Despite the development of targeted therapy, drug resistance remains a primary hindrance to curative treatment of various cancers. Among several novel approaches to overcome drug resistance, modulating N⁶-methyladenosine (m⁶A) RNA modification was found to be an important strategy in various types of cancer cells. Considered as one of the most common epigenetic RNA modifications, m⁶A regulates multiple biological processes including cellular proliferation, metabolism, and metastasis through modulation of RNA splicing, degradation, and translation, leading to anticancer drug resistance. This regulatory network is orchestrated mainly by several m⁶A regulators, including “writers”, “readers”, and “erasers”. It is encouraging that several small molecules targeting m⁶A regulators have shown great potential in overcoming drug resistance in different cancer cell types, two of which entacapone and meclofenamate, are currently undergoing evaluation. However, the m⁶A modification participates in complex biological processes and its functions are context-dependent, which has challenged the clinical application of targeting the m⁶A modification in cancer therapy.

In this review, we discuss the molecular mechanisms underlying the m⁶A modification in regulating anticancer drug resistance through modulation of drug-target interaction and drug-mediated cell death signaling. Alteration of the m⁶A modification interferes with drug efficacy through modulation of the expression of multidrug efflux transporters (e.g., ABCG2, ABCC9, ABCC10), drug metabolizing enzymes (e.g., CYP2C8), and drug targets (e.g., p53 R273 H). Furthermore, alterations of the m⁶A modification may protect cells from drug-mediated cell death by regulating DNA damage repair (e.g., p53, BRCA1, Pol κ, UBE2B, and ERCC1), downstream adaptive response (e.g., critical regulators of apoptosis, autophagy, pro-survival signaling, and oncogenic bypass signaling), cell stemness, and tumor microenvironment (e.g., ITGA6, ITGB3, and PD-1). We particularly highlight recent advances in therapeutic strategies targeting the m⁶A modification with the aim to surmount chemoresistance. The comprehensive understanding of the role of the m⁶A modification integrated with combined therapeutic strategies, should facilitate the development of future therapeutic strategies to circumvent or surmount drug resistance, thus enhancing therapeutic efficacy.

尽管靶向治疗有了发展，耐药性仍然是各种癌症治愈性治疗的主要障碍。在克服耐药性的几种新方法中，发现调节 N ⁶ -甲基腺苷 (m ⁶ A) RNA 修饰是各种类型癌细胞的重要策略。m ⁶ A被认为是最常见的表观遗传 RNA 修饰之一，它通过调节 RNA 剪接、降解和翻译来调节包括细胞增殖、代谢和转移在内的多种生物过程，从而导致抗癌药物耐药性。这个监管网络主要由几个 m ⁶A 监管者，包括“作家”、“读者”和“橡皮擦”。令人鼓舞的是，几种靶向 m ⁶ A 调节剂的小分子在克服不同癌细胞类型的耐药性方面显示出巨大潜力，目前正在评估其中两种，恩他卡朋和甲氯芬酯。然而，m ⁶ A 修饰参与复杂的生物过程，其功能是上下文相关的，这对靶向m ⁶ A 修饰在癌症治疗中的临床应用提出了挑战。

在这篇综述中，我们讨论了 m ⁶ A 修饰通过调节药物靶点相互作用和药物介导的细胞死亡信号来调节抗癌药物耐药性的分子机制。m ⁶ A 修饰的改变通过调节多药外排转运蛋白（例如，ABCG2、ABCC9、ABCC10）、药物代谢酶（例如，CYP2C8）和药物靶标（例如，p53 R273 H）的表达来干扰药物功效。此外，m ^{6 的}改动修饰可以通过调节 DNA 损伤修复（例如 p53、BRCA1、Pol κ、UBE2B 和 ERCC1）、下游适应性反应（例如，细胞凋亡、自噬、促生存信号传导、和致癌旁路信号）、细胞干性和肿瘤微环境（例如，ITGA6、ITGB3 和 PD-1）。我们特别强调了针对 m ⁶ A 修饰的治疗策略的最新进展，旨在克服化学耐药性。对 m ⁶ A 修饰与联合治疗策略相结合的作用的全面理解，应该有助于未来治疗策略的发展，以规避或克服耐药性，从而提高治疗效果。