In recent years, pancreatic adenosquamous carcinoma (PASC) has drawn growing attention owing to its rarity and highly aggressive characteristics. As a distinct subtype defined by the co-existence of adenocarcinoma and squamous carcinoma components, PASC is linked to substantially worse prognoses compared to pancreatic ductal adenocarcinoma, with a median survival period of merely six months. This review outlines the key molecular mechanisms underlying PASC, such as the inactivation of the TP53/NOTCH pathways, the up-regulation of the transcriptional regulator ΔNp63 and the transcription factor SRY-box transcription factor 2 (SOX2), along with enhancer of zeste homolog 2 (EZH2)-mediated epigenetic remodeling, and deliberates on their functions in lineage transdifferentiation and tumor plasticity. We further synthesize findings from high-throughput sequencing and single-cell multi-omics studies to depict the immunosuppressive traits of the PASC tumor microenvironment and their implications for therapeutic resistance. Current challenges are also addressed, including the scarce number of reported cases, the absence of high-level clinical evidence, and the disparity between mechanistic studies and clinical translation. Finally, we suggest that future research ought to concentrate on establishing multicenter clinical cohorts and molecular stratification approaches, and on exploring novel therapeutic strategies like combining epigenetic inhibitors with immunotherapy, with the ultimate aim of enhancing patient outcomes.