Squeezing Treatment-Induced Metabolic Alterations in Melanoma Cells Are Accompanied by Impaired Cluster of Differentiation 8-Positive T Cell and Natural Killer Cell Antitumor Effector Functions
- 1Department of Oncology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121000 China
- 2Department of Orthopedics, The First Affiliated Hospital of Jinzhou Medical University, No. 2, Sect. 5, Renmin Street, Guta District, Jinzhou, 121000 Liaoning Province China
Abstract
Background: The physical microenvironment of solid tumors exerts compressive forces on cancer cells, but how such mechanical stress contributes to melanoma immune evasion remains largely unknown. This study investigates whether compression-induced nuclear deformation and metabolic reprogramming facilitate immune escape and explores the regulatory role of microphthalmia-associated transcription factor (MITF).
Methods: A three-dimensional (3D) melanoma spheroid model was established and subjected to microfluidic-based compressive stress. Nuclear morphology and cellular stiffness were evaluated using confocal microscopy and atomic force microscopy. Transcriptome sequencing and The Cancer Genome Atlas Skin Cutaneous Melanoma (TCGA-SKCM) transcriptomic analyses, together with differentially expressed gene (DEG) analysis, Gene Set Enrichment Analysis (GSEA), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, Seahorse metabolic assays, and flow cytometry, were used to identify key metabolic pathways and evaluate cluster of differentiation 8-positive (CD8+) T cell and natural killer (NK) cell function. MITF was silenced via lentiviral short hairpin RNA (shRNA) to determine its functional involvement.
Results: Squeezing (Sqz) treatment triggered marked nuclear elongation, reduced cellular stiffness, and enhanced both mitochondrial oxidative phosphorylation and glycolysis in melanoma cells. These metabolic alterations were accompanied by impaired interferon-gamma (IFN-gamma) and Granzyme B production in CD8+ T cells and reduced NK cell effector activity, together with increased immune cell apoptosis. Public TCGA-SKCM analyses further supported an association between high MITF expression, reduced cytotoxic immune signatures, lower immune infiltration, and MITF-related metabolic pathway enrichment. MITF knockdown attenuated nuclear deformation, suppressed metabolic overactivation, restored mitochondrial membrane potential, and rescued CD8+ T cell- and NK cell-mediated cytotoxicity.
Conclusion: Sqz-induced metabolic alterations in melanoma cells are accompanied by impaired CD8+ T cell and NK cell antitumor effector functions. MITF may act as an important molecular link connecting nuclear mechanotransduction, metabolic reprogramming, and immune escape, suggesting a potential strategy for counteracting physical stress-driven immunosuppression.
Graphic Abstract: The schematic illustration of the molecular mechanism by which compressive stress in the TME induces 3D melanoma nuclear deformation and metabolic reprogramming promotes immune evasion.
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1007/s00262-026-04495-9.
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BibTeX
@article{jing2026squeezing,
title = {{Squeezing Treatment-Induced Metabolic Alterations in Melanoma Cells Are Accompanied by Impaired Cluster of Differentiation 8-Positive T Cell and Natural Killer Cell Antitumor Effector Functions}},
author = {Yu Jing and Yunlong Bi},
journal = {Cancer Immunology, Immunotherapy : CII},
year = {2026},
month = aug,
doi = {10.1007/s00262-026-04495-9},
url = {https://doi.org/10.1007/s00262-026-04495-9},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Squeezing Treatment-Induced Metabolic Alterations in Melanoma Cells Are Accompanied by Impaired Cluster of Differentiation 8-Positive T Cell and Natural Killer Cell Antitumor Effector Functions
AU - Yu Jing
AU - Yunlong Bi
PY - 2026
DA - 2026/08/06
JO - Cancer Immunology, Immunotherapy : CII
DO - 10.1007/s00262-026-04495-9
UR - https://doi.org/10.1007/s00262-026-04495-9
AB - Background: The physical microenvironment of solid tumors exerts compressive forces on cancer cells, but how such mechanical stress contributes to melanoma immune evasion remains largely unknown. This study investigates whether compression-induced nuclear deformation and metabolic reprogramming facilitate immune escape and explores the regulatory role of microphthalmia-associated transcription factor (MITF). Methods: A three-dimensional (3D) melanoma spheroid model was established and subjected to microfluidic-based compressive stress. Nuclear morphology and cellular stiffness were evaluated using confocal microscopy and atomic force microscopy. Transcriptome sequencing and The Cancer Genome Atlas Skin Cutaneous Melanoma (TCGA-SKCM) transcriptomic analyses, together with differentially expressed gene (DEG) analysis, Gene Set Enrichment Analysis (GSEA), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, Seahorse metabolic assays, and flow cytometry, were used to identify key metabolic pathways and evaluate cluster of differentiation 8-positive (CD8+) T cell and natural killer (NK) cell function. MITF was silenced via lentiviral short hairpin RNA (shRNA) to determine its functional involvement. Results: Squeezing (Sqz) treatment triggered marked nuclear elongation, reduced cellular stiffness, and enhanced both mitochondrial oxidative phosphorylation and glycolysis in melanoma cells. These metabolic alterations were accompanied by impaired interferon-gamma (IFN-gamma) and Granzyme B production in CD8+ T cells and reduced NK cell effector activity, together with increased immune cell apoptosis. Public TCGA-SKCM analyses further supported an association between high MITF expression, reduced cytotoxic immune signatures, lower immune infiltration, and MITF-related metabolic pathway enrichment. MITF knockdown attenuated nuclear deformation, suppressed metabolic overactivation, restored mitochondrial membrane potential, and rescued CD8+ T cell- and NK cell-mediated cytotoxicity. Conclusion: Sqz-induced metabolic alterations in melanoma cells are accompanied by impaired CD8+ T cell and NK cell antitumor effector functions. MITF may act as an important molecular link connecting nuclear mechanotransduction, metabolic reprogramming, and immune escape, suggesting a potential strategy for counteracting physical stress-driven immunosuppression. Graphic Abstract: The schematic illustration of the molecular mechanism by which compressive stress in the TME induces 3D melanoma nuclear deformation and metabolic reprogramming promotes immune evasion. Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1007/s00262-026-04495-9.
SN - 0340-7004
SN - 1432-0851
ER -