WNT/β-连环蛋白是研究最广泛的细胞信号传导途径之一，涉及几种致命癌症的发生和进展。现在人们了解到，在肿瘤进展过程中，WNT/β-连环蛋白信号传导以一种非常复杂的方式运作，超出了早期假设的简单 WNT“开”或“关”模式，因为它招募了大量的 WNT 配体、受体、转录因子，并且还交叉作用。 -与其他信号分子（包括非规范 WNT 调节剂）对话。 WNT/β-连环蛋白信号分子在不同的癌症中经常发生突变，这使得它们很难被抑制，有时将它们列为不可成药的靶点。此外，由于该通路的进化保守性，抑制WNT/β-连环蛋白会对正常细胞造成显着的毒性。这些挑战反映在临床试验数据中，其中 WNT/β-连环蛋白抑制剂作为独立治疗的使用仍然有限。在这篇综述中，我们强调了多种 WNT/β-连环蛋白信号调节因子与癌症进展和肿瘤细胞表型转换的关键功能关联。接下来，我们阐明了 WNT/β-连环蛋白信号在耐药性、克隆进化、肿瘤异质性和免疫逃避中的作用。本综述还重点关注各类常规和新型 WNT/β-连环蛋白治疗方案，同时解决与靶向这一复杂途径的调节因子相关的挑战。根据WNT/β-连环蛋白抑制剂的多个案例研究，我们还强调了涉​​及这些治疗的未来临床试验策略的挑战和机遇。此外，我们还为未来基于 WNT/β-catenin 的药物发现试验提出了策略，强调了联合疗法和 AI/ML 驱动的预测方法的潜力。总的来说，我们在这里展示了 WNT/β-连环蛋白信号调节治疗方案作为未来有前途的精准癌症药物的机会、可能性和潜力。版权所有 © 2024 Elsevier B.V. 保留所有权利。

The WNT/β-catenin is among one of the most extensively studied cellular signaling pathways involved in the initiation and progression of several deadly cancers. It is now understood that the WNT/β-catenin signaling, during tumor progression operates in a very complex fashion beyond the earlier assumed simple WNT 'On' or 'Off' mode as it recruits numerous WNT ligands, receptors, transcriptional factors and also cross-talks with other signaling molecules including the noncanonical WNT regulators. WNT/β-catenin signaling molecules are often mutated in different cancers which makes them very challenging to inhibit and sometimes ranks them among the undruggable targets. Furthermore, due to the evolutionary conservation of this pathway, inhibiting WNT/β-catenin has caused significant toxicity in normal cells. These challenges are reflected in clinical trial data, where the use of WNT/β-catenin inhibitors as standalone treatments remains limited. In this review, we have highlighted the crucial functional associations of diverse WNT/β-catenin signaling regulators with cancer progression and the phenotypic switching of tumor cells. Next, we have shed light on the roles of WNT/β-catenin signaling in drug resistance, clonal evolution, tumor heterogeneity, and immune evasion. The present review also focuses on various classes of routine and novel WNT/β-catenin therapeutic regimes while addressing the challenges associated with targeting the regulators of this complex pathway. In the light of multiple case studies on WNT/β-catenin inhibitors, we also highlighted the challenges and opportunities for future clinical trial strategies involving these treatments. Additionally, we have proposed strategies for future WNT/β-catenin-based drug discovery trials, emphasizing the potential of combination therapies and AI/ML-driven prediction approaches. Overall, here we showcased the opportunities, possibilities, and potentialities of WNT/β-catenin signaling modulatory therapeutic regimes as promising precision cancer medicines for the future.Copyright © 2024 Elsevier B.V. All rights reserved.