Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Shanghai, 200032, China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
J Hematol Oncol. 2022 Dec 8;15(1):174. doi: 10.1186/s13045-022-01392-3.
Many types of human cells self-destruct to maintain biological homeostasis and defend the body against pathogenic substances. This process, called regulated cell death (RCD), is important for various biological activities, including the clearance of aberrant cells. Thus, RCD pathways represented by apoptosis have increased in importance as a target for the development of cancer medications in recent years. However, because tumor cells show avoidance to apoptosis, which causes treatment resistance and recurrence, numerous studies have been devoted to alternative cancer cell mortality processes, namely necroptosis, pyroptosis, ferroptosis, and cuproptosis; these RCD modalities have been extensively studied and shown to be crucial to cancer therapy effectiveness. Furthermore, evidence suggests that tumor cells undergoing regulated death may alter the immunogenicity of the tumor microenvironment (TME) to some extent, rendering it more suitable for inhibiting cancer progression and metastasis. In addition, other types of cells and components in the TME undergo the abovementioned forms of death and induce immune attacks on tumor cells, resulting in enhanced antitumor responses. Hence, this review discusses the molecular processes and features of necroptosis, pyroptosis, ferroptosis, and cuproptosis and the effects of these novel RCD modalities on tumor cell proliferation and cancer metastasis. Importantly, it introduces the complex effects of novel forms of tumor cell death on the TME and the regulated death of other cells in the TME that affect tumor biology. It also summarizes the potential agents and nanoparticles that induce or inhibit novel RCD pathways and their therapeutic effects on cancer based on evidence from in vivo and in vitro studies and reports clinical trials in which RCD inducers have been evaluated as treatments for cancer patients. Lastly, we also summarized the impact of modulating the RCD processes on cancer drug resistance and the advantages of adding RCD modulators to cancer treatment over conventional treatments.
许多类型的人类细胞会自我毁灭，以维持生物内稳态并抵御病原体。这个过程称为程序性细胞死亡（RCD），对于各种生物活动都很重要，包括清除异常细胞。因此，近年来，以细胞凋亡为代表的 RCD 途径作为开发癌症药物的靶点变得越来越重要。然而，由于肿瘤细胞逃避凋亡，导致治疗耐药和复发，因此许多研究致力于寻找替代的癌细胞死亡过程，即坏死性凋亡、细胞焦亡、铁死亡和铜死亡；这些 RCD 方式已被广泛研究，并且被证明对癌症治疗效果至关重要。此外，有证据表明，经历程序性死亡的肿瘤细胞可能在某种程度上改变肿瘤微环境（TME）的免疫原性，使其更适合抑制癌症进展和转移。此外，TME 中的其他类型的细胞和成分也会经历上述形式的死亡，并引发对肿瘤细胞的免疫攻击，从而增强抗肿瘤反应。因此，本综述讨论了坏死性凋亡、细胞焦亡、铁死亡和铜死亡的分子过程和特征，以及这些新型 RCD 方式对肿瘤细胞增殖和癌症转移的影响。重要的是，它介绍了新型肿瘤细胞死亡形式对 TME 的复杂影响，以及 TME 中其他细胞的程序性死亡对肿瘤生物学的影响。它还总结了基于体内和体外研究以及评估 RCD 诱导剂作为癌症患者治疗方法的临床试验报告中，诱导或抑制新型 RCD 途径的潜在药物和纳米颗粒及其对癌症的治疗效果。最后，我们还总结了调节 RCD 过程对癌症药物耐药性的影响，以及将 RCD 调节剂添加到癌症治疗中相对于传统治疗的优势。
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