Work

Rbpj restrains regulatory T cell exhaustion in tumors

Year: 2026

Type: article

Abstract: Although regulatory T (Treg) cells are vital for immune homeostasis and prevention of autoimmunity, they also exert an essential role in promoting tumor development. The mechanisms explaining why Treg cells remain functional in the hostile tumor microenvironment, while their effector counterparts become exhausted, remain incompletely understood. Here, we demonstrate that Treg-cell-specific deletion of Rbpj, the master transcription factor regulating Notch signaling, reduces tumor burden in mice. This is associated with the induction of an exhausted phenotype characterized by marked PD-1 upregulation. PD-1 deletion in Rbpj-deficient Treg cells reverses their exhausted phenotype and restores their tumor-promoting function. Finally, pharmacological inhibition of Rbpj using a novel small molecule promotes Treg cell exhaustion and reduces tumor growth. Collectively, our findings indicate that Notch-Rbpj signaling may act as an immune checkpoint pathway that hinders Treg exhaustion in tumors. The mechanisms explaining how the tumour microenvironment promotes regulatory T cell function, while rendering effector T cells exhausted, are incompletely understood. Here, the authors demonstrate that the transcription factor Rbpj, acts as checkpoint that prevents regulatory T cell exhaustion in tumours

Source: Nature Communications

DOI: 10.1038/s41467-026-79069-5