Related Experiment Video

Updated: Mar 1, 2026

Natural Killer NK and CAR-NK Cell Expansion Method using Membrane Bound-IL-21-Modified B Cell Line
11:02

Natural Killer NK and CAR-NK Cell Expansion Method using Membrane Bound-IL-21-Modified B Cell Line

Published on: February 8, 2022

6.5K

Metabolic reinvigoration of NK cells by IL-21 enhances immunotherapy against MHC class I-deficient solid tumors

Yi Wang1, Chao Huang2, Guoxin Cai3

  • 1Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland; Institute of Materials Science & Engineering, EPFL, 1015 Lausanne, Switzerland.

Cell Reports
|February 27, 2026
PubMed

Insights

Interleukin 21-Fc (IL-21-Fc) fusion protein revitalizes natural killer (NK) cells by reprogramming their metabolism. This approach enhances NK cell anti-tumor activity, overcoming the immunosuppressive tumor microenvironment for cancer immunotherapy.

Area of Science:

  • Immunology
  • Cancer Biology
  • Metabolic Engineering

Background:

  • Natural killer (NK) cells are cytotoxic lymphocytes crucial for cancer immunotherapy, especially against tumors with downregulated MHC class I.
  • The tumor microenvironment (TME) often suppresses NK cell function, limiting their therapeutic potential.
  • Developing strategies to overcome TME-mediated suppression is vital for effective NK cell-based cancer therapies.

Purpose of the Study:

  • To investigate the efficacy of a novel fusion protein, interleukin 21-Fc (IL-21-Fc), in restoring NK cell function within the TME.
  • To elucidate the metabolic mechanisms by which IL-21-Fc enhances NK cell effector functions.
  • To evaluate IL-21-Fc in combination therapies for eradicating MHC class I-deficient tumors.

Main Methods:

  • Administration of IL-21-Fc in murine cancer models.
  • Assessment of NK cell metabolism, focusing on glycolysis and lactate dehydrogenase A (LDHA) activity.
  • Evaluation of synergistic effects of IL-21-Fc with IL-15 superagonist (IL-15SA) or adoptive NK cell transfer.
  • Analysis of tumor eradication and durable protection in vivo.

Main Results:

  • IL-21-Fc safely and effectively reprograms NK cell metabolism and restores effector function in vivo.
  • IL-21-Fc synergizes with IL-15SA or adoptive NK cell transfer to eradicate MHC class I-deficient tumors.
  • IL-21-Fc enhances NK cell glycolysis in an LDHA-dependent manner, boosting anti-tumor activity.
  • Durable protection was observed across multiple murine models.

Conclusions:

  • LDHA-dependent metabolic reprogramming is a key mechanism for rejuvenating NK cells.
  • IL-21-Fc represents a promising, clinically translatable strategy to overcome TME-mediated suppression in solid tumors.
  • This approach enhances NK cell-based cancer immunotherapy efficacy.
Keywords:
CP: cancerCP: metabolismLDHAMHC class I-deficient tumorNK cell exhaustionNK cell therapycancer immunotherapyglycolysisimmunometabolisminterleukin 21

More Related Videos

Expansion, Purification, and Functional Assessment of Human Peripheral Blood NK Cells10:44

Expansion, Purification, and Functional Assessment of Human Peripheral Blood NK Cells

Published on: February 2, 2011

49.6K
Advances in Human Induced Pluripotent Stem Cell-Derived Chimeric Antigen Receptor-Expressing Natural Killer Cells11:08

Advances in Human Induced Pluripotent Stem Cell-Derived Chimeric Antigen Receptor-Expressing Natural Killer Cells

Published on: February 14, 2025

1.9K

Related Concept Videos

Cytotoxic T Cells-mediated Immune Response01:27

Cytotoxic T Cells-mediated Immune Response

Cytotoxic T cells are a vital component of the immune system. They have the remarkable ability to identify and target antigens on infected or abnormal cells. These antigens often originate from intracellular pathogens such as viruses or abnormal proteins cancer cells produce.
Immunological surveillance is the ability of immune cells to monitor and eliminate infected cells with intracellular pathogens, neoplastically transformed cells, and cells with non-self antigens. Cytotoxic T cells and NK...
7.7K
Tumor Immunotherapy01:27

Tumor Immunotherapy

Immunotherapy is a treatment that boosts or manipulates the immune system to fight diseases, including cancer. For instance, by stimulating an immune response through vaccinations against viruses that cause cancers, like hepatitis B virus and human papillomavirus, these diseases can be prevented. Nonetheless, some cancer cells can avoid the immune system due to their rapid mutation and division. The immune response to many cancers involves three phases: elimination, equilibrium, and escape.
2.1K
Cells of the Innate Immune Response01:28

Cells of the Innate Immune Response

The innate immune response is an immediate and non-specific response against pathogens, acting swiftly to prevent the spread of infections. The primary cells involved in this response are phagocytes and natural killer (NK) cells.
Phagocytes
Phagocytes police the peripheral tissues by removing cellular debris and responding to the invasion of foreign substances or pathogens. Many phagocytes attack and remove microorganisms even before lymphocytes detect them. The human body has two general...
9.8K
Immune Surveillance by NK Cells and Phagocytes01:25

Immune Surveillance by NK Cells and Phagocytes

Immune surveillance is an integral part of the innate immune system, involving the continuous monitoring of peripheral tissues to detect and respond to pathogens, infected cells, or cancerous cells. This surveillance is conducted primarily by natural killer (NK) cells and phagocytes, which employ distinct but complementary mechanisms to identify and eliminate threats.
Natural Killer Cells: The Fast Responders
NK cells are large granular lymphocytes found in the blood and lymphatic system. These...
9.1K