This research explores how transcription factors (TFs) dictate the differentiation of CD8+ T cells into distinct functional or dysfunctional states during infection and cancer. Using the Taiji pipeline, scientists mapped the regulatory fingerprints of nine cellular states, specifically contrasting protective tissue-resident memory (TRM) cells with terminally exhausted (TEXterm) cells. The study identifies the proteasome pathway as a previously unrecognized hallmark of T cell exhaustion and uses in vivo CRISPR screens to pinpoint TFs that drive these specific identities. Functional experiments revealed that deleting newly identified factors like Zscan20 and Jdp2 can reduce exhaustion and significantly improve the success of immunotherapy. These findings provide a systematic framework for engineering T cells to enhance their therapeutic durability and anti-tumor performance. Ultimately, the work establishes a computational and experimental atlas to guide the programming of beneficial immune cell states for medical treatment.

References:

• Chung H K, Liu C, Battu A, et al. Atlas-guided discovery of transcription factors for T cell programming[J]. Nature, 2026: 1-11.