The transcriptional repressor Fli1 inhibits proteostasis during nutrient stress to limit NK cell persistence in solid tumors

• Solid tumor-infiltrating human NK cells induce proteostasis regulation genes • TIFM is sufficient to drive proteostasis imbalance and human NK cell dysfunction • Fli1 epigenetically represses unfolded protein response genes in NK cells • Fli1 deletion improves NK cell persistence, enhancing antitumor responses in vivo Solid tumor-infiltrating human NK cells induce proteostasis regulation genes TIFM is sufficient to drive proteostasis imbalance and human NK cell dysfunction Fli1 epigenetically represses unfolded protein response genes in NK cells Fli1 deletion improves NK cell persistence, enhancing antitumor responses in vivo Tumor-infiltrating natural killer (NK) cells display reduced persistence and effector functions. Here, we examined the mechanisms underlying NK cell dysfunction in cancer. Gene expression analyses of matched tumor-infiltrating and tumor-adjacent human NK cells revealed that regulators of proteostasis were associated with worse survival outcomes. In mice, NK cells accumulated intracellular protein aggregates within 24 h of tumor infiltration. Nutrient stress in the tumor microenvironment (TME) triggered proteostasis imbalance in primary human NK cells, decreasing translation of cytokine receptors and inhibiting NK cell activation. SCENIC regulon and multiomic analyses identified FLI1 as a transcriptional repressor of the unfolded protein response (UPR) in NK cells. FLI1 induction following IL-15 signaling suppressed pro-survival UPR gene expression, limiting human NK cell proteostasis and intra-tumoral persistence. Fli1 deletion reduced protein aggregates and enhanced NK cell-mediated tumor control in vivo . Thus, the TME metabolome induces NK cell dysfunction through proteostasis imbalance, and FLI1 targeting may enhance NK cell anti-tumor function.