Study flow chart.

GPRC5A-CXCL8-NET-cfDNA axis contributes to chemotherapy resistance in pancreatic ductal adenocarcinoma. Part 1 illustrates tissue microarray and prognosis analysis of PDAC patients undergoing GnP therapy revealed that neutrophil levels were associated with treatment outcomes. Part 2 shows that in murine models, GnP therapy increased neutrophil infiltration in tumors. Conditioned medium from PDAC cells promoted neutrophil extracellular trap (NET) formation through CXCL8 secretion. Mechanistically, GPRC5A enhanced CXCL8 secretion via NF-κB signaling in GnP-resistant PDAC cells, while NET formation was mediated by NLRP3 activation in neutrophils. Part 3 presents that inhibition of GPRC5A in PDAC-bearing mice reduced tumor growth and improved survival under GnP therapy, highlighting the therapeutic potential of targeting GPRC5A. *, P < 0.05; **, P < 0.01 (created with biorender.com).