Chimeric antigen receptor (CAR) T‐cell therapy represents a major advancement in personalized cancer treatment. In this strategy, a patient's own T cells are genetically engineered to express a synthetic receptor that binds a tumor antigen. CAR T cells are then expanded for clinical use and infused back into the patient's body to attack and destroy chemotherapy‐resistant cancer. Dramatic clinical responses and high rates of complete remission have been observed in the setting of CAR T‐cell therapy of B‐cell malignancies. This resulted in two recent FDA approvals of CAR T cells directed against the CD19 protein for treatment of acute lymphoblastic leukemia and diffuse large B‐cell lymphoma. Thus, CAR T cells are arguably one of the first successful examples of synthetic biology and personalized cellular cancer therapy to become commercially available. In this review, we introduce the concept of using CAR T cells to break immunological tolerance to tumors, highlight several challenges in the field, discuss the utility of biomarkers in the context of predicting clinical responses, and offer prospects for developing next‐generation CAR T cell‐based approaches that will improve outcome.

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& Johnson, Poseida Therapeutics, and IASO Biotherapeutics; and serves on the medical advisory board and scientific advisory board (SAB) for IASO Biotherapeutics. BLL and CHJ are scientific founders of Tmunity Therapeutics, for which they have founder's stock. BLL, MMD, CHJ, and JAF have received royalties from Tmunity Therapeutics. CHJ and JAF are founders of DeCART Therapeutics. BLL is a consultant for Novartis and Terumo and SAB member for Avectas, Patheon/Thermo Fisher Scientific Viral Vector Services, Immuneel, In8bio, Ori Biotech, and Vycellix. MMD is a consultant and member of the SAB for Cellares Corporation. SFL is a consultant for Gilead/ Kite. JAF is a consultant for Guidepoint and LEK Consulting.

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Chimeric antigen receptor (CAR) T cell therapy has shown promise in treating hematologic cancers, but resistance is common and efficacy is limited in solid tumors. We found that CAR T cells autonomously propagate epigenetically programmed type I interferon signaling through chronic stimulation, which hampers antitumor function. EGR2 transcriptional regulator knockout not only blocks this type I interferon–mediated inhibitory program but also independently expands early memory CAR T cells with improved efficacy against liquid and solid tumors. The protective effect of EGR2 deletion in CAR T cells against chronic antigen-induced exhaustion can be overridden by interferon-β exposure, suggesting that EGR2 ablation suppresses dysfunction by inhibiting type I interferon signaling. Finally, a refined EGR2 gene signature is a biomarker for type I interferon–associated CAR T cell failure and shorter patient survival. These findings connect prolonged CAR T cell activation with deleterious immunoinflammatory signaling and point to an EGR2–type I interferon axis as a therapeutically amenable biological system. Significance: To improve CAR T cell therapy outcomes, modulating molecular determinants of CAR T cell–intrinsic resistance is crucial. Editing the gene encoding the EGR2 transcriptional regulator renders CAR T cells impervious to type I interferon pathway–induced dysfunction and improves memory differentiation, thereby addressing major barriers to progress for this emerging class of cancer immunotherapies.