It has been reported in many clinical studies that LKB1 is mutated in 20%–30% of NSCLC (Non-small-cell lung carcinoma) patients, which causes enhanced sensitivity to metabolic inhibitors or stress-induced mitochondrial dysfunction [95]. Further, Yang et al. have reported that Tregs need the LKB1 gene to manage their metabolic and immunological homeostasis function, and deficiency of LKB1 resulted in the apoptotic and functional exhaustion of Tregs [85]. Xiuhua Su et al. have demonstrated that Tregs from acute graft- versus- host disease (aGVHD) patients show an exhausted phenotype, which is characterized by the unstable FOXP3 expression, diminished suppressive functions, defective migration capacity, increased apoptosis, and downregulation of LKB1 expression [96]. In addition to maintaining suppressive activity, LKB1 maintain FOXP3 stability in Tregs by demethylation of conserved non-coding sequences (CNS2) at the FOXP3 locus [75] through the activation of signal transducer and activator of transcription 4 (STAT-4), and partially through suppressing nuclear factor-κB (NF-κB) signaling [97]. Meanwhile, LKB1 promotes Treg suppressor function by increasing the expression of various immunosuppressive genes by enhancing transforming growth factor-β (TGF-β) signaling. The deletion of TGF-β leads to autoimmune glomerulonephritis and impaired Treg activity [98]. Thus, TGF- β pathway is vital for nTreg and iTreg development [94, 95].