Lipid metabolism in γδ T-cell activation: Implications for immunotherapy in ovarian cancer

Ovarian cancer (OC) remains a leading cause of cancer-related mortality among women worldwide, largely due to asymptomatic progression, late-stage diagnosis, therapeutic resistance, and profound immunosuppression within the tumor microenvironment (TME). This is particularly relevant in advanced disease, where metastatic spread to the omentum creates a lipid-rich niche that promotes tumor growth and weakens anti-tumor immunity. This review examines lipid metabolic reprogramming and γδ T-cell function as a targetable immunometabolic axis in OC, with selected discussion of iNKT and CD8+ T-cells as comparative models. Direct evidence from OC patient samples demonstrates that the omental TME drives CD36-mediated lipid uptake and fatty acid (FA) oxidation, while chronic lipid exposure impairs γδ T-cell mitochondrial oxidative phosphorylation and promotes exhaustion, including up-regulation of PD-1 and TIGIT. The major γδ T-cell subsets exhibit distinct metabolic vulnerabilities: Vδ1 T-cells can recognize CD1-presented lipid antigens and rely on FA oxidation, favoring pro-tumoral IL-17 production, whereas Vδ2 T-cells detect phosphoantigens via BTN3A and depend more strongly on glycolysis, rendering them susceptible to glucose deprivation in the OC TME. Concurrent adenosine signaling via A2A receptors, potentially amplified by lipid-induced CD39/CD73 up-regulation, further suppresses γδ T-cell function. We also evaluate nanoparticle-based platforms for co-delivery of metabolic modulators, γδ T-cell agonists, and immune checkpoint blockers, while highlighting key translational barriers, including variable enhanced permeability and retention effects, limited γδ T-cell-specific targeting, and potential systemic toxicity of FASN or CD36 inhibition. Finally, this review proposes future strategies including single-cell metabolomics to map subset-specific vulnerabilities, CRISPR-based validation of exhaustion mechanisms, metabolic engineering of CAR-γδ T-cells through CD36 knockout or CPT1A overexpression, intraperitoneal nanoparticle delivery in patient-derived xenograft models, and TME-restricted delivery systems. Together, these approaches may help overcome lipid-driven immune dysfunction and support the development of next-generation immunotherapies for OC.