Abstract Introduction: Immune checkpoint blockade (ICB) therapy has been revolutionary in its ability to treat advanced malignancies. Yet many patients receiving ICB develop Immune related adverse events (IRAEs), a leading cause for patients to discontinue treatment. Analyzing patients who develop IRAEs can help advance our knowledge of the molecular drivers of these poorly understood off target toxicities. Methods: Our recent study of plasma from patients undergoing ipilimumab (anti-CTLA4) or pembrolizumab (anti-PD1) therapy for melanoma, lung cancer or other solid tumors was assessed using high-resolution liquid chromatography-tandem mass spectrometry. Results: We uncovered a novel protective mechanism related to a class of circulating bio-active lipids that suppress ICB-related IRAEs. Significant reduction of bio-active lipids in circulation was associated with increased ICB-mediated IRAEs. Mouse-models (both DSS-colitis and humanized models) were used to show that supplementation with these lipids ameliorated colonic inflammation without impacting ICB-driven tumor regression. We also uncovered a significant correlation between increasing neutrophil counts and decreased bioactive lipids in circulation. Conclusion: These results uncover a previously unidentified regulatory mechanism whereby the identified lipids in circulation specifically suppress deleterious inflammation during ICB therapy, while preserving anti-tumor immunity, suggesting that supplementation of bio-active lipids can be developed as a new therapeutic strategy to improve clinical outcomes in cancer immunotherapy. Supported by grants from NIH (R01CA256133-02)