Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China.
Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China.
Cell Death Dis. 2024 Jul 13;15(7):500. doi: 10.1038/s41419-024-06875-4.
In recent years, immunotherapy, particularly PD-1 antibodies, have significantly enhanced the outcome of gastric cancer patients. Despite these advances, some patients do not respond well to treatment, highlighting the need to understand resistance mechanisms and develop predictive markers of treatment effectiveness. This study retrospectively analyzed data from 106 patients with stage IV gastric cancer who were treated with first-line immunotherapy in combination with chemotherapy. By comparing plasma cytokine levels between patients resistant and sensitive to PD-1 antibody therapy, the researchers identified elevated IL-4 expression in the resistant patients. Mechanical investigations revealed that IL-4 induces metabolic changes in macrophages that activate the PI3K/AKT/mTOR pathway. This alteration promotes ATP production, enhances glycolysis, increases lactic acid production, and upregulates FcγRIIB expression in macrophages. Ultimately, these changes lead to CD8+ T cell dysfunction and resistance to PD-1 antibody therapy in gastric cancer. These findings highlight the role of IL-4-induced macrophage polarization and metabolic reprogramming in immune resistance and verify IL-4 as potential targets for improving treatment outcomes in gastric cancer patients.
近年来，免疫疗法，特别是 PD-1 抗体，显著提高了胃癌患者的治疗效果。尽管取得了这些进展，但一些患者对治疗反应不佳，这凸显了需要了解耐药机制并开发治疗效果的预测标志物的重要性。本研究回顾性分析了 106 例接受一线免疫联合化疗治疗的 IV 期胃癌患者的数据。通过比较对 PD-1 抗体治疗耐药和敏感的患者的血浆细胞因子水平，研究人员在耐药患者中发现了 IL-4 表达升高。机械研究表明，IL-4 诱导巨噬细胞发生代谢变化，激活 PI3K/AKT/mTOR 通路。这种改变促进了 ATP 的产生，增强了糖酵解，增加了乳酸的产生，并上调了巨噬细胞中 FcγRIIB 的表达。最终，这些变化导致 CD8+T 细胞功能障碍和对胃癌 PD-1 抗体治疗的耐药性。这些发现强调了 IL-4 诱导的巨噬细胞极化和代谢重编程在免疫耐药中的作用，并验证了 IL-4 作为改善胃癌患者治疗效果的潜在靶点。
