Stem-like TCF7+ CD8 T cells sustain anti-tumor responses and support immune checkpoint blockade. We systematically identified regulators of this cell state using genome-wide CRISPR screens in primary T cells in vitro. Using random barcodes to link clonal relationships with guide identity and transcriptional states in single cells, we inferred differentiation trajectories and differentiation rates of CD8 T cells in tumors, while mitigating confounding clonal bias. We found that Trim28-deficient T cells in tumors were enriched in the TCF7+ cell state, depleted in cycling and terminal effector states, and uniquely generated a tissue-resident memory (TRM)-like state with increased chromatin accessibility at known TRM loci as well as repeat elements. Despite the increase in TCF7+ CD8 T cells, loss of Trim28 did not improve tumor control, likely because of reduced effector differentiation, highlighting the need for tuning the balance and dynamics of stem-like versus effector states for effective tumor clearance.
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