2. Academic Validation
  3. The transcriptional repressor Fli1 inhibits proteostasis during nutrient stress to limit NK cell persistence in solid tumors

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

  • Immunity. 2026 Mar 10;59(3):717-733.e10. doi: 10.1016/j.immuni.2026.01.017.
Jeong Hyun Ji 1,  Wesley R Armstrong 2,  Joey H Li 2,  Areeba Lalani 3,  Cassidy D Lee 2,  Varchas Bharadwaj 3,  Kenneth Ho 3,  Jingtong Liang 3,  Alexander Muir 4,  Timothy E O'Sullivan 5
Affiliations

Affiliations

  • 1 Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA.
  • 2 Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA; Medical Scientist Training Program, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
  • 3 Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
  • 4 Department of Cancer Research, University of Chicago, Chicago, IL, USA.
  • 5 Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA. Electronic address: [email protected].
PMID: 41713422 DOI: 10.1016/j.immuni.2026.01.017
Abstract

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.

Keywords

Fli1; dysfunction; metabolism; natural killer cells; protein aggregate; proteostasis; solid tumors; tumor interstitial fluid; tumor microenvironment; unfolded protein response.

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