Related Experiment Video

Updated: May 5, 2026

SorLA and CLC:CLF-1-dependent Downregulation of CNTFRα as Demonstrated by Western Blotting, Inhibition of Lysosomal Enzymes, and Immunocytochemistry
10:16

SorLA and CLC:CLF-1-dependent Downregulation of CNTFRα as Demonstrated by Western Blotting, Inhibition of Lysosomal Enzymes, and Immunocytochemistry

Published on: January 6, 2017

7.2K

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

Jeong Hyun Ji1, Wesley R Armstrong2, Joey H Li2

  • 1Department 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.

Immunity
|February 19, 2026
PubMed

Insights

Tumor-infiltrating natural killer (NK) cells become dysfunctional due to protein buildup in the tumor microenvironment. Targeting FLI1 may restore NK cell anti-tumor activity.

Area of Science:

  • Immunology
  • Cell Biology
  • Cancer Research

Background:

  • Tumor-infiltrating natural killer (NK) cells exhibit impaired persistence and effector functions in the tumor microenvironment (TME).
  • Understanding the mechanisms of NK cell dysfunction is crucial for improving cancer immunotherapy.

Purpose of the Study:

  • To investigate the molecular mechanisms driving NK cell dysfunction within the TME.
  • To identify potential therapeutic targets for enhancing NK cell anti-tumor activity.

Main Methods:

  • Gene expression analysis of human NK cells from tumors and adjacent tissues.
  • In vivo studies using mouse models to assess NK cell behavior and tumor control.
  • Multiomic analyses, including SCENIC regulon analysis, to identify key regulatory factors.
  • Assessment of proteostasis, protein aggregation, and unfolded protein response (UPR) in NK cells.

Main Results:

  • Regulators of proteostasis correlated with poorer survival outcomes in cancer patients.
  • NK cells infiltrating tumors rapidly accumulated intracellular protein aggregates.
  • Nutrient stress in the TME induced proteostasis imbalance, impairing NK cell activation and cytokine receptor translation.
  • FLI1 was identified as a repressor of the UPR, and its induction suppressed pro-survival UPR genes, limiting NK cell proteostasis and persistence.
  • Deletion of Fli1 in mice reduced protein aggregates and improved NK cell-mediated tumor control.

Conclusions:

  • The TME metabolome contributes to NK cell dysfunction via proteostasis imbalance.
  • FLI1 plays a critical role in suppressing NK cell proteostasis and intra-tumoral persistence.
  • Targeting FLI1 presents a potential strategy to enhance NK cell anti-tumor functions in cancer therapy.
Keywords:
Fli1dysfunctionmetabolismnatural killer cellsprotein aggregateproteostasissolid tumorstumor interstitial fluidtumor microenvironmentunfolded protein response

More Related Videos

A Chromatin Immunoprecipitation Assay to Identify Novel NFAT2 Target Genes in Chronic Lymphocytic Leukemia09:52

A Chromatin Immunoprecipitation Assay to Identify Novel NFAT2 Target Genes in Chronic Lymphocytic Leukemia

Published on: December 4, 2018

7.2K
Transfer of Manipulated Tumor-associated Neutrophils into Tumor-Bearing Mice to Study their Angiogenic Potential In Vivo08:19

Transfer of Manipulated Tumor-associated Neutrophils into Tumor-Bearing Mice to Study their Angiogenic Potential In Vivo

Published on: July 20, 2019

5.3K

Related Concept Videos

Eukaryotic Transcription Inhibitors01:52

Eukaryotic Transcription Inhibitors

Certain biochemical processes, such as embryonic development and cell growth regulation, depend on the repression of specific genes. DNA binding proteins known as eukaryotic transcription inhibitors regulate the repression of gene expression in eukaryotes. The presence of these inhibitors at the required location and time in the cell is triggered by the presence of hormones and additional signals from other cells.
Eukaryotic transcription inhibitors usually contain two distinct domains, a...
9.1K
Regulation of Nuclear Protein Sorting01:45

Regulation of Nuclear Protein Sorting

Nuclear protein sorting regulates nucleus composition and gene expression, crucial for determining the fate of a eukaryotic cell. Hence, the entry and exit of molecules across the nuclear envelope is a tightly controlled process. Nuclear protein sorting can be inhibited by one of the following ways: 1) masking cargo signal sequences, 2) modifying the nuclear receptor's affinity for cargo, 3) controlling the nuclear pore size, 4) retaining the cargo during its transit to the cytosol or the...
2.5K
NF-κB-dependent Signaling Pathway02:26

NF-κB-dependent Signaling Pathway

The transcription factor NF-κB was discovered in 1986 in the lab of Nobel laureate Professor David Baltimore, for its interaction with the immunoglobulin light chain enhancer in B-cells. After more than three decades of study, it is now evident that NF-κB regulates the expression of over 100 genes. Most of these genes play an essential role in the innate and adaptive immune responses as well as the inflammatory responses of animals.
NF-κB-dependent Signaling Mechanism
The...
7.7K
Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
4.0K
Regulation of the Unfolded Protein Response01:31

Regulation of the Unfolded Protein Response

Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
2.2K
Stringent Response in E. coli01:23

Stringent Response in E. coli

Bacterial growth is closely tied to nutrient availability, with cells proliferating exponentially under favorable conditions and entering a stationary phase when resources become scarce. This transition is mediated by a regulatory mechanism known as the stringent response, which allows bacteria to adapt to nutrient deprivation by modulating gene expression and metabolic activity.During nutrient scarcity, intracellular amino acid levels decline. It results in the accumulation of uncharged tRNAs...
533