Amino acids shape the metabolic and immunologic landscape in the tumor immune microenvironment: from molecular mechanisms to therapeutic strategies

Abstract

The tumor immune microenvironment (TIME) represents a complex battlefield where metabolic competition and immune evasion mechanisms converge to drive cancer progression. Amino acids, with their multifaceted biological roles, have emerged as pivotal regulators of tumor cell proliferation and immune cell functionality. The sensing mechanisms by which amino acids within the tumor microenvironment influence cellular growth, survival, and immune function are systematically explored in this review; the latest advances in understanding amino acid metabolism in tumor biology are also reviewed. In addition, the multifaceted roles of key amino acids in shaping the TIME with particular emphasis on tumor immunity and malignant growth were investigated. Finally, emerging therapeutic strategies targeting amino acid metabolism to reprogram the TIME are discussed, highlighting promising approaches, such as CAR-T cell therapy and engineered bacterial interventions. Through this comprehensive analysis, critical insights into future research directions and potential clinical translation of amino acid-targeted interventions are provided.

Keywords: Tumor microenvironment (TME); amino acid metabolism; amino acid sensing; immunotherapy; metabolic reprogramming.

Figure 1

Regulation of mTORC1 signaling by amino acid sensors and the GATOR complex. This schematic depicts how amino acid availability regulates mTORC1 through a network of cytosolic and lysosomal sensors. Leucine (L) is sensed by two distinct proteins: ① Sestrin2 [a leucine-binding GTPase involved in mTORC1 inhibition (Kd ≈ 20 μM)]; and ② SAR1B [a stress-responsive regulator of cell viability with high leucine affinity (Kd ≈ 2 μM)]. Upon binding leucine, both sensors undergo conformational changes and dissociate from the GATOR2 complex (SAR1B from MIOS; Sestrin2 from SEH1L), which relieves GATOR1 inhibition. GATOR1 acts as a GTPase-activating protein (GAP) for RagA/B, promoting the conversion to the GDP-bound (inactive) state. The inactive RagA/B–GDP:RagC/D–GTP heterodimer is unable to recruit mTORC1 to the lysosomal membrane. When amino acids are sufficient, GATOR2 inhibits GATOR1, thereby relieving GAP activity. This situation enables formation of the active RagA/B–GTP:RagC/D–GDP heterodimer, which facilitates recruitment and activation of mTORC1. Methionine (M) is detected via SAMTOR, which binds SAM and modulates GATOR1 activity, acting in parallel to the leucine pathway. Threonine (T) activates mTORC1 via TARS2. Upon threonine binding, TARS2 preferentially associates with GTP-bound RagC, which promotes RagA GTP-loading and facilitates mTORC1 recruitment. Arginine (R) is monitored by three spatially distinct sensors: ③ CASTOR1, a cytosolic sensor that interacts with GATOR2 to regulate mTORC1 in response to cytoplasmic arginine; ④ SLC38A9, a lysosomal arginine transporter that interacts with inactive Rag dimers and promotes activation in response to luminal arginine; and ⑤ TM4SF5, a lysosomal lumen sensor that binds free arginine and cooperates with SLC38A9 and mTOR to activate the mTOR/S6K1 signaling axis. The figure was created with BioRender.com. CASTOR1, cytosolic arginine sensor for mTORC1 regulation; GDP, guanosine diphosphate; GTP, guanosine triphosphate; Kd, dissociation constant; mTORC1, mechanistic target of rapamycin complex 1; SAM, S-adenosylmethionine; SAMTOR, SAM sensor regulating mTORC1 via GATOR1; SLC, solute carrier; TARS2, threonyl-tRNA synthetase 2; TM4SF5, transmembrane 4 L six family member 5.

Figure 2

The metabolic tug-of-war for amino acids between cancer cells and immune cells. Within the tumor immune microenvironment (TIME), cancer cells upregulate various solute carriers (SLCs) to enhance amino acid uptake and amino acid-derived metabolite transport, which supports proliferation, immune evasion, and metastasis. SLCs are functionally categorized and labeled, as follows: SLC① (e.g., SLC1A5 and SLC7A5) mediates amino acid import and is commonly upregulated in tumor cells to meet biosynthetic and energetic demands. SLC② (e.g., SLC7A5 and MCT1) exports tumor metabolites, such as Kyn and lactate, and is frequently upregulated, while SLC③ mediates amino acid uptake by immune cells with stable expression. In contrast, immune cells also rely on amino acids for proliferation, differentiation, and effective anti-tumor responses. Competition for amino acids and amino acid derivatives within the TIME impairs immune cell function and promotes tumor progression. PD-L1 and PD-1 are upregulated in response to metabolic stress. Blue and yellow dots represent amino acids and amino acid-derived metabolites, respectively. The figure was created with BioRender.com. AAs, amino acids; Kyn, kynurenine; MCT, monocarboxylate transporter; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; SLC, solute carrier; TIME, tumor immune microenvironment.

Figure 3

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.