Frontiers in immunology · 2026
Cancer stem cell programs S-nitrosylation and deubiquitination of FoxP3 protein to promote regulatory T cell differentiation.
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Liu Xiyu, Lei Jiaxin, Jiang Xinhang, Li Lingyi, Yu Longhao, Wang Gengxue, Guo Kaixun, Wen Zhenke, Wang Yan
Аннотация
BACKGROUND: Cancer stem cells (CSCs) are critical drivers of tumor progression and therapeutic resistance in non-small cell lung cancer (NSCLC). However, how CSCs remodel the immunosuppressive tumor microenvironment (TME) of NSCLC remains largely unclear.
METHODS: Flow cytometry was performed to evaluate the immunomodulatory effects of NSCLC CSCs on T cell differentiation. RNA-sequencing-based metabolic profiling was conducted to identify pivotal metabolic pathways activated in CSCs. Mitochondrial reactive oxygen species (ROS) encapsulated in CSC-derived exosomes were quantified, and the molecular mechanism by which exosomal ROS modulates intracellular nitric oxide (NO) production and FoxP3 post-translational modifications in T cells was further explored. Patient-derived organoids (PDOs) were utilized as a preclinical model to verify the therapeutic potential of glutamine metabolism targeting.
RESULTS: NSCLC CSCs potently induced tumor immunosuppression by promoting regulatory T (Treg) cell differentiation. Mechanistically, hyperactive glutamine metabolism in CSCs substantially increased mitochondrial ROS generation. Exosomal ROS secreted by CSCs was transferred to T cells, thereby elevating intracellular NO synthesis. Increased NO further triggered S-nitrosylation and deubiquitination of FoxP3, which ultimately stabilized FoxP3 expression and facilitated Treg cell differentiation. In NSCLC PDO models, pharmacological inhibition of glutamine metabolism reversed the immunosuppressive T cell phenotype and efficiently suppressed PDO growth.
CONCLUSION: NSCLC CSCs mediate TME immunosuppression via a glutamine metabolism-dependent regulatory axis. Exosomal ROS-initiated FoxP3 post-translational modification is a novel mechanism underlying CSC-driven Treg differentiation. This study reveals an unreported immune evasion pathway in NSCLC and identifies glutamine metabolism as a viable therapeutic target for overcoming tumor immunosuppression.
METHODS: Flow cytometry was performed to evaluate the immunomodulatory effects of NSCLC CSCs on T cell differentiation. RNA-sequencing-based metabolic profiling was conducted to identify pivotal metabolic pathways activated in CSCs. Mitochondrial reactive oxygen species (ROS) encapsulated in CSC-derived exosomes were quantified, and the molecular mechanism by which exosomal ROS modulates intracellular nitric oxide (NO) production and FoxP3 post-translational modifications in T cells was further explored. Patient-derived organoids (PDOs) were utilized as a preclinical model to verify the therapeutic potential of glutamine metabolism targeting.
RESULTS: NSCLC CSCs potently induced tumor immunosuppression by promoting regulatory T (Treg) cell differentiation. Mechanistically, hyperactive glutamine metabolism in CSCs substantially increased mitochondrial ROS generation. Exosomal ROS secreted by CSCs was transferred to T cells, thereby elevating intracellular NO synthesis. Increased NO further triggered S-nitrosylation and deubiquitination of FoxP3, which ultimately stabilized FoxP3 expression and facilitated Treg cell differentiation. In NSCLC PDO models, pharmacological inhibition of glutamine metabolism reversed the immunosuppressive T cell phenotype and efficiently suppressed PDO growth.
CONCLUSION: NSCLC CSCs mediate TME immunosuppression via a glutamine metabolism-dependent regulatory axis. Exosomal ROS-initiated FoxP3 post-translational modification is a novel mechanism underlying CSC-driven Treg differentiation. This study reveals an unreported immune evasion pathway in NSCLC and identifies glutamine metabolism as a viable therapeutic target for overcoming tumor immunosuppression.