American Association for the Advancement of Science (AAAS)

Nhiều đặc điểm khác nhau của khối u và hệ miễn dịch ảnh hưởng đến sự thành công của liệu pháp miễn dịch chống ung thư.

CXCR1 as a mediator of neutrophil fungal killing and host defense against systemic fungal infection in mice and humans.

PRMT5 expression in melanoma suppresses inflammation and antigen presentation, suggesting that its inhibition could potentiate immunotherapy.

Genetic engineering of T cells may extend immunotherapy successes to common epithelial cancers.

Denosumab, an antibody targeting RANKL, is effective against osteosarcoma in mouse models.

Fibrosis is a central pathway that drives progression of multiple chronic diseases, yet few safe and effective clinical antifibrotic therapies exist. In most fibrotic disorders, transforming growth factor–β (TGF-β)–driven scarring is an important pathologic feature and a key contributor to disease progression. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are two closely related transcription cofactors that are important for coordinating fibrogenesis after organ injury, but how they are activated in response to tissue injury has, so far, remained unclear. Here, we describe NUAK family kinase 1 (NUAK1) as a TGF-β–inducible profibrotic kinase that is up-regulated in multiple fibrotic organs in mice and humans. Mechanistically, we show that TGF-β induces a rapid increase in NUAK1 in fibroblasts. NUAK1, in turn, can promote profibrotic YAP and TGF-β/SMAD signaling, ultimately leading to organ scarring. Moreover, activated YAP and TAZ can induce further NUAK1 expression, creating a profibrotic positive feedback loop that enables persistent fibrosis. Using mouse models of kidney, lung, and liver fibrosis, we demonstrate that this fibrogenic signaling loop can be interrupted via fibroblast-specific loss of NUAK1 expression, leading to marked attenuation of fibrosis. Pharmacologic NUAK1 inhibition also reduced scarring, either when initiated immediately after injury or when initiated after fibrosis was already established. Together, our data suggest that NUAK1 plays a critical, previously unrecognized role in fibrogenesis and represents an attractive target for strategies that aim to slow fibrotic disease progression.

Blue light and carvacrol synergistically promote broad-spectrum bactericide in multidrug-resistant murine burn and skin infections.

Chitinase 3–like 1 protects against lung injury but has a profibrotic role during the repair phase.

Combining an immunogenic cell death inducer with dendritic cell immunotherapy treats high-grade glioma in a preclinical model.

In situ vaccination with low doses of TLR ligands and anti-OX40 antibodies can cure widespread cancers in preclinical models.