Objective To explore the characteristics of tumor immune microenvironment of pancreatic ductal adenocarcinoma (PDAC) based on the differentially expressed genes associated with macrophages in early and late tumor tissues of PDAC patients, so as to provide new targets for early diagnosis and treatment of PDAC. Methods Three early-stage and 4 late-stage tumor samples were collected from PDAC patients. Tissue transcriptome data were analyzed by single-cell sequencing technology. With The Cancer Genome Atlas (TCGA) database, macrophage related genes differentially expressed in early and late PDAC related to prognosis were obtained. The prognostic risk scoring model was constructed using the least absolute shrinkage and selection operator (LASSO)-Cox method. The risk genes associated with PDAC prognosis were screened using the Gene Expression Profiling Interaction Analysis 2 (GEPIA2) online survival analysis tool. Their immune infiltration was analyzed using the cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) method, and their expression in different subpopulations of macrophages at different periods was resolved by t-distributed stochastic nearest-neighbour embedding (tSNE) clustering downscaling and the Monocle package. The protein-protein interactions and immunohistochemistry were further analyzed with the help of STRING database and The Human Protein Atlas (HPA) database. Results A total of 48 differentially expressed macrophage-related genes in early and late PDAC were found to be associated with prognosis. Eleven differentially expressed macrophage genes were screened as PDAC prognostic genes, and they were used to construct a prognostic risk scoring model for PDAC. Two prognostic genes with significant risk indicators were screened: 2'-5'-oligoadenylate synthetase 2 (OAS2) was mainly expressed in secreted phosphoprotein 1 (SPP1)-positive macrophages, and assembly factor for spindle microtubules (ASPM) was mainly expressed in proliferation marker protein Ki-67 (MKI67)-positive macrophages. There were significant differences in the expression of OAS2 in PDAC macrophages at different stages. Immune infiltration studies showed that OAS2 and ASPM were highly expressed in regulatory T cells and M2-type macrophages (both P＜0.05). Protein-protein interaction network showed the expression relationship between OAS2 and ASPM and other co-expressed proteins. Immunohistochemistry results showed that the expression of OAS2 was higher in tumor tissues than in normal tissues. Conclusion OAS2 and ASPM are both poor prognostic genes that are specifically expressed and exert negative immune effects in SPP1⁺ macrophages and MKI67⁺ macrophages, respectively, promoting the progression of PDAC and ultimately leading to a poor prognosis, and it is expected to provide new targets for the prevention and treatment of PDAC.