Per-and polyfluoroalkyl substances (PFAS), specifically perfluorooctanesulfonate (PFOS) and its alternative, 2- [(6-chloro-1,1,2,2,3,3,4,4,5,5,6,6-dodecafluorohexyl)oxy]-1,1,2,2tetrafluoroethanesulfonic acid (6:2 Cl-PFESA), are associated with environmental health concerns and potential cancer progression. However, their impact on multidrug resistance (MDR) in pancreatic cancer (PC) chemotherapy remains unclear. Here, we employed drug-sensitivity assays, including IC 50 calculations, in vitro and in vivo models with various chemotherapeutics, and paclitaxel (PTX) as a representative agent, combined with transcriptomic/proteomic sequencing and clinical prognostic analysis, to identify MDR-related genes and validate their relevance, with the objective of establishing the correlation between PFOS/6:2 Cl-PFESA exposure and MDR in PC at molecular, cellular, and animal model levels. Our findings demonstrate that PFOS/6:2 Cl-PFESA exposure increases the drug IC 50 in three different PC cell lines for various chemotherapeutic agents. Compared with PFOS, 6:2 Cl-PFESA demonstrated a more pro-MDR effect on PC cells in vitro. In vivo experiments further revealed that PFOS/6:2 Cl-PFESA exposures significantly reduced the efficacy of PTX in PC, with inhibition rates dropping from 78.3% to 23.8%/6.1%, respectively (p < 0.05). This effect was driven by the aberrant activation of the PI3K−ABCB1 pathway, with 6:2 Cl-PFESA demonstrating a stronger capacity to promote this signal pathway's expression and function compared with PFOS. These data suggest that exposure to PFAS may elevate the risk of MDR and subsequent disease progression. Although marketed as a safer alternative to PFOS, the notable impact of 6:2 Cl-PFESA on MDR highlights the necessity for a comprehensive assessment of its potential carcinogenic risks.
