Fig. 5.

The occurrence and rescue of CD8⁺ T cell exhaustion program within solid tumors. (a) In solid tumors, chronic antigen stimulation signals from the TCR are transduced and transformed into increased accessibility of TOX and decreased availability of TCF1, ultimately driving the occurrence of the exhaustion program characterized by increased expression of immunosuppressive receptors, which limits the anti-tumor ability of CD8⁺ T cells. (b) By blocking inhibitory receptor signals, regulating the availability of intracellular immune checkpoints, and knocking out or knocking in of gene loci with weakened or enhanced function, the exhausted state of CD8⁺ T cells can be effectively reversed, restoring their anti-tumor function. (c) The use of orthogonal cytokine receptor engineering and synthetic Notch (synNotch) receptor engineering to increase the availability and specificity of cytokines for CD8⁺ T cells enable engineered CD8⁺ T cells to achieve effective expansion and improved adaptability