Acetyl-CoA synthetase 2: metabolic-epigenetic regulation, tumor immunity, and therapeutic opportunities in cancer
Year: 2026
Type: article
Abstract: Acetate is an important carbon source linking tumor metabolic adaptation to acylation-dependent regulation. Under hypoxia, nutrient limitation, and therapeutic stress, acetyl-CoA synthetase 2 (ACSS2)-mediated conversion of acetate to acetyl-CoA can support cytoplasmic anabolic metabolism while also contributing to local nuclear acetyl-CoA production and acylation-dependent transcriptional regulation. ACSS2-dependent acetate metabolism has further been implicated in autophagy-lysosome regulation, tumor-cell immune evasion, immune-cell metabolic adaptation, ferroptosis, and treatment tolerance. However, these functions are jointly shaped by tissue of origin, acetate availability, subcellular localization, post-translational modifications, driver alterations, and compensatory metabolic pathways, precluding a simple classification of ACSS2 as a uniformly tumor-promoting factor across cancer types. Here, we synthesize mechanistic evidence linking ACSS2 to hypoxic adaptation, epigenetic regulation, autophagy, tumor immunity, ferroptosis, and therapeutic adaptation, highlighting its context-dependent roles across tumor types and reviewing advances in the development of ACSS2 inhibitors. The immunological consequences of ACSS2 activity may differ between tumor cells and effector T cells under metabolic stress, complicating predictions about the immunological effects of systemic ACSS2 inhibition. Current evidence supports ACSS2 as a context-dependent metabolic vulnerability that may be actionable in biomarker-defined tumor states rather than as a universal therapeutic target. Clinical translation will require the identification of acetate-dependent tumor subsets, the development of biomarkers integrating ACSS2 localization with metabolic state, and rigorous evaluation of compensatory mechanisms, long-term safety, and rational combination-treatment windows.
Source: Frontiers in Immunology
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W7225802574