Metabolite-mediated modulation of the tumor microenvironment

Metabolites within the TME may emerge from cancer cells, stromal and immune cells with considerable work to-date describing the biological impact of metabolic by-products such as lactate, kynurenine, and adenosine on the TME (Chen et al., 2024; Tang et al., 2023; Zhang et al., 2026; Watson et al., 2021; Dahal et al., 2024). Additional lipid-associated metabolites such as acetate, phosphoethanolamine (pEtn), and bioactive aldehydes within the TME have since been identified to promote cancer progression.

Specifically, Murthy and colleagues demonstrated that cancer-associated fibroblasts (CAFs) release acetate to fuel pancreatic cancer (PDAC) survival under metabolic stress through acetyl-CoA synthetase short-chain family member 2 (ACSS2)-mediated acetylation of SP1 and spermidine/spermine N1-acetyltransferase 1 (SAT1)-drives upregulation of polyamine metabolism (Murthy et al., 2024). Genetic or pharmacological inhibition of the ACSS2-SP1-SAT1 axis attenuated tumor development in cell line- and patient-derived xenograft models of PDAC (Murthy et al., 2024). CAF-derived lactate has also been shown to induce lactylation of the spliceosome component SNRPA at Lys123 (K123), resulting in enhanced chromatin binding and androgen receptor splicing in prostate cancer cells that drives resistance to androgen-deprivation therapy (ADT) (Zhao et al., 2026). Targeting of the lactate transporter via monocarboxylate transport inhibitors effectively restored sensitivity to ADT (Zhao et al., 2026).

Wang et al. identified phosphoethanolamine (pEtn), an intermediate in phospholipid biosynthesis, to be highly elevated in tumor interstitial fluid and increased accumulation of this onco-metabolite was found to suppress CD8+ T-cell effector function and increase expression of inhibitory molecules PD-1, Tim-3, and Lag3 (Wang et al., 2025). Mechanistically, pEtn promoted CD8+ T-cell dysfunction by limiting diacylglycerol-dependent TCR signaling (Wang et al., 2025). Using a B16-Pcyt2 overexpression model of melanoma, authors further found that reduction of intratumoral pEtn levels improved T-cell function and tumor control compared to B16-empty vector control-tumor bearing mice, supporting the notion that pEtn is an immunosuppressive onco-metabolite (Wang et al., 2025).

Beyond pEtn, lipid byproducts such as the reactive aldehyde acrolein also contribute to an immunosuppressive TME. Haku and colleagues showed that loss of HADHA and SLC25A20 impairs fatty acid oxidation, causing mitochondrial stress, acrolein accumulation, AKT-mTOR activation, GLUT1 upregulation, and T cell exhaustion. Blocking acrolein accumulation with lipid peroxidation inhibitors or N-benzylhydroxylamine enhanced PD-1 blockade efficacy in MC38 colon adenocarcinoma models (Haku et al., 2026).