Albumin-bound paclitaxel induced stromal reprogramming drives PDAC resistance to AG neoadjuvant chemotherapy

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy for which neoadjuvant chemotherapy with albumin-bound paclitaxel plus gemcitabine (AG) is a standard first-line approach. However, secondary resistance to AG therapy 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 myCAFs to iCAFs states and identified a previously unrecognized TMEM100 + CAFs subset enriched in non-responders. 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 or antibody blockade of TMEM100 + CAFs in mouse models reversed CAFs switching and significantly enhanced the antitumor efficacy of AG therapy. These findings map chemotherapy-induced CAFs plasticity, reveal a TMEM100-AREG axis of resistance, and highlight TMEM100 + CAFs as a promising target to sensitize PDAC to neoadjuvant treatment.