Drug Delivery Engineering Strategies Targeting CD4+/CD8+ T Cell Exhaustion to Improve the Tumor Immunosuppressive Microenvironment

Abstract: CD4⁺/CD8⁺ T cell exhaustion, characterized by impaired effector function, sustained expression of inhibitory receptors, and diminished proliferative capacity, is a core driver in the formation of the tumor immunosuppressive microenvironment (TME) and a major obstacle to antitumor immunotherapy. Nanomaterial-based drug delivery systems (NDDSs) have emerged as potential tools for targeting exhausted T cells (Tex), leveraging their unique advantages in precise targeting, controlled release, enhanced bioavailability, and reduced off-target toxicity. This article reviews the latest advances in NDDS-mediated delivery strategies targeting CD4⁺/CD8⁺ Tex cells, encompassing the delivery of immune checkpoint inhibitors, cytokines, small molecule modulators, and nucleic acid drugs. These strategies aim to reverse Tex cell dysfunction by modulating key molecular pathways involved in T cell exhaustion (like, PD-1/PD-L1, CTLA-4, NF-κB, and STAT signaling pathways), thereby enhancing T cell-mediated antitumor immune responses and remodeling the tumor immunosuppressive microenvironment. Finally, the challenges and prospects of utilizing NDDSs to target T cell exhaustion for tumor immunotherapy are briefly discussed, providing a reference for the development of novel antitumor therapeutic strategies. Keywords: nanomaterials, tumor immunotherapy, T cells, T cell exhaustion, tumor microenvironment