The Love-Hate Relationship Between TGF-β Signaling and the Immune System During Development and Tumorigenesis

Since TGF-beta was recognized as an essential secreted cytokine in embryogenesis and adult tissue homeostasis a decade ago, our knowledge of the role of TGF-beta in mammalian development and disease, particularly cancer, has constantly been updated. Mounting evidence has confirmed that TGF-beta is the principal regulator of the immune system, as deprivation of TGF-beta signaling completely abrogates adaptive immunity. However, enhancing TGF-beta signaling constrains the immune response through multiple mechanisms, including boosting Treg cell differentiation and inducing CD8(+) T-cell apoptosis in the disease context. The love-hate relationship between TGF-beta signaling and the immune system makes it challenging to develop effective monotherapies targeting TGF-beta, especially for cancer treatment. Nonetheless, recent work on combination therapies of TGF-beta inhibition and immunotherapy have provide insights into the development of TGF-beta-targeted therapies, with favorable outcomes in patients with advanced cancer. Hence, we summarize the entanglement between TGF-beta and the immune system in the developmental and tumor contexts and recent progress on hijacking crucial TGF-beta signaling pathways as an emerging area of cancer therapy.

Automated summary

Since its recognition as an essential cytokine in embryogenesis and tissue homeostasis, our understanding of the role of TGF-beta in mammalian development and disease, especially cancer, has been constantly updated. TGF-beta acts as the principal regulator of the immune system, but strengthening its signaling can limit immune response. The love-hate relationship between TGF-beta signaling and the immune system poses challenges in developing effective monotherapies, but recent studies on combination therapies have shown promising outcomes in cancer treatment.