Prospect of ULK1 modulators in targeting regulatory T cells.

Regulatory T (Treg) cells play an instrumental role in coordinating immune homeostasis via potent inhibitory effects. Defects in Treg cells lead to autoimmunity, but an overwhelming proportion of Treg cells encourages cancer progression. Hence, targeting Treg cells has emerged as a promising approach for mitigating disease severity. Recent studies have revealed that kinases are a critical component for tuning the fate of Treg cells, but the entire network of Treg-modulating kinases is still unclear. Here, we propose that the autophagy-activating UNC-51-like kinase 1 (ULK1) is a candidate for Treg cell modulation. While accumulating evidence has highlighted the role of autophagy-related kinases in Treg cells, the ULK1-Treg cell axis is yet to be examined. In this review, we predicted the potential role of ULK1 in Treg cell modulation. Furthermore, we summarized current ULK1 activators and inhibitors that can be investigated as Treg-targeting strategies, which might have beneficial outcomes in autoimmunity and cancer.

Niche-specific control of tissue function by regulatory T cells-Current challenges and perspectives for targeting metabolic disease.

Tissue regulatory T cells (Tregs) exert pivotal functions in both immune and metabolic regulation, maintaining local tissue homeostasis, integrity, and function. Accordingly, Tregs play a crucial role in controlling obesity-induced inflammation and supporting efficient muscle function and repair. Depending on the tissue context, Tregs are characterized by unique transcriptomes, growth, and survival factors and T cell receptor (TCR) repertoires. This functional specialization offers the potential to selectively target context-specific Treg populations, tailoring therapeutic strategies to specific niches, thereby minimizing potential side effects. Here, we discuss challenges and perspectives for niche-specific Treg targeting, which holds promise for highly efficient and precise medical interventions to combat metabolic disease.

Role of CD4+CD25+FOXP3+ TReg cells on tumor immunity.

Not all T cells are effector cells of the anti-tumor immune system. One of the subpopulations of CD4+ T cells that express CD25+ and the transcription factor FOXP3, known as Regulator T cells (TReg), plays an essential role in maintaining tolerance and immune homeostasis preventing autoimmune diseases, minimalize chronic inflammatory diseases by enlisting various immunoregulatory mechanisms. The balance between effector T cells (Teff) and regulator T cells is crucial in determining the outcome of an immune response. Regarding tumors, activation or expansion of TReg cells reduces anti-tumor immunity. TReg cells inhibit the activation of CD4+ and CD8+ T cells and suppress anti-tumor activity in the tumor microenvironment. In addition, TReg cells also promote tumor angiogenesis both directly and indirectly to ensure oxygen and nutrient transport to the tumor. There is accumulating evidence showing a positive result that removing or suppressing TReg cells increases anti-tumor immune response. However, depletion of TReg cells will cause autoimmunity. One strategy to improve or restore tumor immunity is targeted therapy on the dominant effector TReg cells in tumor tissue. Various molecules such as CTLA-4, CD4, CD25, GITR, PD-1, OX40, ICOS are in clinical trials to assess their role in attenuating TReg cells' function.

The Yin and Yang of Targeting KLRG1+ Tregs and Effector Cells.

The literature surrounding KLRG1 has primarily focused on NK and CD8+ T cells. However, there is evidence that the most suppressive Tregs express KLRG1. Until now, the role of KLRG1 on Tregs has been mostly overlooked and remains to be elucidated. Here we review the current literature on KLRG1 with an emphasis on the KLRG1+ Treg subset role during cancer development and autoimmunity. KLRG1 has been recently proposed as a new checkpoint inhibitor target, but these studies focused on the effects of KLRG1 blockade on effector cells. We propose that when designing anti-tumor therapies targeting KLRG1, the effects on both effector cells and Tregs will have to be considered.