The CXCL5/CXCR2 Axis Attenuates Ferroptosis in Intrahepatic Cholangiocarcinoma Through the Positive Feedback Loop Between PTGS2 Transcriptional Activation and Neutrophil Recruitment

Intrahepatic cholangiocarcinoma (ICC) presents significant therapeutic challenges due to its late-stage diagnosis and inherent treatment resistance, resulting in dismal prognosis. While ferroptosis induction has emerged as a promising antitumor strategy, its clinical implementation in ICC has been impeded by poorly defined resistance mechanisms. Here, we systematically investigated the immunomodulatory role of the CXCL5/CXCR2 axis in governing ferroptosis susceptibility through dual mechanistical pathways. In vitro studies revealed that CXCL5/CXCR2 signaling confers ferroptosis resistance by transcriptional upregulation of prostaglandin-endoperoxide synthase 2 (PTGS2), which can serve as a functional regulatory factor for ferroptosis. Utilizing a tumor-immune co-culture platform, we further demonstrated that CXCL5/CXCR2 axis-driven recruitment of N2 tumor-associated neutrophils (TANs) orchestrates a protective microenvironment against ferroptosis. Intriguingly, PTGS2 enhances N2 TANs chemotaxis via CCL2 and CCL7, and the recruited N2 TANs subsequently activate the NF-κB/PTGS2 pathway, thereby establishing a synergistic positive feedback loop. Notably, combinatorial treatment with the CXCR2 antagonist SB225002 and ferroptosis inducer Erastin exhibited synergistic antitumor activity in preclinical ICC models. This study provides mechanistic insights into the ferroptosis-immune crosstalk and proposes a novel combinatorial therapeutic paradigm for overcoming treatment resistance in ICC.