Stazione Zoologica Anton Dohrn, Istituto Nazionale di Biologia, Ecologia e Biotecnologie Marine, Villa Comunale, 80121 Napoli, Italy.
Unit of Molecular Pathology, Biochemistry and Immunology, IRCCS MultiMedica, 20138 Milan, Italy.
Cells. 2021 Jan 25;10(2):231. doi: 10.3390/cells10020231.
Regulated cell death (RCD) has always been considered a tolerogenic event. Immunogenic cell death (ICD) occurs as a consequence of tumour cell death accompanied by the release of damage-associated molecular patterns (DAMPs), triggering an immune response. ICD plays a major role in stimulating the function of the immune system in cancer during chemotherapy and radiotherapy. ICD can therefore represent one of the routes to boost anticancer immune responses. According to the recommendations of the Nomenclature Committee on Cell Death (2018), apoptosis (type I cell death) and necrosis (type II cell death) represent are not the only types of RCD, which also includes necroptosis, pyroptosis, ferroptosis and others. Specific downstream signalling molecules and death-inducing stimuli can regulate distinct forms of ICD, which develop and promote the immune cell response. Dying cells deliver different potential immunogenic signals, such as DAMPs, which are able to stimulate the immune system. The acute exposure of DAMPs can prime antitumour immunity by inducing activation of antigen-presenting cells (APC), such as dendritic cells (DC), leading to the downstream response by cytotoxic T cells and natural killer cells (NK). As ICD represents an important target to direct and develop new pharmacological interventions, the identification of bioactive natural products, which are endowed with low side effects, higher tolerability and preferentially inducing immunogenic programmed cell death, represents a priority in biomedical research. The ability of ICD to drive the immune response depends on two major factors, neither of which is intrinsic to cell death: 'Antigenicity and adjuvanticity'. Indeed, the use of natural ICD-triggering molecules, alone or in combination with different (immuno)therapies, can result in higher efficacy and tolerability. Here, we focused on natural (marine) compounds, particularly on marine microalgae derived molecules such as exopolysaccharides, sulphated polysaccharides, glycopeptides, glycolipids, phospholipids, that are endowed with ICD-inducing properties and sulfavants. Here, we discuss novel and repurposed small-molecule ICD triggers, as well as their ability to target important molecular pathways including the IL-6, TNF-α and interferons (IFNs), leading to immune stimulation, which could be used alone or in combinatorial immunotherapeutic strategies in cancer prevention and therapies.
程序性细胞死亡(RCD)一直被认为是一种耐受事件。免疫原性细胞死亡(ICD)是肿瘤细胞死亡伴随着损伤相关分子模式(DAMPs)的释放而发生的,触发免疫反应。ICD 在化疗和放疗期间刺激癌症中免疫系统的功能方面发挥着重要作用。因此,ICD 可以代表增强抗癌免疫反应的途径之一。根据细胞死亡命名委员会(2018 年)的建议,细胞凋亡(I 型细胞死亡)和坏死(II 型细胞死亡)并不是唯一类型的 RCD,还包括坏死性凋亡、细胞焦亡、铁死亡等。特定的下游信号分子和诱导死亡的刺激物可以调节不同形式的 ICD,从而发展和促进免疫细胞反应。垂死的细胞传递不同的潜在免疫原性信号,例如 DAMPs,这些信号能够刺激免疫系统。DAMPs 的急性暴露可以通过诱导抗原呈递细胞(APC)如树突状细胞(DC)的激活来诱导抗肿瘤免疫,从而导致细胞毒性 T 细胞和自然杀伤细胞(NK)的下游反应。由于 ICD 是指导和开发新的药理学干预措施的重要目标,因此确定具有低副作用、更高耐受性和优先诱导免疫原性程序性细胞死亡的生物活性天然产物是生物医学研究的优先事项。ICD 驱动免疫反应的能力取决于两个主要因素,这两个因素都不是细胞死亡所固有的:“抗原性和佐剂性”。事实上,单独使用或与不同的(免疫)疗法联合使用天然 ICD 触发分子可以提高疗效和耐受性。在这里,我们重点关注天然(海洋)化合物,特别是海洋微藻衍生的分子,如胞外多糖、硫酸多糖、糖肽、糖脂、磷脂,它们具有 ICD 诱导特性和磺化剂。在这里,我们讨论了新型和再利用的小分子 ICD 触发物,以及它们靶向重要分子途径的能力,包括 IL-6、TNF-α 和干扰素(IFNs),从而导致免疫刺激,这些触发物可以单独使用或组合使用在癌症预防和治疗的联合免疫治疗策略中。
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