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Elemental selenium activates GPX1 to reprogram NK cell lipid metabolism and restores antitumor immunity
Haoqiang Lai1, Guizhen Li1, Kexin Guo1
1Department 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.
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.
Insights
Selenium nanoparticles (SeNPs) combat lipid accumulation in NK cells, restoring their anti-tumor immunity. This metabolic intervention enhances NK cell function, offering a new strategy for cancer immunotherapy.
Area of Science:
- Immunology
- Metabolic pathways
- Cancer research
Background:
- Immune dysfunction in solid tumors limits NK cell immunotherapy efficacy.
- Tumor-infiltrating NK cells show lipid accumulation and reduced infiltration.
- Targeted metabolic interventions are crucial for enhancing NK cell activity.
Purpose of the Study:
- To investigate the role of lipid metabolism in NK cell dysfunction within tumors.
- To evaluate selenium species, specifically selenium nanoparticles (SeNPs), as metabolic regulators for NK cells.
- To elucidate the mechanisms by which SeNPs restore NK cell antitumor immunity.
Main Methods:
- Assessing NK cell lipid metabolism and infiltration in various tumor models (B16F10, MC38, 4T1, LLC).
- Treating NK cells with SeNPs and evaluating the reversal of lipid metabolism abnormalities and immune exhaustion.
- Investigating the molecular mechanisms involving CD36 palmitoylation, PPARδ, mTOR, and GPX1.
- Correlating GPX1 expression with tumor-infiltrating NK cells in human breast cancer tissues.
Main Results:
- SeNPs reversed lipid accumulation and immune exhaustion in NK cells induced by fatty acids or tumor-conditioned media.
- SeNPs restored NK cell antitumor activity in vivo.
- Mechanistically, SeNPs inhibited CD36 palmitoylation, reduced lipid uptake, prevented mitochondrial dysfunction, and maintained GPX1 levels.
- High GPX1 expression positively correlated with tumor-infiltrating NK cells in human breast cancer.
Conclusions:
- SeNPs act as metabolic regulators, reprogramming dysregulated lipid metabolism to restore NK cell antitumor immunity.
- This study provides a mechanistic basis for selenium-based metabolic strategies to enhance cancer immunotherapy.
- SeNPs represent a promising therapeutic approach to overcome NK cell dysfunction in solid tumors.