The Streptomyces Metabolite Thiostrepton Inhibits Regulatory T Cell Differentiation and Function to Boost Antitumor Immune Responses

Abstract

Regulatory T cells (Tregs) are associated with enhanced tumor progression and reduced therapy response rates. Therefore, overcoming the Treg-mediated immunosuppressive barrier within the tumor to enhance antitumor immune responses is of central interest to advance cancer immunotherapy. To date, no tools exist that can be exploited to dampen Treg function and differentiation in vivo. Here, we show for the first time that the antibiotic thiostrepton exerts a potent inhibitory effect on Tregs. Mechanistically, thiostrepton disrupts Treg differentiation, reduces the expression of Treg activation markers, and inhibits Treg suppressive functions. Accordingly, using an MC38 tumor model, we demonstrate that thiostrepton treatment reduces the number of intratumoral Foxp3⁺ Treg cells and prevents tumor growth. These effects are conserved in human T cells, as thiostrepton also inhibits the differentiation of human Tregs. Our findings highlight thiostrepton as a promising Treg-targeting immunomodulatory compound with the potential to enhance antitumor immune responses.