image: Amino acid metabolism in the TIME. The TIME is shaped by metabolic competition between tumor and immune cells. Amino acids have key roles in modulating immune responses and tumor progression. (A) Glutamine: tumor cells upregulate the glutamine transporter, SLC1A5, increasing glutamine uptake to fuel the TCA cycle and promote PD-L1 expression. PD-L1 on tumor cells interacts with PD-1 receptors on CD8⁺ T cells, inhibiting TCR signaling initiated by MHC I–TCR antigen presentation and thereby suppressing T cell activation and inducing exhaustion. Excessive glutamine uptake by tumor cells reduces glutamine availability in the microenvironment, thereby limiting TCA cycle activity and metabolic fitness in T cells. (B) Tryptophan: tumor cells overconsume tryptophan and convert tryptophan into kynurenine via IDO. Kynurenine activates AhR signaling in T cells, which leads to downregulation of co-stimulatory molecules (e.g., CD80/CD86) and upregulation of PD-1, thereby suppressing T cell activation and fostering an immunosuppressive microenvironment. (C) Serine: tumor cells excessively uptake serine to fuel SGOC metabolism via ATF4, supporting nucleotide biosynthesis and proliferation. In contrast, serine deprivation promotes M1 macrophage polarization by upregulating IGF1 and activating STAT1 signaling. (D) Arginine: TAMs and MDSCs express ARG1 to deplete extracellular arginine and produce NO, both contributing to immune suppression. Tregs secrete IL-10 and TGF-β, further reinforcing immunosuppression and shaping the TIME. The figure was created with BioRender.com. AhR, aryl hydrocarbon receptor; ARG1, arginase-1; ATF4, activating transcription factor 4; CD80, cluster of differentiation 80; CD86, cluster of differentiation 86; IDO, indoleamine 2,3-dioxygenase; IGF1, insulin-like growth factor 1; IL-10, interleukin-10; Kyn, kynurenine; MDSC, myeloid-derived suppressor cell; NO, nitric oxide; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; SGOC, serine–glycine–one-carbon; SLC, solute carrier; STAT1, signal transducer and activator of transcription 1; TAM, tumor-associated macrophage; TCR, T cell receptor; TGF-β, transforming growth factor-beta; TIME, tumor immune microenvironment; Treg, regulatory T cell.
Credit: Cancer Biology & Medicine
Far from being mere cellular building blocks, amino acids have emerged as powerful regulators of cancer growth and immune function. This review reveals how tumors manipulate amino acid metabolism to gain a competitive edge, starving immune cells and reshaping the tumor immune microenvironment (TIME). Key players such as glutamine, arginine, tryptophan, and methionine are now recognized not only as fuel but also as signaling agents that modulate immunity and therapeutic resistance. The study also outlines innovative strategies—from enzyme inhibitors to engineered probiotics—that leverage this metabolic vulnerability to reprogram the TIME and enhance anti-cancer immunity.
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," said Dr. Ping Wang, co-corresponding author of the review. "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."
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.
###
References
DOI
10.20892/j.issn.2095-3941.2025.0115
Original Source URL
https://doi.org/10.20892/j.issn.2095-3941.2025.0115
Funding information
This work was supported by grants from the National Key Research and Development Program of China (Grant No. 2022YFC3401500 to P.W.; Grant No. 2021YFA1302200 to L.F.) and the National Natural Science Foundation of China (Grant Nos. 82341028 and 31920103007 to P.W.; Grant Nos. 82472815 and U24A20727 to L.F.).
About Cancer Biology & Medicine
Cancer Biology & Medicine (CBM) is a peer-reviewed open-access journal sponsored by China Anti-cancer Association (CACA) and Tianjin Medical University Cancer Institute & Hospital. The journal monthly provides innovative and significant information on biological basis of cancer, cancer microenvironment, translational cancer research, and all aspects of clinical cancer research. The journal also publishes significant perspectives on indigenous cancer types in China. The journal is indexed in SCOPUS, MEDLINE and SCI (IF 8.4, 5-year IF 6.7), with all full texts freely visible to clinicians and researchers all over the world.
Journal
Cancer Biology & Medicine
Subject of Research
Not applicable
Article Title
Amino acids shape the metabolic and immunologic landscape in the tumor immune microenvironment: from molecular mechanisms to therapeutic strategies
Article Publication Date
24-Jul-2025
COI Statement
The authors declare that they have no competing interests.