Chaperone-mediated autophagy (CMA), a proteolytic system contributing to the degradation of intracellular proteins in lysosomes, is upregulated in tumors for pro-tumorigenic and pro-survival purposes. In this study, bioinformatics analysis revealed the co-occurrence of upregulated CMA and PD-L1 accumulation in metastatic melanoma with adaptive immune resistance (AIR) to anti-PD1 treatment, suggesting the potential therapeutic effects of rewiring CMA for PD-L1 degradation. Furthermore, this co-occurrence is attributed to IFN-γ-mediated compensatory up-regulation of PD-L1 and CMA, accompanied by enhanced macropinocytosis. Drawing inspiration from the cellular uptake of prions via macropinocytosis, a prion-like chemical inducer of proximity called SAP was engineered using self-assembly of the designed chiral peptide PHA. By exploiting sensitized macropinocytosis, SAP clandestinely infiltrates tumor cells and subsequently disintegrates into PHA, which reprograms CMA by inducing PD-L1 close to HSPA8. SAP degrades PD-L1 in a CMA-dependent manner and effectively restores the anti-tumor immune response in both allografting and Hu-PDX melanoma mouse models with AIR while upholding a high safety profile. Collectively, the reported SAP not only presents an immune reactivation strategy with clinical translational potential for overcoming AIR in cutaneous melanomas but serves as a reproducible example of precision-medicine-guided drug development that fully leverages specific cellular indications in pathological states.

中文翻译：

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通过类似朊病毒的化学诱导剂重新连接癌症中分子伴侣介导的自噬，以抵消适应性免疫抵抗

伴侣介导的自噬 (CMA) 是一种蛋白水解系统，有助于溶酶体中细胞内蛋白质的降解，在肿瘤中上调，以达到促肿瘤发生和促生存的目的。在这项研究中，生物信息学分析揭示了在对抗 PD1 治疗具有适应性免疫抵抗 (AIR) 的转移性黑色素瘤中，CMA 和 PD-L1 积累上调同时发生，这表明重新连接 CMA 对 PD-L1 降解具有潜在的治疗作用。此外，这种同时发生归因于 IFN-γ 介导的 PD-L1 和 CMA 代偿性上调，并伴有巨胞饮作用增强。受到细胞通过巨胞饮作用摄取朊病毒的启发，利用设计的手性肽 PHA 的自组装设计了一种名为 SAP 的类朊病毒化学邻近诱导剂。通过利用敏化巨胞饮作用，SAP 秘密渗透肿瘤细胞，随后分解为 PHA，PHA 通过诱导 PD-L1 接近 HSPA8 来重新编程 CMA。SAP 以 CMA 依赖性方式降解 PD-L1，并在使用 AIR 的同种异体移植和 Hu-PDX 黑色素瘤小鼠模型中有效恢复抗肿瘤免疫反应，同时保持高安全性。总的来说，所报告的 SAP 不仅提出了一种具有临床转化潜力的免疫再激活策略，可以克服皮肤黑色素瘤中的 AIR，而且可以作为精准医学指导药物开发的可重复示例，充分利用病理状态下的特定细胞适应症。