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2-methylbutanal remodels arachidonic acid metabolism and antitumor immunity through ENO1 in colorectal cancer
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DOI：10.1186/s12967-026-08762-2.png)
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Abstract
En 中文
Active aldehydes are increasingly recognized as bioactive metabolites, but their roles in tumor immune regulation remain poorly defined. In colorectal cancer (CRC), prostaglandin metabolism contributes to immune suppression, whereas its upstream metabolic regulators are incompletely understood. Here, we investigated 2-methylbutanal (2-MBTL), a branched-chain small-molecule aldehyde, in CRC. The antitumor and immunoregulatory effects of 2-methylbutanal (2-MBTL) were examined in CRC cell systems and mouse models. Its molecular target and downstream pathway were investigated using target-identification assays, RNA interaction analyses, genetic manipulation, transcriptomic profiling, and PGE2 supplementation. 2-MBTL suppressed CRC growth at well-tolerated doses, increased tumor immunogenic signals, enhanced intratumoral CD8⁺ T-cell infiltration and effector activity, and reduced suppressive myeloid populations. Its direct antiproliferative effect was limited, whereas its antitumor activity was markedly weakened in immunodeficient mice or after CD8⁺ T-cell depletion. Mechanistically, 2-MBTL bound ENO1 and impaired its association with YAP1 mRNA, reducing YAP1 protein expression without substantially altering ENO1 abundance or glycolysis-associated readouts. This was accompanied by increased HPGD expression and reduced PGE2 levels. ENO1 overexpression attenuated the effects of 2-MBTL, while exogenous PGE2 partially reversed tumor suppression and immune remodeling. In human CRC tissues, ENO1 and HPGD showed opposing associations with CD8⁺ T-cell infiltration and survival. 2-MBTL also enhanced the efficacy of PD-1 blockade. 2-MBTL promotes CD8⁺ T-cell-dependent antitumor immunity by modulating ENO1-associated post-transcriptional regulation and suppressing YAP1-related PGE2 metabolism.
Keywords:
2-methylbutanal
Colorectal cancer
ENO1
PGE2
Antitumor immunity
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