免疫原性细胞死亡（ICD）可用于治疗对当前标准和创新疗法无反应的非免疫反应性肿瘤。并非所有化疗药物都会触发 ICD，在确实发挥这种作用的药物中，有蒽环类药物、伊立替康、一些铂衍生物和溶瘤肽。我们研究了两种新的分支溶瘤肽 BOP7 和 BOP9，它们被证明能够在胰腺癌细胞中引发损伤相关分子模式 DAMPS 的释放，DAMPS 是 ICD 的介质。这两种 BOP 选择性结合并杀死肿瘤细胞，特别是 PANC-1 和 Mia PaCa-2，但不能结合和杀死非肿瘤来源的细胞，例如 RAW 264.7、CHO-K1 和 pgsA-745。两种 BOP 的癌症选择性可能归因于它们重复的阳离子序列，这些序列能够与硫酸乙酰肝素糖胺聚糖 (HSPG) 多价结合，在癌细胞上具有多种阴离子硫酸化模式。 BOP 与 HSPG 的这种相互作用不仅在体外促进抗转移作用（如 PANC-1 癌细胞粘附和迁移减少所证明），而且还显示出有希望的肿瘤特异性细胞毒性和低溶血活性。值得注意的是，BOP 诱导的细胞毒性会触发死亡细胞释放 DAMP，特别是 HMGB1、IFN-β 和 ATP，其持续时间比传统化疗药物（如伊立替康和柔红霉素）的细胞毒性持续时间更长。裸鼠体内试验显示，BOP9 对胰腺癌模型中的肿瘤移植和生长具有令人鼓舞的 20% 抑制作用。版权所有 © 2024 Rencinai、Tollapi、Marianantoni、Brunetti、Henriquez、Pini、Bracci 和 Falciani。

Immunogenic cell death (ICD) can be exploited to treat non-immunoreactive tumors that do not respond to current standard and innovative therapies. Not all chemotherapeutics trigger ICD, among those that do exert this effect, there are anthracyclines, irinotecan, some platinum derivatives and oncolytic peptides. We studied two new branched oncolytic peptides, BOP7 and BOP9 that proved to elicit the release of damage-associated molecular patterns DAMPS, mediators of ICD, in pancreatic cancer cells. The two BOPs selectively bound and killed tumor cells, particularly PANC-1 and Mia PaCa-2, but not cells of non-tumor origin such as RAW 264.7, CHO-K1 and pgsA-745. The cancer selectivity of the two BOPs may be attributed to their repeated cationic sequences, which enable multivalent binding to heparan sulfate glycosaminoglycans (HSPGs), bearing multiple anionic sulfation patterns on cancer cells. This interaction of BOPs with HSPGs not only fosters an anti-metastatic effect in vitro, as demonstrated by reduced adhesion and migration of PANC-1 cancer cells, but also shows promising tumor-specific cytotoxicity and low hemolytic activity. Remarkably, the cytotoxicity induced by BOPs triggers the release of DAMPs, particularly HMGB1, IFN-β and ATP, by dying cells, persisting longer than the cytotoxicity of conventional chemotherapeutic agents such as irinotecan and daunorubicin. An in vivo assay in nude mice showed an encouraging 20% inhibition of tumor grafting and growth in a pancreatic cancer model by BOP9.Copyright © 2024 Rencinai, Tollapi, Marianantoni, Brunetti, Henriquez, Pini, Bracci and Falciani.