A combinatorial transcription factor screening platform for immune cell reprogramming

Comprehensive Summary

This study presents REPROcode, a combinatorial single-cell screening platform developed to identify transcription factor combinations that enable direct reprogramming of human fibroblasts into immune cell types. Using barcoded lentiviral transcription factor libraries and single cell RNA sequencing, the authors tested hundreds of immune related transcription factors and their combinations. REPROcode successfully identified transcription factor sets capable of inducing specific cellular identities. The platform also resolved optimal transcription factor stoichiometry, identified factors that enhance reprogramming fidelity, and revealed regulators that bias cells toward specific immune states.

Outcomes and Implications

These findings advance the understanding of transcriptional control of immune cell identities and provide a tool for engineering immune cells. By enabling the creation of diverse and functional immune cell types directly from fibroblasts, this work addresses major limitations in immune cell sourcing for immunotherapy. The ability to induce dendritic cells and cytotoxic natural killer-like cells expands opportunities for cancer treatment and immune based therapies. Overall, REPROcode helps establish another approach to study immune cell reprogramming and supports the development of cancer immunotherapies.