Related Experiment Video
Updated: Aug 22, 2026
Exploring the Regulation of Lipid Droplet Catabolism through Lipophagy
Published on: January 31, 2025
Long-chain fatty acid metabolism reprograms antitumor immunity: from molecular mechanisms to clinical translation
Guo Guo1, Huang Xin2, Weng Xiufang2
1School of Basic Medicine, Huazhong University of Science and Technology, Wuhan 430030, China.
Abstract:
This review summarizes how LCFA metabolic enzymes and transporters orchestrate antitumor immunity, underscoring their cell-type-specific dualities and druggability. AlphaFold3-predicted structures of CPT1A, ACSL4, ACSL5, FABP4, FABP5, and CD36 reveal deep hydrophobic pockets (Fpocket scores 0.67-0.81), and molecular docking maps inhibitor interactions: etomoxir (CPT1A His473 covalent), PRGL493 (ACSL4 AMP pocket), triacsin C (ACSL5 substrate tunnel), SBFI-26 (FABP5 β-barrel), and sulfo-N-succinimidyl oleate (CD36 SMAC pocket). Certain dietary LCFAs potently enhance antitumor responses: elaidic acid promotes MHC-I antigen presentation via the ACSL5-SIRT6-NLRC5 axis, sensitizing tumors to CD8+ T-cell-mediated killing and immune checkpoint blockade; docosahexaenoic acid (DHA) incorporates into phospholipids via ACSL4/6 to drive immunogenic ferroptosis, amplified by CD8+ T-cell-derived IFN-γ. In contrast, chronic LCFA accumulation fosters an immunosuppressive landscape: CPT1A-dependent FAO sustains Tregs, yet its succinyltransferase activity promotes PD-L1 degradation; myeloid FABP5 drives immunosuppressive macrophage differentiation; and CD36-mediated uptake of lipids or oxidized lipoproteins induces CD8+ T-cell dysfunction via the p38-CEBPB-TfR1 cascade and iron-dependent lipid peroxidation. Moreover, tumor-intrinsic ACSL4 can alternatively promote neoplastic proliferation and therapeutic resistance, revealing an oncogenic facet. Accordingly, we assess translational strategies that target these metabolic nodes in a context-aware manner: context-dependent CPT1A inhibition or non-enzymatic activation; selective blockade of CD36 or FABP5; inhibition of oncogenic ACSL4; and complementary approaches harnessing ACSL4/5-mediated antitumor pathways (e.g., ferroptosis induction and antigen presentation enhancement) through tailored dietary interventions and combination therapies. This integrated structural, biochemical, and pharmacological framework highlights the necessity of uncoupling the opposing immunomodulatory roles of LCFAs using cell-type-resolved and context-aware strategies in cancer therapy.
Insights
Long-chain fatty acid (LCFA) metabolism enzymes and transporters have dual roles in antitumor immunity, offering new therapeutic targets. Strategies must consider cell-type and context to harness beneficial effects while mitigating immunosuppression.
Area of Science:
- Immunology
- Metabolic pathways
- Cancer therapy
Background:
- Long-chain fatty acids (LCFAs) and their metabolic enzymes/transporters play complex roles in antitumor immunity.
- Understanding these roles is crucial for developing novel cancer therapies.
Purpose of the Study:
- To review how LCFA metabolic enzymes and transporters influence antitumor immunity.
- To explore their cell-type specific dualities and druggability.
- To assess translational strategies for cancer treatment.
Main Methods:
- Utilized AlphaFold3 for structural predictions of key enzymes and transporters.
- Performed molecular docking to map inhibitor interactions.
- Reviewed existing literature on LCFA metabolism in cancer immunity.
Main Results:
- LCFA metabolic enzymes and transporters exhibit context-dependent dual roles in immunity, promoting or suppressing antitumor responses.
- Specific dietary LCFAs like elaidic acid and docosahexaenoic acid enhance antitumor immunity via antigen presentation and ferroptosis.
- Chronic LCFA accumulation and certain enzymes (e.g., CPT1A, FABP5, CD36) promote immunosuppression and T-cell dysfunction.
- Tumor-intrinsic ACSL4 can drive proliferation and resistance.
Conclusions:
- Targeting LCFA metabolic nodes requires cell-type-resolved and context-aware strategies.
- Therapeutic approaches include enzyme inhibition/activation, transporter blockade, and dietary interventions.
- Uncoupling opposing immunomodulatory roles of LCFAs is key for effective cancer therapy.
