ARG1 Function in Tumor Immunology

Cancer cell-derived arginine fuels polyamine biosynthesis in tumor-associated macrophages to promote immune evasion:- •Arginine metabolism reshapes the tumor microenvironment (#TME) into a pro-tumor niche through complex metabolic cross-feeding among various cell types. However, the key intercellular metabolic communication that mediates the collective effects of arginine metabolism within the TME remains unclear. Here, we reveal that the metabolic interplay between cancer cells and macrophages plays a dominant role in arginine-driven breast cancer progression. Within the TME, breast cancer cells serve as the primary source of arginine, which induces a pro-tumor polarization of tumor-associated macrophages (TAMs), thereby suppressing the anti-tumor activity of CD8+ T cells. Notably, this cancer cell-macrophage interaction overrides the arginine-mediated enhancement of CD8+ T cell anti-tumor activity. Mechanistically, polyamines derived from arginine metabolism enhance pro-tumor TAM polarization via thymine DNA glycosylase (TDG)-mediated DNA demethylation, regulated by p53 signaling. Importantly, targeting the arginine-polyamine-TDG axis between cancer cells and macrophages significantly suppresses breast cancer growth, highlighting its therapeutic potential. #highlights:- •Breast cancer cell-derived arginine fuels polyamine synthesis in TAMs. •Spermine promotes TAM polarization via p53/TDG-mediated DNA demethylation. •TDG-mediated PPARG upregulation is required for pro-tumor polarization of TAMs. •Cancer cell-macrophage metabolic interplay dictates the overall impact of arginine.

Within the TME, breast cancer cells serve as the primary source of arginine, which induces a pro-tumor polarization of tumor-associated macrophages (TAMs), thereby suppressing the anti-tumor activity of CD8+ T cells. Notably, this cancer cell-macrophage interaction overrides the arginine-mediated enhancement of CD8+ T cell anti-tumor activity. Mechanistically, polyamines derived from arginine metabolism enhance pro-tumor TAM polarization via thymine DNA glycosylase (TDG)-mediated DNA demethylation, regulated by p53 signaling. Importantly, targeting the arginine-polyamine-TDG axis between cancer cells and macrophages significantly suppresses breast cancer growth, highlighting its therapeutic potential. #breastcancercellarginineweakensmacrophages

In this newsletter, I introduce an intriguing study from Zhejiang Cancer Hospital in China reveals that how cancer cells manipulate the immune system through metabolic crosstalk in the tumor microenvironment. Specifically, breast cancer cells produce excess arginine, which promotes polyamine production in tumor-associated macrophages (TAMs). This triggers a DNA-modifying enzyme called TDG, which reprograms TAMs into pro-tumor allies while suppressing the anti-tumor activity of CD8+ T cells. This finding reveals clever strategy tumors use to evade immune surveillance—essentially “feeding” immune cells into submission. More importantly, targeting the arginine-polyamine-TDG axis significantly reduced tumor growth in preclinical models, providing a promising new therapeutic approach. Together, the study highlights the critical role of metabolic crosstalk in cancer progression and opens new doors for therapies that disrupt tumor-immune cell communication. #CancerImmunology #TumorMicroenvironment #BreastCancer #ArginineMetabolism #ImmuneEvasion #Macrophages #CD8TCells #Epigenetics #CancerTherapy #ScienceNewsletter #MetabolicTargeting #OncologyResearch #CSTEAMBiotech