Acetylcysteine synergizes PD-1 blockers against colorectal cancer progression by promoting TCF1+PD1+CD8+T cell differentiation

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Abstract PD-1 blockade is essential in treating progressive colorectal cancer (CRC). However, some CRC patients do not respond well to immunotherapy, possibly due to the exhaustion of CD8⁺ T cells in the tumor microenvironment. Acetylcysteine (NAC) can reduce CD8⁺ T cell exhaustion in vitro and induce their differentiation into long-lasting phenotypes, thus enhancing the anti-tumor effect of adoptive T cell transfer. However, whether NAC can be combined with PD-1 blockade in CRC treatment and how NAC regulates CD8⁺ T cell differentiation remains unclear. We demonstrated that NAC synergized PD-1 antibodies to inhibit CRC progression in a mouse CRC model mediated by CD8⁺ T cells. We further found that NAC can induce TCF1⁺PD1⁺CD8⁺ T cell differentiation and reduce the formation of exhausted T cells (Tex) in vitro and in vivo. Moreover, NAC enhanced the expression of Glut4 in CD8⁺ T cells, promoting the differentiation of TCF1⁺PD1⁺CD8⁺ T cells. Our study provides a novel idea for immunotherapy of clinically progressive CRC and suggests that Glut4 may be a new immunometabolic molecular target for regulating CD8⁺ T cell differentiation.