The future of brain tumor treatment: integrating platelet-based liquid biopsy, advanced drug delivery systems, and eicosanoid inhibition.

Despite extensive research, brain tumors still have some of the lowest survival rates among cancers. Their marked resistance to both conventional and emerging therapies stems from the unique properties of neural cells and their microenvironment, including the blood-brain barrier, cellular heterogeneity, and an immunosuppressive milieu. Addressing these challenges is essential for developing effective therapeutic strategies that improve patient outcomes. Advancements in brain tumor treatment depend on understanding the biological mechanisms behind potential drug targets and developing appropriate drug discovery strategies to inhibit them effectively. A major barrier remains the difficulty many drugs face in crossing the blood-brain barrier, which greatly restrains treatment effectiveness in brain tumor patients. Therefore, developing innovative drug delivery systems is essential. The brain exhibits a high concentration of fatty acids, notably polyunsaturated fatty acids such as arachidonic acid (AA), which are primarily esterified within membrane phospholipids. Upon release, cyclooxygenases, lipoxygenases, and cytochrome P450 enzymes can transform AA into various eicosanoid classes, producing lipid mediators involved in signal transduction pathways that regulate neurotransmission, neuroinflammation, and neuroplasticity. The diverse eicosanoid families can be synthesized within brain tumors and may contribute to tumor heterogeneity. This includes cell-specific eicosanoid production involving cancer cells, microglia, infiltrating immune cells, and platelets, each expressing distinct enzymes that facilitate tumor progression and immune evasion. This review examines the various mechanisms underlying brain cancer biology, with a particular focus on the roles of eicosanoids and their signaling pathways and how they affect tumor development, progression, and resistance to therapies. The review also describes therapeutic strategies targeting these pathways. The challenge of reduced responsiveness to therapeutic interventions is addressed through platelet-based drug delivery systems, which can increase efficacy by transporting chemotherapeutic agents directly to cancer cells. These systems also include nanoparticles coated with platelet membranes to evade immune clearance of intact cells and extracellular vesicles that provide high biocompatibility. Finally, tumor-educated platelets-which carry RNA and protein cargo-are presented as noninvasive biomarkers for diagnosing and monitoring disease progression and response to therapies in brain tumors.