Targeting Lipid Metabolic Reprogramming to Overcome Immunotherapy Resistance: Systemic Nutritional Modulation and...

Despite the clinical success of immune checkpoint inhibitors (ICIs), resistance driven by a metabolically hostile tumor microenvironment (TME), particularly lipid metabolic reprogramming, remains a formidable challenge. Tumors actively exploit lipid mediators, notably prostaglandin E2 (PGE2), to suppress CD8⁺ T cells and promote immunosuppressive macrophage polarization. Although targeted nanotherapeutics aim to locally reverse these defects, their in vivo efficacy is frequently abrogated by the host's nutritional baseline. Specifically, high dietary intake of Omega-6 polyunsaturated fatty acids fuels systemic PGE2 biosynthesis, creating a metabolic "sink" that localized nanotherapies struggle to neutralize. To address this limitation, this review proposes a dual-compartment therapeutic framework combining systemic dietary modulation with precision nanotherapy. As a distinctive contribution, we bridge these biological mechanisms with pharmaceutical design by integrating critical translational barriers, advanced formulation strategies, and emerging technologies for lipid reprogramming. Building upon this, we critically evaluate the most promising formulations, including stimuli-responsive and lipid-targeted nanocarriers, to elucidate their synergistic potential with nutritional interventions. Ultimately, pairing systemic Omega-3 dietary preconditioning with localized nanotherapeutics provides a biologically rational strategy to dismantle lipid-driven immune evasion. Maximizing patient outcomes and advancing future clinical prospects will depend on the rigorous translation of these combinatorial regimens to effectively overcome ICI resistance.