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

PD-1 blockade is important in treating progressive colorectal cancer (CRC). However, some patients with CRC have a poor or no response to immunotherapy. An important reason for this problem is 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 constructed a mouse CRC model to study the effect of NAC on tumors. The effect of NAC on CD8+ T cell differentiation and its potential mechanism were explored by cell flow assay and other studies in vitro and ex vivo. We demonstrated that NAC synergized PD-1 antibodies to inhibit CRC progression in a mouse CRC model, mediated by CD8+ T cells. NAC induces TCF1+PD1+CD8+ T cell differentiation and reduces the formation of exhausted T cells (Tex). 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.