Publication

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

2026

Abstract

Natural killer (NK) cells, a type of potent cytotoxic lymphocyte, are particularly promising for the treatment of cancers that lose or downregulate major histocompatibility complex class I (MHC class I) expression to evade T cell-mediated immunotherapy. However, the hostile and immunosuppressive tumor microenvironment (TME) greatly hinders the function of tumor-infiltrating NK cells, thus limiting the therapeutic efficacy. Here, we show a fusion protein of interleukin 21 (IL-21-Fc) that safely and effectively reprograms NK cell metabolism and restores their effector function in vivo. IL-21-Fc synergizes with IL-15 superagonist (IL-15SA) or adoptive NK cell transfer to eradicate MHC class I-deficient tumors and confer durable protection across multiple murine models. Mechanistically, we uncover that IL-21-Fc enhances NK cell effector function by upregulating glycolysis in a lactate dehydrogenase A (LDHA)-dependent manner. This study reveals LDHA-dependent metabolic reprogramming as a key axis for NK cell rejuvenation and positions IL-21-Fc as a promising, clinically translatable strategy to overcome TME-mediated suppression in solid tumors.

Official source

https://infoscience.epfl.ch/entities/publication/1cc81184-0923-410f-969d-7e050ff2985f

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2026

Abstract

Official source

https://infoscience.epfl.ch/entities/publication/1cc81184-0923-410f-969d-7e050ff2985f

About this result

Related concepts (32)

Natural killer cell

Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system that belong to the rapidly expanding family of known innate lymphoid cells (ILC) and represent 5–20% of all circulating lymphocytes in humans. The role of NK cells is analogous to that of cytotoxic T cells in the vertebrate adaptive immune response. NK cells provide rapid responses to virus-infected cell and other intracellular pathogens acting at around 3 days after infection, and respond to tumor formation.

Tumor microenvironment

The tumor microenvironment (TME) is the environment around a tumor, including the surrounding blood vessels, immune cells, fibroblasts, signaling molecules and the extracellular matrix (ECM). The tumor and the surrounding microenvironment are closely related and interact constantly. Tumors can influence the microenvironment by releasing extracellular signals, promoting tumor angiogenesis and inducing peripheral immune tolerance, while the immune cells in the microenvironment can affect the growth and evolution of cancerous cells.

Interleukin 15

Interleukin-15 (IL-15) is a protein that in humans is encoded by the IL15 gene. IL-15 is an inflammatory cytokine with structural similarity to Interleukin-2 (IL-2). Like IL-2, IL-15 binds to and signals through a complex composed of IL-2/IL-15 receptor beta chain (CD122) and the common gamma chain (gamma-C, CD132). IL-15 is secreted by mononuclear phagocytes (and some other cells) following infection by virus(es). This cytokine induces the proliferation of natural killer cells, i.e.