P2Y₁₂ is a G-protein-coupled receptor that is activated upon ADP binding. Considering its well-established role in platelet activation, blocking P2Y₁₂ has been used as a therapeutic strategy for antiplatelet aggregation in cardiovascular disease patients. However, receptor studies have shown that P2Y₁₂ is functionally expressed not only in platelets and the microglia but also in other cells of the immune system, such as in monocytes, dendritic cells, and T lymphocytes. As a result, studies were carried out investigating whether therapies targeting P2Y₁₂ could also ameliorate inflammatory conditions, such as sepsis, rheumatoid arthritis, neuroinflammation, cancer, COVID-19, atherosclerosis, and diabetes-associated inflammation in animal models and human subjects. This review reports what is known about the expression of P2Y₁₂ in the cells of the immune system and the effect of P2Y₁₂ activation and/or inhibition in inflammatory conditions. Lastly, we will discuss the major problems and challenges in studying this receptor and provide insights on how they can be overcome.

Pancreatic ductal adenocarcinoma (PDAC) is the third primary cause of cancer-related mortality in the US. PDAC is associated with an immunosuppressive tumor microenvironment (TME) that restricts the effectiveness of immunotherapies. Immunosuppressive tumor-associated macrophages (TAMs), the most abundant cell type in TME, express immune checkpoint ligands, including programmed cell death protein 1 (PD-1) ligand 1 (PD-L1). Targeting PD-1/PD-L1 alone has no effect in PDAC, highlighting the need for combination approaches. P2Y₁₂, an ADP receptor, is expressed by macrophages, and P2Y₁₂ antagonists promote phagocytosis, in turn, is linked to anti-tumor activity. Here, we tested the combined blockade of PD-1/PD-L1 and P2Y₁₂ on TAMs in pancreatic cancer. For this purpose, we set up co-cultures of pancreatic cancer cells and TAMs and treated them with inhibitor BMS-1, which blocks PD-1/PD-L1 interaction, cemiplimab to block PD-1, and ticagrelor to block P2Y₁₂. We observed that the co-treatment of ticagrelor and cemiplimab promoted TAM phagocytic ability and inhibited the TAM-induced growth and migration of cancer cells. The combination of ticagrelor and cemiplimab inhibited TGF-β1 release from TAMs and Smad2 phosphorylation in cancer cells. Our data suggest that co-treatment of ticagrelor and cemiplimab in TAMs inhibits pancreatic cancer cell growth and migration by suppressing the TGF-β1/Smad2 signaling pathway, providing an emerging strategy aimed at re-educating or depleting TAMs to enhance the efficacy of immunotherapy in pancreatic cancer.

The neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) have emerged as potent modulators of immune responses during sepsis, yet their roles remain complex, alternating between protective and permissive depending on timing, tissue compartment, and inflammatory context. This review presents a historical assessment of VIP and PACAP in sepsis research, highlighting the evolution of conceptual advances across five decades. Starting in the 1980s, early studies revealed that VIP levels rise during endotoxemia and correlated with hypotension and mortality, suggesting a deleterious role. By the 1990s, research pivoted toward understanding gut-derived VIP and its interaction with nitric oxide, culminating in the classification of VIP and PACAP as “macrophage deactivating factors” that downregulate TNFα and IL-6. The 2000s further clarified their cell-specific actions through VPAC1/2 and PAC1 receptors, showing anti-inflammatory effects on both innate and adaptive immune cells, while illuminating delivery challenges overcome by liposomal encapsulation. The 2010s expanded this narrative by dissecting receptor dynamics, gut barrier regulation, and VIP’s role in neuroimmune crosstalk and thrombo-inflammation. Most recently, studies in the 2020s provide a nuanced view of how VIP suppresses inflammatory damage but also enables pathogen persistence during live bacterial infection, implicating VIP signaling in trade-offs between tolerance and clearance. Across this chronological framework, VIP and PACAP have oscillated between friend, foe, and frenemy, underscoring the importance of context in leveraging their therapeutic potential in sepsis.