Engineered Exosomes Drive Targeted Stabilization of T Cell Exhaustion to Address Immune Checkpoint Inhibitor Resistance

School of Clinical Medicine, Chifeng University, 10138 No. 1, Yingbin Road, Hongshan District, Chifeng City, Inner Mongolia, China

^* Corresponding author: This email address is being protected from spambots. You need JavaScript enabled to view it.

Abstract

Immune checkpoint inhibitors (ICIs) have significantly changed the treatment landscape for various tumors, but primary and secondary drug resistance still persist. Recent studies have shown that the limited efficacy of ICI is not due to the failure of a single signaling axis, but is closely related to the stabilization of the exhausted state of T cells in the tumor immune microenvironment (TME) . Terminal exhausted T cells exhibit persistent functional impairment and fixed transcriptional and epigenetic programs, which make them less responsive to simple programmed death protein 1 (PD-1) or programmed death ligand 1 (PD-L1) blockade. Exosomes, as one key intercellular communication medium inside the TME, take part in antigen presentation regulation, myeloid network shaping, metabolic reprogramming and so on. Along with the development of engineered modifications, the composition, targeting specificity and delivery behavior of exosomes as carriers can be designed; therefore, they become a potential tool for immune status regulation. Based on the above content, this article summarizes current knowledge about ICI resistance, and thus proposes a mechanism framework that engineered exosomes act as “rearrangement carriers of the microenvironment signal network”.