Amino acid metabolism shapes the tumor immune microenvironment and therapy response

The tumor microenvironment is not just a site of cancer growth—it is a high-stakes metabolic contest where tumor and immune cells vie for limited resources. Amino acids, once seen as passive nutrients, are now known to steer cell fate, immune suppression, and resistance to immunotherapy. Tumors often win this battle by monopolizing amino acids, crippling the metabolism of nearby T cells and macrophages. Recent advances have illuminated how this biochemical imbalance hinders immune surveillance and fosters tumor progression. Due to these challenges, there is a growing urgency to explore how amino acid dynamics influence cancer immunity and identify new therapeutic targets within this hidden battleground.

In a new review (DOI: 10.20892/j.issn.2095-3941.2025.0115) published in Cancer Biology & Medicine, scientists from Tongji University Cancer Center explored how amino acid metabolism governs the intricate dialogue between cancer cells and immune defenses. The paper charts a comprehensive map of how amino acid sensing, transport, and utilization shape tumor behavior and immune cell function. It also highlights pioneering therapies—from CAR-T cell enhancements to microbial-based interventions—that rewire the tumor immune microenvironment (TIME) and offer fresh hope in the fight against cancer.

Tumor cells and immune cells are locked in a biochemical tug-of-war over amino acids. The review uncovers how tumors exploit this metabolic dependency to fuel their growth while sabotaging immune responses. Glutamine feeds tumor proliferation but its depletion cripples T cells. Arginine, essential for T cell activation, is often depleted in the TIME by tumor-associated macrophages expressing arginase. Tryptophan is converted by tumor enzymes into kynurenine, suppressing T cells via the AhR pathway. Methionine, vital for DNA methylation, is hoarded by cancer cells, disrupting T cell epigenetic programming.

Beyond nutrient supply, amino acids act as molecular messengers. Sensors such as mTOR, AMPK, and AhR decode amino acid levels, triggering survival and immune evasion pathways. Newly discovered sensors like TARS2 and HDAC6 open doors to uncharted therapeutic targets. The review further highlights experimental interventions—from enzyme inhibitors and amino acid-loaded nanoparticles to diet-based and microbiota-driven strategies—that selectively reprogram metabolism to favor immune activation. These findings connect molecular pathways to real-world treatments, positioning amino acid metabolism as a powerful lever in cancer therapy.

Amino acids are not just nutrients—they are the language tumors and immune cells use to communicate. By understanding this metabolic dialogue, we can begin to intercept and rewrite it. Our work lays the foundation for a new class of therapies that don't just kill cancer cells but also empower the immune system to fight back more effectively."

Dr. Ping Wang, co-corresponding author of the review

Targeting amino acid metabolism offers a novel and precise strategy to tip the balance of the tumor immune microenvironment. Therapeutic approaches such as glutaminase inhibitors, arginase blockers, and methionine restriction diets are being tested alongside immune checkpoint inhibitors to amplify antitumor effects. Probiotic-based therapies that alter local amino acid levels and engineered immune cells with enhanced nutrient-sensing capacities hold promise for hard-to-treat cancers. As metabolic profiling becomes integrated into oncology, these amino acid-centered interventions may lead to more personalized, effective cancer treatments that overcome immune resistance and improve patient survival.