Eicosanoids in lung cancer: Mechanisms, metabolism, and therapeutic potential

Lung cancer is the leading cause of cancer-related mortality worldwide, and its pathogenesis is intricately associated with chronic inflammation and metabolic reprogramming. Eicosanoids, a diverse class of lipid mediators derived predominantly from arachidonic acid (AA), are integral to both inflammatory and homeostatic processes. Moving beyond historical pathway-centric descriptions, this review synthesizes recent findings by structuring the eicosanoid cascade around key biological themes: metabolic adaptation, tumor heterogeneity, immune evasion, and therapy resistance across major lung cancer histologies, specifically non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). To overcome the fragmentation of pathway-based analyses, this review intimately links distinct lipid signaling networks into broader biological frameworks, specifically delineating how eicosanoids orchestrate innate versus adaptive immune suppression. This review critically evaluates emerging controversies, integrating the dualistic role of AA metabolism in ferroptosis and the paradoxical context- and dose-dependent effects of lipid mediators directly into the framework of therapeutic vulnerability. Salient findings underscore how specific eicosanoids—particularly the cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) and thromboxane A2 (TXA2) axes—function as central coordinators of the tumor microenvironment (TME), promoting immune exclusion and resistance to modern immunotherapies. Conversely, protective mediators, such as prostacyclin (PGI2) and specialized pro-resolving mediators derived from omega-3 fatty acids, exhibit potent anti-neoplastic properties. By integrating multi-omics insights, spatial TME dynamics, and proposing a unified conceptual model, this review highlights how a nuanced understanding of eicosanoid interplay and its inherent biological uncertainties is imperative for identifying novel biomarkers and overcoming resistance in personalized lung cancer oncology.