Chinese scientists have revealed a hidden metabolic partnership between breast cancer cells and immune cells that drives aggressive tumor behavior and resistance to immunotherapies. The study sheds light on how tumor cells exploit the amino acid arginine to both fuel their growth and evade the immune system.

The research was led by Prof. HU Hai, who holds dual appointments as professor at the Hangzhou Institute of Medicine (HIM) of the Chinese Academy of Sciences (CAS), and Chief Physician at Zhejiang Cancer Hospital, in collaboration with Prof. LUO Manli from Sun Yat-Sen University and Prof. LI Hongde from HIM. The findings were published in Cancer Cell on April, 3.

The team discovered that breast cancer cells act as "arginine factories" within the tumor microenvironment, saturating the tumor microenvironment with this nutrient. Although arginine is essential for healthy immune function, cancer cells weaponize it to reprogram nearby tumor-associated macrophages (TAMs), a type of immune cell. Once reprogrammed, these TAMs suppress cancer-fighting CD8+ T cells, the immune system's primary cancer-fighting cells, driving disease progression.

Using cutting-edge single-cell and metabolic analyses, the researchers mapped how cancer-derived arginine reshapes the tumor microenvironment. They found that TAMs absorb arginine and convert it into polyamines - molecules that rewire the macrophages' genetic programming. The TAMs are locked into a pro-tumor state, silencing immune attacks and enabling tumors to thrive.

These findings offer the promise of new treatments. By disrupting arginine metabolism, the researchers successfully restored CD8+ T cell activity and slowed tumor growth in preclinical models. Based on these findings, they have proposed combining arginine- or polyamine-targeting drugs with existing immunotherapies to break the cycle of immune suppression.

Although this study is focused on breast cancer, the researchers suggest that this metabolic crosstalk may be exploited by other tumors as well to escape immune surveillance. This discovery marks a critical step in developing precision therapies that simultaneously starve tumors of their metabolic lifelines while empowering the immune system - a dual approach that could redefine cancer treatment.

Zhu Y, Zhou Z, Du X, Lin X, Liang ZM, Chen S, Sun Y, Wang Y, Na Z, Wu Z, Zhong J, Han B, Zhu X, Fu W, Li H, Luo ML, Hu H.
Cancer cell-derived arginine fuels polyamine biosynthesis in tumor-associated macrophages to promote immune evasion.
Cancer Cell. 2025 Apr 1:S1535-6108(25)00116-3. doi: 10.1016/j.ccell.2025.03.015