An ideal form of cancer therapy is the harnessing of innate immunity to eradicate spontaneously arising clones of malignant cells. To date, attempts to develop effective immunotherapies have met with limited success. Prostaglandins and leukotrienes, collectively known as eicosanoids, are important mediators of immune and inflammatory responses. Harnessing these compounds could be a method to treat cancers. Eicosanoids are formed after cleavage of fatty acids from phospholipids by phospholipase enzymes. We have previously described, characterized and cloned a naturally occurring mammalian activator of phospholipase A2. Injection of a 24 amino acid peptide from this phospholipase A2 activating protein (PLAP), resulted in induction of an acute inflammatory response, and a concomitant regression of gliomas in rats. Administration of 500 micrograms of this protein resulted in a 50% decrease of the tumor mass within 72 h. Tumor regression coincided with a greater than twenty-fold increase in levels of prostaglandin E2(PGE2) and leukotriene B4(LTB4), and a marked infiltration of natural killer(NK) cells. These data suggest that activation of phospholipase A2 and modulation of the eicosanoid biosynthetic pathway may provide a novel therapeutic strategy for the successful treatment of malignant tumors of the nervous system.