Long-chain fatty acid metabolism reprograms antitumor immunity: from molecular mechanisms to clinical translation.

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.