Research has shown that sarcomas and carcinomas have proven more resistant to CAR T immunotherapy approaches in part because engineered T-cells progressively lose tumor-fighting capacity once they infiltrate a tumor. Immunologists call this cellular fatigue T-cell “exhaustion” or “dysfunction.” In efforts to understand why, La Jolla Institute for Immunology investigators Anjana Rao, PhD, and Patrick Hogan, PhD, have published a series of papers over the last years reporting that a transcription factor that regulates gene expression, called NFAT, switches on downstream genes that weaken T-cell responses to tumors and thus perpetrates T-cell exhaustion. One set of these downstream genes encodes transcription factors known as NR4A, and a previous graduate student, Joyce Chen, showed that genetic elimination of NR4A proteins in tumor-infiltrating CAR T cells improved tumor rejection. However, the identity of additional players cooperating with NFAT and NR4A in that pathway has remained unknown. In a study (“TOX and TOX2 cooperate with NR4A transcription factors to impose CD8+T cell exhaustion”) published online in PNAS from the Rao and Hogan labs, a more complete list of participants in a gene expression network that establishes and maintains T-cell exhaustion is described. The work employs a mouse model to show that genetically eliminating two new factors, TOX and TOX2, also improves eradication of solid melanoma tumors in the CAR T model. This research suggests that comparable interventions to target NR4A and TOX factors in patients may extend the use of CAR T-based immunotherapy to solid tumors.