The dichotomous function of eicosanoid signaling in the pathogenesis and therapeutic management of lung cancer

Lung cancer remains the leading cause of cancer-related mortality globally. Its persistence is driven by a combination of genetic mutations and a tumor-promoting microenvironment (TME). A key component of this environment is the profound dysregulation of eicosanoid signaling. This review examines the distinct clinical and mechanistic dichotomy of this pathway. Pro-inflammatory eicosanoids from the cyclooxygenase-2 (COX-2) pathway, notably prostaglandin E₂ (PGE₂), are established drivers of tumorigenesis, promoting proliferation, angiogenesis, and immune suppression. Crucially, this PGE₂-driven suppression is a major mechanism of resistance to immune checkpoint blockade (ICB) therapies. In contrast, other eicosanoids, such as prostacyclin (PGI₂) and omega-3 fatty acid derivatives (resolvins), exhibit potent anti-tumor properties. These protective roles are supported by clinical trials where PGI₂ analogues successfully reversed premalignant lesions, highlighting a potential strategy for chemoprevention. This paper synthesizes current knowledge on these opposing pathways, dissecting their biosynthetic routes and divergent roles in tumor progression versus suppression. It analyzes how eicosanoids regulate the TME and drive resistance to chemotherapy, targeted therapy, and immunotherapy. Furthermore, the clinical landscape is evaluated, discussing why broad COX-2 inhibitors failed in advanced disease and proposing new strategies centered on biomarker-driven combinations and nutritional interventions. By consolidating these findings, this review underscores the critical need for a nuanced approach to targeting eicosanoid signaling for both treatment and prevention.