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FLI-ing the script on NK cell persistence: Proteostasis as a limiting factor

Yi-Ju Chou1, Stanley Ching-Cheng Huang1

  • 1Department of Microbial Infection and Immunity, The Ohio State University College of Medicine, Columbus, OH, USA; Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.

Immunity
|March 11, 2026
PubMed

Insights

Natural killer (NK) cells are promising for cancer immunotherapy but struggle in solid tumors. Nutrient stress disrupts their survival by repressing key protein-response programs, limiting their anti-cancer function.

Area of Science:

  • Immunology
  • Cancer Biology
  • Cellular Stress Response

Background:

  • Natural killer (NK) cells are crucial immune cells with potential in cancer immunotherapy.
  • Limited persistence and function of NK cells within solid tumor microenvironments hinder their therapeutic efficacy.

Purpose of the Study:

  • To investigate the mechanisms underlying NK cell dysfunction and limited persistence in solid tumors.
  • To identify key molecular pathways affected by the tumor microenvironment that impact NK cell survival and function.

Main Methods:

  • Analysis of NK cell behavior and gene expression under nutrient-deprived conditions.
  • Investigation of the role of the transcription factor FLI1 in regulating NK cell responses.
  • Assessment of proteostasis and unfolded protein response (UPR) pathways in tumor-infiltrating NK cells.

Main Results:

  • Nutrient stress within tumors triggers FLI1-mediated repression of pro-survival unfolded protein response (UPR) pathways.
  • This repression disrupts proteostasis, leading to impaired NK cell function.
  • Reduced NK cell persistence and effector functions were observed in the tumor microenvironment.

Conclusions:

  • FLI1 acts as a critical regulator linking nutrient stress to NK cell dysfunction in solid tumors.
  • Targeting FLI1 or UPR pathways may enhance NK cell persistence and immunotherapy outcomes.
  • Understanding these mechanisms is vital for improving adoptive NK cell-based cancer therapies.

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