For a study, researchers sought to investigate TIME-related alterations during IPMN progression using multiplex immunofluorescence (mIF) and high-resolution image analyses. While genomic changes during multistep IPMN progression had been well documented, changes within the tumor immune microenvironment (TIME) had not been thoroughly studied. The 2 sets of formalin-fixed, paraffin-embedded tissue samples were analyzed from surgically resected IPMNs. The training set included 11 low-grade IPMN (LG-IPMN), 17 high-grade IPMN (HG-IPMN), and 2 IPMN with PDAC, while the validation set included 55 LG-IPMN and 38 HG-IPMN. The training set included 2 panels of immuno-oncology–related biomarkers, while the validation set included a subset of markers found to be significantly altered in the training set. Cell types associated with enhanced immune surveillance, such as cytotoxic and memory T cells and antigen-experienced T and B cells, were found at higher densities in isolated LG-IPMNs than HG-IPMNs. Notably, the TIME of LG-IPMNs that had progressed at the time of surgical resection (progressor LGD) matched that of synchronous HG-IPMNs, indicating that immune surveillance was compromised even in LG-IPMNs destined for progression. Investigators’ findings laid the groundwork for preventing cystic neoplasia from progressing to PDAC through vaccines and other preventive measures.