Elemental selenium activates GPX1 to reprogram NK cell lipid metabolism and restores antitumor immunity

  • Biomaterials. 2026 Jun 1:335:124354. doi: 10.1016/j.biomaterials.2026.124354.
Haoqiang Lai  1 ,  Guizhen Li  1 ,  Kexin Guo  1 ,  Haimei Zhang  1 ,  Shuoshan Li  1 ,  Fang Yang  2 ,  Tianfeng Chen  3
Affiliations
  • 1. Department of Chemistry, Institute of Nanotechnology And Intelligence (inAI), State Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, Jinan University, Guangzhou, 510632, China.
  • 2. Department of Chemistry, Institute of Nanotechnology And Intelligence (inAI), State Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, Jinan University, Guangzhou, 510632, China. Electronic address: [email protected].
  • 3. Department of Chemistry, Institute of Nanotechnology And Intelligence (inAI), State Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, Jinan University, Guangzhou, 510632, China. Electronic address: [email protected].
PMID: 42263649 DOI: 10.1016/j.biomaterials.2026.124354
Abstract

Metabolic rewiring-induced immune dysfunction limits the efficacy of NK cell-based immunotherapy for solid tumors, underscoring the need for targeted metabolic interventions. In this study, we found that NK cells within tumor tissues exhibited lipid accumulation and decreased infiltration across multiple tumor models, including B16F10 melanoma, MC38 colon carcinoma, 4T1 breast Cancer, and LLC lung carcinoma. Among the selected common selenium species, including Selenocystine (SeCys2), selenomethionine (SeMet) and selenium nanoparticles (SeNPs), SeNPs were found to effectively reverse abnormal lipid metabolism-mediated NK cell immune exhaustion induced by palmitic acid, oleic acid, or tumor-conditioned media. Additionally, SeNPs also effectively reverse palmitic acid-induced diminished antitumor activities in NK cells in vivo. Mechanistically, SeNPs inhibited palmitoylation of the fatty acid transporter CD36, restricting membrane localization and excessive lipid uptake, thereby preventing PPARδ-mediated mTOR inactivation and mitochondrial dysfunction. Importantly, SeNPs maintained Glutathione Peroxidase 1 (GPX1) protein abundance by counteracting palmitoylation-dependent downregulation, preserving redox homeostasis and sustaining mTOR signaling to enhance NK cell immunity. Furthermore, we also found that there is a positive correlation between high GPX1 expression and tumor-infiltrating NK cells in human breast tumor tissues, which further highlights the importance of elevated GPX1 expression in NK cell-mediated antitumor activity. Taken together, this study identifies SeNPs as a metabolic regulator that reprograms dysregulated lipid metabolism to restore NK cell antitumor immunity, which provides a mechanistic framework for developing selenium-based metabolic strategies to enhance Cancer Immunotherapy.

Keywords
GPX1; Lipid metabolism; Natural killer cell; Palmitoylation; Selenium.
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