Cancer cell-derived arginine fuels polyamine biosynthesis in tumor-associated macrophages to promote immune evasion

Cancer cell metabolic reprogramming reshapes the tumor microenvironment (TME) into a pro-tumor niche. Arginine metabolism plays complex roles in regulating tumor progression through metabolic cross-feeding among various cell types within the TME, but the primary intercellular communication dominating the collective impact of arginine on tumor progression remains unclear. Here, we investigated the role of arginine metabolism in breast cancer progression using clinical analysis, single-cell RNA sequencing data analysis, and in vivo animal models. We found that the metabolic interplay between cancer cells and macrophages exerts a predominant influence on breast cancer progression mediated by arginine metabolism. Breast cancer cells act as the major source of arginine within the TME, where this tumor-derived arginine fosters a pro-tumor shift in tumor-associated macrophages (TAMs), leading them to suppress the anti-tumor activity of CD8+ T cells. Notably, this cancer cell-macrophage interaction overrides the stimulatory effect of arginine on the anti-tumor capability of CD8+ T cells. Mechanistically, polyamines derived from arginine metabolism mediate TAM polarization via TDG-mediated DNA demethylation, driven by p53 signaling. Importantly, inhibiting the arginine-polyamine-TDG axis across cancer cells to macrophages effectively suppresses breast cancer growth by modulating the immune microenvironment, suggesting therapeutic potential in targeting this axis for breast cancer therapy. The study involved the utilization of six-week-old BALB/c mice, C57BL/6 mice. For the allograft experiments,Wild-type(WT) or Ass1 knockdown (shAss1) 4T1 cells or EO771 cells were injected into the mammary fat pads of mice with the genetic background of the BALB/c and C57BL/6 (1 × 106 cells in 100 μL PBS), respectively. Single-cell RNA seqencing (Chromium, 10X Genomics) was performed to compare the difference of the tumor microenvironment between WT group and shAss1 group.