Zhu et al. found that serum arginine increased during breast cancer progression and originated primarily from cancer epithelial cells, which expressed the arginine biosynthetic enzyme ASS1. Macrophage polyamines downstream of arginine signaling regulated TAM suppressive activity, and Ass1 KD in breast cancer cells inhibited tumor growth only in the presence of macrophages. Activity of spermine, a potent suppressive polyamine, was critically dependent on p53 signaling, which promoted demethylation of key genes, including PPARG by the enzyme TDG. In vivo, TDG KD inhibited TAM polarization and increased CD8+ T cell infiltration to promote tumor control.
Contributed by Morgan Janes
ABSTRACT: 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.
Author Info: (1) Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Department of Genetic Medicine, Dongguan Children's Hospital Affiliated
Author Info: (1) Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Department of Genetic Medicine, Dongguan Children's Hospital Affiliated to Guangdong Medical University, Dongguan, China. (2) Department of Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China. (3) Department of Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China. (4) Diagnosis and Treatment Center of Breast Diseases, Shantou Central Hospital, Shantou 515031, China. (5) Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China. (6) Department of Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China. (7) Hangzhou Institute of Medicine, Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou 310018, China; Experimental Research Center, Zhejiang Cancer Hospital, Hangzhou 310022, China. (8) Experimental Research Center, Zhejiang Cancer Hospital, Hangzhou 310022, China. (9) Hangzhou Institute of Medicine, Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou 310018, China. (10) Diagnosis and Treatment Center of Breast Diseases, Shantou Central Hospital, Shantou 515031, China. (11) Department of Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China. (12) Department of Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China. (13) Department of Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China. (14) Department of Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China. (15) Hangzhou Institute of Medicine, Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou 310018, China. Electronic address: lihongde@him.cas.cn. (16) Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China. Electronic address: luomli@mail.sysu.edu.cn. (17) Breast Cancer Center, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine, Chinese Academy of Sciences, Hangzhou 310022, China. Electronic address: huhai@zjcc.org.cn.
