Fli1 inhibits proteostasis during nutrient stress to limit NK cell persistence in solid tumors [CUT&Tag_FLI1_Human]

Natural killer (NK) cells are critical for the immune response to cancer. However, solid tumor-infiltrating NK cells display reduced persistence and effector functions, limiting their clinical efficacy. To understand the mechanisms that induce human NK cell dysfunction in solid tumors, we compared single-cell gene expression in patient-matched tumor-infiltrating compared to tumor-adjacent NK cells to identify unfolded protein response (UPR) genes associated with worse cancer patient survival. Primary human NK cells accumulated unfolded proteins and induced a chronic UPR response to nutrient stress from the tumor microenvironment metabolome (TMM), sufficient to cause pronounced dysfunction and decreased persistence. Mechanistically, the transcription factor Fli1 epigenetically repressed UPR genes to limit human NK cell proteostasis in the presence of the TMM. CRISPR-mediated Fli1 deletion enhanced unfolded protein clearance, persistence, and tumor control in vivo. Thus, our results suggest that the TMM is sufficient to induce human NK cell dysfunction in solid tumors through the regulation of proteostasis.