Chemotherapy, the standard of care treatment for cancer patients with advanced disease, has been increasingly recognized to activate host immune responses to produce durable outcomes. Here, in colorectal adenocarcinoma (CRC) we identify oxaliplatin-induced Thioredoxin-Interacting Protein (TXNIP), a MondoA-dependent tumor suppressor gene, as a negative regulator of Growth/Differentiation Factor 15 (GDF15). GDF15 is a negative prognostic factor in CRC and promotes the differentiation of regulatory T cells (Tregs), which inhibit CD8 T-cell activation. Intriguingly, multiple models including patient-derived tumor organoids demonstrate that the loss of TXNIP and GDF15 responsiveness to oxaliplatin is associated with advanced disease or chemotherapeutic resistance, with transcriptomic or proteomic GDF15/TXNIP ratios showing potential as a prognostic biomarker. These findings illustrate a potentially common pathway where chemotherapy-induced epithelial oxidative stress drives local immune remodeling for patient benefit, with disruption of this pathway seen in refractory or advanced cases.

中文翻译：

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MondoA 依赖性 TXNIP/GDF15 轴可预测结直肠腺癌中奥沙利铂的反应。


化疗是晚期癌症患者的标准护理治疗，人们越来越认识到它可以激活宿主免疫反应以产生持久的结果。在此，在结直肠腺癌 (CRC) 中，我们鉴定出奥沙利铂诱导的硫氧还蛋白相互作用蛋白 (TXNIP)（一种 MondoA 依赖性肿瘤抑制基因）作为生长/分化因子 15 (GDF15) 的负调节因子。 GDF15 是 CRC 的负面预后因素，可促进调节性 T 细胞 (Treg) 的分化，从而抑制 CD8 T 细胞的激活。有趣的是，包括患者来源的肿瘤类器官在内的多个模型表明，TXNIP 和 GDF15 对奥沙利铂反应性的丧失与晚期疾病或化疗耐药相关，转录组或蛋白质组 GDF15/TXNIP 比率显示出作为预后生物标志物的潜力。这些发现说明了化疗诱导的上皮氧化应激驱动局部免疫重塑以造福患者的潜在常见途径，在难治性或晚期病例中观察到该途径的破坏。