Cell biology

Ecology

Immunosurveillance

Biology

Lymphokine-activated killer cell

T cell

Cancer research

Biochemistry

Cytotoxicity

Immunology

Genetics

Immune system

In vitro

Natural killer cell

Tumor microenvironment

Tumor cells

Mitochondrion

Cell

Mitochondrial fission

Cancer

Interleukin 21

NKG2D

Cancer cell

Fragmentation (computing)

Nature Immunology

Natural killer (NK) cells have crucial roles in tumor surveillance. We found that tumor-infiltrating NK cells in human liver cancers had small, fragmented mitochondria in their cytoplasm, whereas liver NK cells outside tumors, as well as peripheral NK cells, had normal large, tubular mitochondria. This fragmentation was correlated with reduced cytotoxicity and NK cell loss, resulting in tumor evasion of NK cell-mediated surveillance, which predicted poor survival in patients with liver cancer. The hypoxic tumor microenvironment drove the sustained activation of mechanistic target of rapamycin-GTPase dynamin-related protein 1 (mTOR-Drp1) in NK cells, resulting in excessive mitochondrial fission into fragments. Inhibition of mitochondrial fragmentation improved mitochondrial metabolism, survival and the antitumor capacity of NK cells. These data reveal a mechanism of immune escape that might be targetable and could invigorate NK cell-based cancer treatments. NK cells make an important contribution to the destruction of tumors. Wei and colleagues demonstrate that NK cells within the tumor microenvironment undergo mitochondrial fragmentation leading to impairment of their function and survival.

Mitochondrial fragmentation limits NK cell-based tumor immunosurveillance