Sherry Christopher, Dadgar Neda, Liu Zuqiang, Fan Yong, Xiao Kunhong, Zaidi Ali H, Donnenberg Vera S, Donnenberg Albert D, Bartlett David L, Wagner Patrick L
Allegheny Health Network Cancer Institute, Pittsburgh, PA 15224, USA.
Department of Cardiothoracic Surgery Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA.
Curr Oncol. 2025 Sep 5;32(9):496. doi: 10.3390/curroncol32090496.
Peritoneal carcinomatosis (PC) is a late-stage manifestation of abdominopelvic malignancies with poor prognosis and limited treatment options. Unique biochemical mechanisms within the peritoneal cavity play a key role in disease progression and resistance to therapy. Despite current therapies like systemic chemotherapy and cytoreductive surgery, patients frequently develop severe complications, including bowel obstruction, nutritional decline, and ascites, driving the need to address the pro-tumorigenic niche in the peritoneal cavity. The immune microenvironment in PC is marked by elevated proinflammatory mediators, such as IL-6 and IL-8, which skew the response toward innate rather than adaptive immune responses. IL-8 signaling, through its receptors CXCR1 and CXCR2, promotes neutrophil recruitment, chronic inflammation, angiogenesis, epithelial-mesenchymal transition, and immune evasion, making the IL-8/CXCR1/CXCR2 axis a potential therapeutic target in PC. Pre-clinical models provide evidence that IL-8 or CXCR1/CXCR2 blockade may be a valuable therapeutic strategy. IL-8 targeting agents such as monoclonal antibodies (BMS-986253) and small-molecule inhibitors (SX-682, AZD5069, navarixin) have shown efficacy in mitigating tumor growth and improving the efficacy of immune checkpoint inhibitors. Phase I and II trials have demonstrated encouraging safety profiles and preliminary efficacy when treating multiple abdominopelvic malignancies. In this review, we discuss the influence of the IL-8/CXCR1/CXCR2 axis within the peritoneal immune environment in PC and highlight recent work using IL-8 or CXCR1/CXCR2 blockade as a therapeutic strategy for PC. Continued research into the peritoneal immune microenvironment and the development of targeted therapies are essential for improving the management and prognosis of PC, potentially enhancing antitumor immunity and patient outcomes.
腹膜癌病（PC）是腹盆腔恶性肿瘤的晚期表现，预后较差且治疗选择有限。腹腔内独特的生化机制在疾病进展和对治疗的抵抗中起关键作用。尽管有全身化疗和减瘤手术等当前疗法，但患者仍经常出现严重并发症，包括肠梗阻、营养状况下降和腹水，这促使人们需要解决腹腔内的促肿瘤微环境问题。PC中的免疫微环境以促炎介质如IL-6和IL-8升高为特征，这些介质使免疫反应偏向先天免疫而非适应性免疫反应。IL-8通过其受体CXCR1和CXCR2发出信号，促进中性粒细胞募集、慢性炎症、血管生成、上皮-间质转化和免疫逃逸，使得IL-8/CXCR1/CXCR2轴成为PC中一个潜在的治疗靶点。临床前模型提供了证据表明阻断IL-8或CXCR1/CXCR2可能是一种有价值的治疗策略。靶向IL-8的药物，如单克隆抗体（BMS-986253）和小分子抑制剂（SX-682、AZD5069、那伐瑞辛）已显示出在减轻肿瘤生长和提高免疫检查点抑制剂疗效方面的效果。I期和II期试验已证明在治疗多种腹盆腔恶性肿瘤时具有令人鼓舞的安全性和初步疗效。在本综述中，我们讨论了IL-8/CXCR1/CXCR2轴在PC腹膜免疫环境中的影响，并强调了最近将阻断IL-8或CXCR1/CXCR2作为PC治疗策略的研究工作。对腹膜免疫微环境的持续研究和靶向治疗的开发对于改善PC的管理和预后至关重要，有可能增强抗肿瘤免疫力和患者预后。
