Targeting the COX-2/PGE

Aggressive brain tumors such as glioblastoma (GBM) remain among the most lethal human cancers, with a median survival of only 15 months despite multimodal treatment. Their resistance arises from a triad of barriers-the blood-brain barrier (BBB), marked intratumoral heterogeneity, and a profoundly immunosuppressive tumor microenvironment (TME). Immunotherapeutic strategies based on natural killer (NK) and T cells, leveraging antigen-independent cytotoxicity and antigen-specific precision, respectively, offer potential breakthroughs but are often limited by chronic neuroinflammation. A key driver of TME suppression is prostaglandin E2 (PGE2), produced via the cyclooxygenase-2 (COX-2) pathway. PGE2 exerts a dual role: Intracellularly, it can promote apoptosis, whereas extracellularly, it fosters tumor progression, immune evasion, and therapeutic resistance. Through activation of EP2 and EP4 receptors, PGE2 signals via Gαs proteins to elevate cyclic adenosine monophosphate (cAMP), leading to impaired cytotoxic immunity. This signaling downregulates NK cell activating receptors (e.g., NKG2D, NKp30), induces CD8⁺ T cell exhaustion, and promotes regulatory T cell expansion. The COX-2/PGE₂ axis further mediates resistance to checkpoint inhibitors, CAR-T therapy, and chemotherapy by enhancing neuronal excitation through EP1 receptor activation in GBM. Targeting this pathway has therefore emerged as a compelling therapeutic strategy, which can restore NK and T cell function and sensitize tumors to immunotherapy. Combining PGE₂ modulation with next-generation NK/T cell approaches-including CAR-NK and CAR-T platforms-holds promise to overcome immune resistance and redefine therapeutic paradigms for GBM and other central nervous system malignancies.