肿瘤治疗场 (TTFields) 采用低强度交变电场来发挥抗肿瘤活性，并已证明对多种癌症有效，包括胶质母细胞瘤 (GBM)。不幸的是，癌细胞不可避免地会对 TTFields 产生耐药性，这凸显了阐明潜在机制以开发诱导持久反应的方法的必要性。使用基于基因网络的机器学习算法，我们研究了 TTFields 抗性 GBM 细胞，并发现了由前列腺素 E 受体 3 (EP3) 和转录因子锌指 488 (ZNF488) 锚定的调节轴。从机制上讲，TTFields 诱导 EP3 上调和核膜定位，与 ZNF488 形成复合物，通过促进神经胶质瘤干样细胞 (GSC) 的自我更新来诱导对 TTFields 的抵抗。在 TTFields 敏感的 GSC 中过度表达 EP3 和/或 ZNF488 会产生抗性并增强自我更新，而这些蛋白质的非相互作用突变体的表达会消除核复合物的形成并防止抗性。在耐药 GSC 中，包括那些刚从 TTFields 耐药性 GBM 肿瘤中分离出来的细胞，抑制该蛋白复合物中的任一伙伴，可使细胞对 TTFields 的细胞毒性作用重新敏感，同时减少自我更新和体内致瘤性。重要的是，在 TTFields 敏感的 GSC 中抑制 EP3 可预先阻止耐药性的发展。 EP3-ZNF488轴在TTFields耐药的GBM肿瘤中显着上调，而EP3和ZNF488在其他癌症中的共表达与较低的存活率相关。总的来说，这些结果表明核 EP3-ZNF488 轴对于建立 TTFields 耐药性是必要且充分的，强调了靶向该轴以预防或逆转 GBM 和可能的其他癌症的耐药性的潜力。

Tumor Treating Fields (TTFields) employ low-intensity, alternating electric fields to exert antitumor activity and have demonstrated efficacy against multiple cancers, including glioblastoma (GBM). Unfortunately, cancer cells inevitably develop resistance to TTFields, highlighting the need to elucidate the underlying mechanisms to develop approaches to induce durable responses. Using a gene network-based machine-learning algorithm, we interrogated TTFields-resistant GBM cells and uncovered a regulatory axis anchored by the prostaglandin E receptor 3 (EP3) and the transcription factor zinc finger 488 (ZNF488). Mechanistically, TTFields induced EP3 upregulation and nuclear envelope localization, where it formed a complex with ZNF488 to induce resistance to TTFields by promoting self-renewal of glioma stem-like cells (GSC). Overexpression of EP3 and/or ZNF488 in TTFields-sensitive GSC conferred resistance and enhanced self-renewal, while expression of non-interacting mutants of these proteins abrogated formation of the nuclear complex and prevented resistance. Inhibition of either partner in this protein complex in resistant GSC, including those freshly isolated from TTFields-resistant GBM tumors, re-sensitized cells to the cytotoxic effects of TTFields, concomitant with reduced self-renewal and in vivo tumorigenicity. Importantly, inhibition of EP3 in TTFields-sensitive GSC preemptively halted the development of resistance. The EP3-ZNF488 axis was significantly upregulated in TTFields-resistant GBM tumors, and co-expression of EP3 and ZNF488 in other cancers correlated with lower survival rates. Collectively, these results indicate that the nuclear EP3-ZNF488 axis is necessary and sufficient to establish TTFields resistance, underscoring the potential to target this axis to prevent or reverse resistance in GBM and possibly other cancers.