NR4a1/2 deletion promotes accumulation of TCF1+ stem-like precursors of exhausted CD8+ T cells in the tumor microenvironment

T cell exhaustion impairs tumor immunity and contributes to resistance against immune checkpoint inhibitors. The nuclear receptor subfamily 4 group A (NR4a) family of nuclear receptors plays a crucial role in driving T cell exhaustion. In this study, we observe that NR4a1 and NR4a2 deficiency in CD8+ tumor-infiltrating lymphocytes (TILs) results in potent tumor eradication and exhibits not only reduced exhaustion characteristics but also an increase in the precursors/progenitors of exhausted T (Pre-Tex) cell fraction. Serial transfers of NR4a1−/−NR4a2−/−CD8+ TILs into tumor-bearing mice result in the expansion of TCF1+ (Tcf7+) stem-like Pre-Tex cells, whereas wild-type TILs are depleted upon secondary transfer. NR4a1/2-deficient CD8+ T cells express higher levels of stemness/memory-related genes and illustrate potent mitochondrial oxidative phosphorylation. Collectively, these findings suggest that inhibiting NR4a in tumors represents a potent immuno-oncotherapy strategy by increasing stem-like Pre-Tex cells and reducing exhaustion of CD8+ T cells. [Display omitted] •The deletion of NR4a1/2 in T cells enhances anti-tumor immunity•Loss of NR4a1/2 increases TCF1+ stem-like precursors of exhausted CD8+ T cells•Lack of NR4a1/2 in T cells promotes glycolysis and oxidative phosphorylation•NR4a1/2-deficient T cells enhance persistence in the tumor microenvironment Srirat et al. demonstrate that loss of NR4a nuclear orphan receptors in T cells enhances the accumulation of TCF1+ stem-like precursors of exhausted CD8+ T cells and potently promotes anti-tumor immunity. NR4a deletion enhances cellular energy metabolism, driven by glycolysis and oxidative phosphorylation.