Diallyl Trisulfide Suppresses Tumor-Associated Macrophage M2-Like Polarization and Recruitment and Improves the Tumor Microenvironment Through Blocking CCL5/STAT3 Signaling Pathway Against Lung Cancer

Diallyl trisulfide (DATS) is a promising small molecule phytochemical derived from allium vegetables with antitumor potential. Tumor-associated macrophages (TAMs) are the most abundant tumor-infiltrating immune cells within the lung tumor microenvironment (TME), and significantly promote immunosuppression and tumor progression. However, the effect of DATS on TAM phenotype and function and its role in tumor immunity remain unexplored. Lewis lung Cancer (LLC) mouse model was established to observe the effects of DATS on tumor growth, populations of TAMs and T cells in vivo. Meanwhile, a lung Cancer cell/macrophage co-culture system was used to evaluate the effects of DATS on TAM phenotype and function in vitro. A transcriptome database was used to further explore the underlying mechanisms of DATS in TAMs. Our results showed that DATS worked as a modulator of TAM phenotype and function. DATS inhibited TAMs' polarization toward the immunosuppressive M2 phenotype and promoted TAMs' polarization to the M1 phenotype in vivo and in vitro. Mechanistically, we observed a significant decrease in CCL5 levels and a negative enrichment of the JAK-STAT3 signaling pathway in DATS-treated TAMs. Further investigation revealed that DATS hindered the immunosuppressive phenotype and migration ability of TAMs through the CCL5/STAT3/PD-L1 axis. Additionally, DATS reshaped the lung TME and enhanced antitumor immunity by increasing the numbers of CD4⁺ and CD8⁺ T cells and decreasing regulatory T cells (Tregs). In summary, our results illustrate that DATS enhances antitumor immunity and suppresses lung Cancer progression by regulating TAM phenotype and function via blocking the CCL5/STAT3/PD-L1 pathway. These findings provide a new mechanism of DATS against lung Cancer, suggesting the potential clinical value of DATS in lung Cancer treatment.

CCL5; STAT3; diallyl trisulfide; lung cancer; tumor associated macrophages.