Data Sheet 1_Cancer stem cell programs S-nitrosylation and deubiquitination of FoxP3 protein to promote regulatory T cell differentiation.pdf

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.</p>Conclusion<p>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.</p>