Disrupting Smad3 potentiates immunostimulatory function of NK cells against lung carcinoma by promoting GM-CSF production.

Through Smad3-dependent signalings, transforming growth factor-β (TGF-β) suppresses the development, maturation, cytokine productions and cytolytic functions of NK cells in cancer. Silencing Smad3 remarkably restores the cytotoxicity of NK-92 against cancer in TGF-β-rich microenvironment, but its effects on the immunoregulatory functions of NK cells remain obscure. In this study, we identified Smad3 functioned as a transcriptional repressor for CSF2 (GM-CSF) in NK cells.

Self-carried nanodrug (SCND-SIS3): A targeted therapy for lung cancer with superior biocompatibility and immune boosting effects.

Transforming growth factor β (TGF-β) is a well-known key mediator for the progression and metastasis of lung carcinoma. However, cost-effective anti-TGF-β therapeutics for lung cancer remain to be explored. Specifically, the low efficacy in drug delivery greatly limits the clinical application of small molecular inhibitors of TGF-β.

Challenges and Recent Advances in NK Cell-Targeted Immunotherapies in Solid Tumors.

Natural killer (NK) cell is a powerful malignant cells killer, providing rapid immune responses via direct cytotoxicity without the need of antigen processing and presentation. It plays an essential role in preventing early tumor, metastasis and minimal residual disease. Although adoptive NK therapies achieved great success in clinical trials against hematologic malignancies, their accumulation, activation, cytotoxic and immunoregulatory functions are severely impaired in the immunosuppressive microenvironment of solid tumors.

Inhibition of tumor invasion and metastasis by targeting TGF-β-Smad-MMP2 pathway with Asiatic acid and Naringenin.

Transforming growth factor β (TGF-β) has been shown to promote tumor invasion and metastasis by activating the matrix metalloproteinases (MMPs); however, signaling mechanisms remain controversial and therapies targeting MMPs are still suboptimal. In the present study, we found that combined therapy with Asiatic acid (AA), a Smad7 agonist, and Naringenin (NG), a Smad3 inhibitor, effectively retrieved the balance between Smad3 and Smad7 signaling in the TGF-β-rich tumor microenvironment and thus significantly suppressed tumor invasion and metastasis in mouse models of melanoma and lung carcinoma. Mechanistically, we unraveled that Smad3 acted as a transcriptional activator of MMP2 and as a transcriptional suppressor of tissue inhibitors of metalloproteinase-2 (TIMP2) via binding to 5' UTR of MMP2 and 3' UTR of TIMP2, respectively.

Macrophages in Renal Fibrosis.

Monocytes/macrophages are highly involved in the process of renal injury, repair and fibrosis in many aspects of experimental and human renal diseases. Monocyte-derived macrophages, characterized by high heterogeneity and plasticity, are recruited, activated, and polarized in the whole process of renal fibrotic diseases in response to local microenvironment. As classically activated M1 or CD11b/Ly6C macrophages accelerate renal injury by producing pro-inflammatory factors like tumor necrosis factor-alpha (TNFα) and interleukins, alternatively activated M2 or CD11b/Ly6C macrophages may contribute to kidney repair by exerting anti-inflammation and wound healing functions.

Transforming growth factor-β signalling in renal fibrosis: from Smads to non-coding RNAs.

Transforming growth factor-β (TGF-β) is the key player in tissue fibrosis. However, antifibrotic therapy targeting this multifunctional protein may interfere with other physiological processes to cause side effects. Thus, precise therapeutic targets need to be identified by further understanding the underlying mechanisms of TGF-β1 signalling during fibrogenesis.