Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy and is unresponsive to conventional therapeutic modalities due to its high heterogeneity, expounding the necessity, and priority of searching for effective biomarkers and drugs. Autophagy, as an evolutionarily conserved biological process, is upregulated in PDAC and its regulation is linked to a poor prognosis. Increased autophagy sequestered MHC-I on PDAC cells and weaken the antigen presentation and antitumor immune response, indicating the potential therapeutic strategies of autophagy inhibitors.By performing 10 state-of-the-art multi-omics clustering algorithms, we constructed a robust PDAC classification model to reveal the autophagy-related genes among different subgroups.After building a more comprehensive regulating network for potential autophagy regulators exploration, we concluded the top 20 autophagy-related hub genes (GAPDH, MAPK3, RHEB, SQSTM1, EIF2S1, RAB5A, CTSD, MAP1LC3B, RAB7A, RAB11A, FADD, CFKN2A, HSP90AB1, VEGFA, RELA, DDIT3, HSPA5, BCL2L1, BAG3, and ERBB2), six miRNAs, five transcription factors, and five immune infiltrated cells as biomarkers. The drug sensitivity database was screened based on the biomarkers to predict possible drug-targeting signal pathways, hoping to yield novel insights, and promote the progress of the anticancer therapeutic strategy.We succefully constructed an autophagy-related mRNA/miRNA/TF/Immune cells network based on a 10 state-of art algorithm multi-omics analysis, and screened the drug sensitivity dataset for detecting potential signal pathway which might be possible autophagy modulators' targets.© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.