeutic effects of antibodies are dependent on a high dose and long-term usage in the clinic, thereby leading to immune-related adverse effects. Accordingly, ICB combined with nano-delivery systems could be used to overcome T cell exhaustion, which reduces the side effects and the usage of antibodies with higher response rates in patients. In this review, the authors aim to overcome T cell exhaustion in TME via immune checkpoint modulation with nano-delivery systems for enhanced immunotherapy. Several strategies are summarized to combine ICB and nano-delivery systems to further enhance immunotherapy: a) expressing immune checkpoint on the surface of nano-delivery systems; b) loading immune checkpoint inhibitors into nano-delivery systems; c) loading gene-editing technology into nano-delivery systems; and d) nano-delivery systems mediated immune checkpoint modulation. Taken together, ICB combined with nano-delivery systems might be a promising strategy to overcome T cell exhaustion in TME for enhanced immunotherapy.