BACKGROUND: Acute pancreatitis (AP) initiates as primarily sterile local inflammation that triggers pro-inflammatory response, which is subsequently counterbalanced by an anti-inflammatory response. Immune checkpoints, such as PD-1/PD-L1, play a pivotal role in modulating these responses to prevent excessive immune activation and associated inflammatory damage. This study aimed to investigate the underlying mechanisms of these processes in both murine and human AP. METHODS: We conducted a comprehensive integration of data from cerulein-induced AP mouse models (CER-AP), utilizing single-cell RNA sequencing and digital spatial profiling for pancreatic samples, as well as single-cell Cytometry by Time Of Flight (CyTOF) for blood samples. Additionally, bulk-RNA sequencing performed on blood samples from AP patients was employed to investigate innate and adaptive immune changes at early stage of the disease. RESULTS: Across the four analytical approaches, we observed consistent immune cell type distributions. Our integrative analysis revealed a significant imbalance between increased innate immune cells, including neutrophils, macrophages, and monocytes, and decreased adaptive immune cells, including CD4 CONCLUSION: This multi-omics analysis deciphers a distinct imbalance between increased innate immunity and decreased adaptive immunity during the early phase of AP. The PD-L1 checkpoint emerges as a key regulator of immune homeostasis and a critical factor in the pathogenesis of AP.