Albumin-bound paclitaxel–induced stromal reprogramming drives resistance to neoadjuvant chemotherapy in patients with pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy for which neoadjuvant chemotherapy with albumin-bound paclitaxel combined with gemcitabine (AG) is a standard first-line approach for borderline resectable and locally advanced disease. However, secondary resistance to this regimen is common, and its underlying mechanisms remain poorly defined. In this study, we investigated how neoadjuvant AG therapy shapes the tumor stroma in PDAC. Single-cell transcriptomics of patient tumors revealed that AG treatment induces a phenotypic switch of cancer-associated fibroblasts (CAFs) from myofibroblastic (myCAF) to inflammatory (iCAF) states and identified a previously unrecognized TMEM100 + CAF subset enriched in nonresponders. Mechanistic studies showed that albumin-bound paclitaxel activates IL-2–STAT5 signaling to drive TMEM100 expression and that TMEM100 + CAFs promote chemoresistance through paracrine secretion of amphiregulin (AREG) and activation of tumor EGFR signaling. Genetic ablation of TMEM100 + CAFs in mouse models reversed CAF switching and enhanced the antitumor efficacy of AG therapy. These findings map chemotherapy-induced CAF plasticity, reveal a TMEM100-AREG axis of resistance, and highlight TMEM100 + CAFs as a promising target to sensitize PDAC to neoadjuvant treatment.