The cytotoxic anti-cancer drugs cisplatin, paclitaxel, doxorubicin, 5-fluorouracil (5-FU), as well as targeted drugs including imatinib, erlotinib, and nivolumab, play key roles in clinical cancer treatment. However, the frequent emergence of drug resistance severely comprosises their anti-cancer efficacy. A number of studies indicated that loss of function of tumor suppressor genes (TSGs) is involved in the development of cancer drug resistance, apart from decreased drug influx, increased drug efflux, induction of anti-apoptosis mechanisms, alterations in tumor microenvironment, drug compartmentalization, enhanced DNA repair and drug inactivation. TSGs are involved in the pathogenesis of tumor formation through regulation of DNA damage repair, cell apoptosis, autophagy, proliferation, cell cycle progression, and signal transduction. Our increased understanding of TSGs in the past decades demonstrates that gene mutation is not the only reason that leads to the inactivation of TSGs. Loss of function of TSGs may be based on the ubiquitin-proteasome pathway, epigenetic and transcriptional regualtion, post-translation modifications like phosphorylation as well as cellular translocation of TSGs. As the above processes can constitute“druggable targets”, these mechanisms provide novel therapeutic approaches in targeting TSGs. Some small molecule compounds targeting these approaches re-activated TSGs and reversed cancer drug resistance. Along this vein, functional restoration of TSGs is a novel and promising approach to surmount cancer drug resistance. In the current review, we draw a scenario based on the role of loss of function of TSGs in drug resistance, on mechanisms leading to inactivation of TSGs and on pharmacological agents acting on these mechanisms to overcome cancer drug resistance. This review discusses novel therapeutic strategies targeting TSGs and offers possible modalities to conquer cancer drug resistance.

细胞毒性抗癌药物顺铂、紫杉醇、多柔比星、5-氟尿嘧啶（5-FU）以及靶向药物伊马替尼、厄洛替尼和纳武单抗在临床癌症治疗中发挥着关键作用。然而，耐药性的频繁出现严重影响了它们的抗癌功效。大量研究表明，肿瘤抑制基因（TSGs）功能的丧失除了药物流入减少、药物流出增加、抗凋亡机制的诱导、肿瘤微环境的改变、药物区室化之外，还参与了癌症耐药性的发展。 , 增强 DNA 修复和药物灭活。TSGs 通过调节 DNA 损伤修复、细胞凋亡、自噬、增殖、细胞周期进程和信号转导参与肿瘤形成的发病机制。我们在过去几十年中对 TSG 的更多了解表明，基因突变并不是导致 TSG 失活的唯一原因。TSGs 的功能丧失可能基于泛素-蛋白酶体途径、表观遗传和转录调节、翻译后修饰（如磷酸化）以及 TSGs 的细胞易位。由于上述过程可以构成“药物靶点”，这些机制为靶向 TSG 提供了新的治疗方法。一些针对这些方法的小分子化合物重新激活了 TSG 并逆转了癌症耐药性。沿着这条思路，TSGs 的功能恢复是克服癌症耐药性的一种新颖且有前景的方法。在当前的审查中，我们根据 TSG 功能丧失在耐药性中的作用绘制了一个场景，导致 TSG 失活的机制以及作用于这些机制以克服癌症耐药性的药物。本综述讨论了针对 TSG 的新治疗策略，并提供了克服癌症耐药性的可能方式。