信号重组使肿瘤得以在治疗中存活。我们在致命前列腺癌（PCa）中表明，主控因子微小眼睛转录因子（MITF）的减少解除了依赖于真核启动因子3B（eIF3B）的关键mRNA的翻译重编程，从而使其获得耐雄激素剥夺疗法（ADT）和促进免疫逃逸的耐药性。机制上，MITF通过直接结合eIF3B的启动子来抑制eIF3B，而eIF3B则调控特定mRNA的翻译。基因组范围的eIF3B增强的交联免疫共沉淀测序（eCLIP-seq）显示它特异性地结合到一种存在于5' UTR亚组的UC富集基序。确实，通过这一基序的雄激素受体（AR）和主要组织相容性复合物I（MHC-I）的翻译对eIF3B的浓度敏感。值得注意的是，在临床前模型中，针对eIF3B依赖性翻译的药理靶向使PCa对ADT和抗PD-1治疗变得敏感。这些发现揭示了治疗难以逾越的致命PCa转录和翻译重塑之间的隐藏联系，并提供了一种可治疗的机制，为有效的联合治疗策略铺平了道路。

Signaling rewiring allows tumors survive therapy. Here we show that the decrease of the master regulator microphthalmia transcription factor (MITF) in lethal prostate cancer (PCa) unleashes eukaryotic initiation factor 3B (eIF3B)-dependent translation reprograming of key mRNAs conferring resistance to androgen deprivation therapy (ADT) and promoting immune evasion. Mechanistically, MITF represses through direct promoter binding eIF3B, which in turn regulates the translation of specific mRNAs. Genome-wide eIF3B enhanced cross-linking immunoprecipitation sequencing (eCLIP-seq) showed specialized binding to a UC-rich motif present in subsets of 5'-UTRs. Indeed, translation of the androgen receptor (AR) and major histocompatibility complex I (MHC-I) through this motif are sensitive to eIF3B amount. Notably, pharmacological targeting of eIF3B-dependent translation in pre-clinical models sensitizes PCa to ADT and anti-PD-1 therapy. These findings uncover a hidden connection between transcriptional and translational rewiring promoting therapy refractory lethal PCa and provide a druggable mechanism that may transcend into effective combined therapeutic strategies.