Thymosin α-1 Reprograms Tumor Macrophages, Boosting Anti-Cancer Immunity

The tumor microenvironment is heavily influenced by tumor-associated macrophages (TAMs), immune cells that infiltrate tumors. These TAMs often adopt an M2-polarized phenotype, a state that promotes tumor growth, angiogenesis (new blood vessel formation), and immunosuppression, hindering effective anti-cancer responses. Efferocytosis, the process by which phagocytes clear apoptotic (dying) cells, is known to influence macrophage polarization. A critical knowledge gap exists in understanding how to effectively reprogram these pro-tumorigenic M2 TAMs into an anti-tumor M1 phenotype, especially in the context of efferocytosis, to enhance cancer therapy.

The researchers found that Thymosin α-1 significantly reversed the M2 polarization of macrophages. In vitro, it reduced the expression of M2 markers like CD206 and Arg1 by approximately 45% and concurrently increased M1 markers such as CD86 and iNOS by about 60% (p<0.001). This beneficial shift in macrophage phenotype was found to be mediated through the modulation of STAT3 and NF-κB signaling pathways, which are crucial for macrophage function. Crucially, in vivo, Thymosin α-1 treatment resulted in a remarkable 43% reduction in tumor volume and a 35% decrease in tumor weight in the melanoma models, directly correlating with a significant increase in M1-like TAMs within the tumor microenvironment. Furthermore, the treatment enhanced systemic anti-tumor immunity, evidenced by a 2.5-fold increase in CD8+ T cell infiltration into the tumors.