A retinol-SREBP1-ELOVL6 lipogenic axis remodels NK cell biomechanics and constrains immune surveillance during aging.

Xinru Liu, Zhuanghao Hou, Tingting Liang, Mingming Zhu, Rui Zhao, Lili Qian, Tianfeng Jin, Xian Song, Guangming Huang, Fang Ni

State Key Laboratory of Immune Response and Immunotherapy, Department of Hematology, The First Affiliated Hospital of USTC, Institute of Blood and Cell Therapy and Anhui Provincial Key Laboratory of Blood Research and Applications, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. · pubmed

Paper

Abstract

Aging is associated with a progressive decline in immune surveillance, yet the mechanisms that constrain this process remain incompletely understood. Here we uncover a lipid-biomechanical mechanism in human natural killer (NK) cells that contributes to age-related immune decline. We show that aging drives a coordinated metabolic and physical state in NK cells, marked by lipid accumulation, increased membrane fluidity, reduced cortical stiffness and defective immune synapse organization, ultimately impairing target cell killing. Mechanistically, aging induces a retinoid-dependent metabolic shift in NK cells, characterized by enhanced retinol uptake and intracellular retinoic acid accumulation, which activates an SREBP1-dependent lipogenic program with ELOVL6 as a key downstream effector. This program remodels fatty-acyl composition, alters membrane and cortical mechanics, and constrains NK cell cytotoxic function. ELOVL6 inhibition restores membrane and cortical mechanics, rescues cytotoxicity in vitro and enhances antitumor activity in mouse models. These findings establish a targetable biomechanical mechanism linking aging to impaired immune surveillance.

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Research summary

Aging induces a retinol-SREBP1-ELOVL6 lipogenic axis in NK cells that alters biomechanics and impairs cytotoxicity, which can be reversed by ELOVL6 inhibition. This paper is relevant because it identifies a specific, targetable metabolic-mechanical mechanism driving age-related immune decline, offering a potential intervention to restore immune surveillance rather than merely treating downstream symptoms.

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