Exploiting stromal vulnerabilities: NFATC2-expressing CAFs enhance chemotherapy sensitivity and reveal a targetable ERBB axis in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) persists as one of the most therapeutically recalcitrant solid tumors, driven in part by an extensive desmoplastic stroma dominated by cancer-associated fibroblasts (CAFs). CAF heterogeneity and transcriptional plasticity are increasingly recognized as key determinants of tumor evolution and treatment response, yet how neoadjuvant therapy reshapes CAF states in human PDAC remains poorly defined. We applied gene regulatory network analysis to single-cell RNA sequencing data from 43 PDAC tumors collected following neoadjuvant therapy. This analysis uncovered a previously undescribed CAF subpopulation defined by expression of the transcription factor NFATC2, classically associated with T-cell signaling. NFATC2-expressing CAFs were significantly enriched in patients exhibiting robust treatment response and extended progression-free survival. Tumors containing this CAF state displayed reduced lymph-node metastasis and a distinct stromal transcriptional program characterized by enhanced pro-apoptotic signaling and suppression of ERBB pathway activity. Functional co-culture assays revealed that NFATC2-expressing CAFs potentiate FOLFIRINOX-induced apoptosis in PDAC cells. Moreover, ERBB inhibition produced strong synergistic cytotoxicity when combined with either FOLFIRINOX or gemcitabine/nab-paclitaxel, suggesting a mechanistically grounded combination strategy for overcoming stromal-mediated resistance. These findings identify NFATC2-expressing CAFs as a predictive stromal biomarker of therapeutic responsiveness and define a tumor-restraining CAF state with actionable molecular features. This work reveals a previously unrecognized vulnerability within the PDAC microenvironment and supports rational integration of ERBB-targeted agents with current neoadjuvant regimens to enhance treatment efficacy in PDAC.