The Anti-fibrosis drug Pirfenidone modifies the immunosuppressive tumor microenvironment and prevents the progression of renal cell carcinoma by inhibiting tumor autocrine TGF-β

Transforming growth factor-beta (TGF-beta) plays a critical role in regulating cell growth and differentiation. Epithelial to mesenchymal transition (EMT) induced by TGF-beta promotes cancer cell migration, invasion, and proliferation. Pirfenidone (5-methyl-1-phenyl-2(1 H)-pyridone, PFD), an approved drug for treating pulmonary and renal fibrosis, is a potent TGF-beta inhibitor and found reduced incidence of lung cancer and alleviated renal function decline. However, whether PFD plays a role in controlling renal cancer progression is largely unknown. In the present study, we demonstrated that high TGF-beta expression was negatively associated with ten-year overall survival of patients with renal cancer. Functionally, blockade of TGF-beta signaling with PFD significantly suppressed the progression of renal cancer in a murine model. Mechanistically, we revealed that PFD significantly decreased the expression and secretion of TGF-beta both in vitro and in vivo tumor mouse model, which further prevented TGF-beta-induced EMT and thus cell proliferation, migration, and invasion. Importantly, the downregulation of TGF-beta upon PFD treatment shaped the immunosuppressive tumor microenvironment by limiting the recruitment of tumor-infiltrating MDSCs. Therefore, our study demonstrated that PFD prevents renal cancer progression by inhibiting TGF-beta production of cancer cells and downstream signaling pathway, which might be presented as a therapeutic adjuvant for renal cancer.

Automated summary

The study demonstrates that PFD can prevent the progression of renal cancer by inhibiting the production of TGF-beta and its downstream signaling pathway in cancer cells. It also regulates the tumor microenvironment to suppress the recruitment of immunosuppressive cells.