肿瘤细胞治疗研究
英文原题：Combating small extracellular vesicle-mediated immunological barriers in the tumor microenvironment via strategically activatable PEGylated peptides.
肿瘤细胞来源的小细胞外囊泡（TDEs）在免疫逃逸中发挥关键作用，包括建立免疫抑制性肿瘤微环境（TME），并构成有效癌症免疫治疗的重大障碍。
肿瘤细胞来源的小细胞外囊泡（TDEs）在免疫逃逸中发挥关键作用，包括建立免疫抑制性肿瘤微环境（TME），并构成有效癌症免疫治疗的重大障碍。在此，我们介绍ExoPERM（pH触发的外泌体膜破裂）策略，这是一种基于pH响应性系统的小细胞外囊泡（EV）破坏性α-螺旋肽，可选择性地靶向定位于TME内的小EV。通过PEG化引入pH敏感连接子，该系统确保了全身稳定性，同时允许肽在弱酸性TME中选择性释放。机制研究揭示，该肽在pH 6.5时优先破裂小EV，有效阻止EV的PD-L1与CD8⁺ T细胞上的PD-1相互作用，并有助于恢复其效应功能。此外，这种靶向破坏显著减弱了TDE诱导的癌症相关成纤维细胞活化，从而重塑了物理限制免疫细胞穿透的致密纤维化基质。体内研究已证明CD8⁺ T细胞肿瘤浸润和活化增强，尤其是在与免疫检查点阻断或过继性T细胞转移联合使用时。这些协同效应在小鼠黑色素瘤和结直肠癌模型中得到了有力验证，成功将免疫冷肿瘤转化为T细胞炎症热肿瘤。ExoPERM策略为克服TDE介导的癌症耐药提供了一种有前景的选择，提示了一种抑制小EV的独特方法。
Tumor cell-derived small extracellular vesicles (TDEs) play a critical role in immune evasion, including the establishment of an immunosuppressive tumor microenvironment (TME), and form a substantial barrier to effective cancer immunotherapy. Here, we introduce the ExoPERM (pH-enabled rupture of exosome membranes) strategy, a pH-responsive system based on small extracellular vesicle (EV)-disrupting alpha-helical peptides that selectively target small EVs localized within the TME. By incorporating a pH-sensitive linker through PEGylation, this system ensures systemic stability while allowing the selective release of peptides within the mildly acidic TME. Mechanistic investigations revealed that the peptide preferentially ruptured small EVs at pH 6.5, effectively preventing EVs' PD-L1 interactions with PD-1 on CD8⁺ T cells and contributing to the restoration of their effector functions. Furthermore, this targeted disruption significantly attenuated TDE-induced activation of cancer-associated fibroblasts, thereby remodeling the dense fibrotic stroma that physically restricts immune cell penetration. In vivo studies have demonstrated enhanced CD8⁺ T-cell tumor infiltration and activation, notably when combined with immune checkpoint blockade or adoptive T-cell transfer. These synergistic effects were robustly validated across murine melanoma and colorectal cancer models, successfully converting immunologically cold tumors into T-cell-inflamed hot tumors. The ExoPERM strategy provides a promising option for overcoming TDE-mediated resistance in cancer, suggesting a distinct approach to small EV inhibition.
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