In a mouse lung cancer model, giving thymosin‑alpha‑1 by itself raised some immune cells (CD8+ T cells) but didn’t shrink the tumors. Instead, it also activated suppressive cells called MDSCs that make an enzyme (Arginase 1) which weakens anti‑cancer immunity. This effect depends on a signaling route (TLR/MyD88), and blocking that route stopped the MDSC activation and let thymosin‑alpha‑1 work better against the tumor.

Thymosin α1 (Tα1) has been tested for cancer therapy for several years, in most cases, the anti-tumor effect of Tα1 was limited, especially when Tα1 was used as a single agent. The role of Tα1 in cancer treatment and the regulatory mechanisms by which Ta1 takes effects are not yet completely understood. Using a Lewis lung caner model, here we report that Tα1 used alone elevated CD8(+) T cells, but failed to inhibit tumor growth. Furthermore, immunosuppressive myeloid-derived suppressor cells (MDSCs) showed heightened Arginase 1 production in response to Tα1 treatment, which led to stronger suppression of anti-tumor immunity. In addition, the upregulation of ARG1 was dependent on TLRs/MyD88 signaling, blocking MyD88 signaling abrogated the enhanced ARG1 expression and restored the anti-tumor efficacy of Tα1. This study provides the first demonstration that Tα1 treatment activates but not expands MDSCs via MyD88 signaling, which indicates better immunotherapeutic strategy of Tα1 against cancer.