Zelenay em et al /em . the incidence, metastasis, and mortality of various solid tumors (1, 2). Even though molecular mechanisms of NSAIDs, especially aspirin, in protecting against cancer are not well recognized, NSAIDs are thought to primarily reduce the production of prostaglandins (PGs) by inhibiting the activity of cyclooxygenase enzymes (COX-1 Succimer and/or COX-2). COX-1 is definitely constitutively expressed in most IkappaBalpha cells and was thought to be a housekeeping enzyme that maintains particular aspects of cells homeostasis. By contrast, COX-2 is an immediate-early response gene that is normally absent from most cells but is definitely highly inducible at sites of swelling, trauma and cancers (2, 3). COX enzymes are responsible for the production of five unique prostanoids, including PGs such as PGE2, PGD2, PGF2, PGI2 and thromboxane A2 (TxA2), by specific PG synthases (Number 1). PGE2 is the only prostanoid demonstrated to play a predominant part in promoting tumor formation, progression, and metastasis by acting directly on tumor cells and also on tumor stromal cells (3, 4). Succimer However, the mechanisms underlying the effects of PGE2 on malignancy development are elusive. In a recent study, Zelenay (10) supports this notion. Given that PGE2 promotes immunosuppression, it is conceivable that non-selective COX inhibitors such as aspirin or selective COX-2 inhibitors such as celecoxib could inhibit tumor formation and growth by subverting PGE2-inducing immunosuppression in the appropriate context. Zelenay em et al /em . have now reported for the first time that aspirin or celecoxib can facilitate anti-PD-1-mediated anti-tumor reactions in mouse transplantation models of melanoma and CRC (5). These findings may provide a rationale for developing fresh therapeutic approaches which include the reactivation of tumor-inhibited effector T cells through checkpoint blockade, while impairing tumor-induced immunosuppression through COX or PGE2 inhibitors (Number 1). In summary, a growing body of evidence supports the hypothesis that effective malignancy therapies should include removal of tumor cells, inhibition of tumor-associated angiogenesis, and subversion of Succimer tumor-induced immunosuppression by enhancing infiltration and activation of standard DCs, focusing on immunosuppressive cells, and reactivating tumor-inhibited effector T cells, partly through checkpoint inhibitors. NSAIDs, including aspirin and celecoxib, Succimer are able to get rid of tumor epithelial cells and reduce tumor-associated angiogenesis. The fascinating observation that aspirin or celecoxib boost the effectiveness of immune checkpoint inhibitors by inhibiting PGE2-induced immunosuppression in certain tumors may pave the way for future combination treatments using both checkpoint blockade and NSAIDs in malignancy treatment. Although further studies are warranted to evaluate the desired synergistic effects of such combined treatments in individuals whose tumors communicate COX-2 at higher levels, the findings from Reis e Sousa’s laboratory provide a significant advance in the field of immunooncology by bringing forth a potentially promising therapeutic approach against malignancy. Acknowledgments Research carried out in the DuBois laboratory is supported, in part, from the NIH R01 DK47297, NCI R01 CA184820, and NCI P01 CA77839. We say thanks to the National Colorectal Cancer Study Alliance (NCCRA) for its good support (R.N.D.). Footnotes Publisher’s Disclaimer: This is a PDF file of an unedited manuscript that has been approved for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the producing proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain..