PMID- 38171078
OWN - NLM
STAT- MEDLINE
DCOM- 20240308
LR  - 20240308
IS  - 1532-2084 (Electronic)
IS  - 1368-7646 (Linking)
VI  - 73
DP  - 2024 Mar
TI  - Rewiring chaperone-mediated autophagy in cancer by a prion-like chemical inducer 
      of proximity to counteract adaptive immune resistance.
PG  - 101037
LID - S1368-7646(23)00120-6 [pii]
LID - 10.1016/j.drup.2023.101037 [doi]
AB  - 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-gamma-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.
CI  - Copyright (c) 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.
FAU - Yan, Jin
AU  - Yan J
AD  - Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong 
      University, Xi'an 710061, PR China; National & Local Joint Engineering Research 
      Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an 
      Jiaotong University, Xi'an, 710004, PR China. Electronic address: 
      yanjin19920602@xjtu.edu.cn.
FAU - Liu, Dan
AU  - Liu D
AD  - Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong 
      University, Xi'an 710061, PR China.
FAU - Wang, Jingmei
AU  - Wang J
AD  - National & Local Joint Engineering Research Center of Biodiagnosis and 
      Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 
      710004, PR China; Institute for Stem Cell & Regenerative Medicine, The Second 
      Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, PR China.
FAU - You, Weiming
AU  - You W
AD  - National & Local Joint Engineering Research Center of Biodiagnosis and 
      Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 
      710004, PR China.
FAU - Yang, Wenguang
AU  - Yang W
AD  - Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong 
      University, Xi'an 710061, PR China.
FAU - Yan, Siqi
AU  - Yan S
AD  - Institute for Stem Cell & Regenerative Medicine, The Second Affiliated Hospital 
      of Xi'an Jiaotong University, Xi'an 710004, PR China.
FAU - He, Wangxiao
AU  - He W
AD  - Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong 
      University, Xi'an 710061, PR China; Institute for Stem Cell & Regenerative 
      Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 
      710004, PR China. Electronic address: hewangxiao5366@xjtu.edu.cn.
LA  - eng
PT  - Journal Article
DEP - 20231225
PL  - Scotland
TA  - Drug Resist Updat
JT  - Drug resistance updates : reviews and commentaries in antimicrobial and 
      anticancer chemotherapy
JID - 9815369
RN  - 0 (B7-H1 Antigen)
RN  - 0 (Prions)
SB  - IM
MH  - Mice
MH  - Animals
MH  - *Chaperone-Mediated Autophagy
MH  - B7-H1 Antigen/metabolism
MH  - *Melanoma/metabolism
MH  - *Prions/metabolism
MH  - Lysosomes/metabolism
OTO - NOTNLM
OT  - Adaptive immune resistance
OT  - PD-L1 degradation
OT  - Peptide
OT  - Prionoid
OT  - Tumor immunotherapy
COIS- Declaration of Competing Interest The authors declare that they have no known 
      competing financial interests or personal relationships that could have appeared 
      to influence the work reported in this paper.
EDAT- 2024/01/04 11:43
MHDA- 2024/03/08 06:42
CRDT- 2024/01/03 18:02
PHST- 2023/09/06 00:00 [received]
PHST- 2023/12/20 00:00 [revised]
PHST- 2023/12/22 00:00 [accepted]
PHST- 2024/03/08 06:42 [medline]
PHST- 2024/01/04 11:43 [pubmed]
PHST- 2024/01/03 18:02 [entrez]
AID - S1368-7646(23)00120-6 [pii]
AID - 10.1016/j.drup.2023.101037 [doi]
PST - ppublish
SO  - Drug Resist Updat. 2024 Mar;73:101037. doi: 10.1016/j.drup.2023.101037. Epub 2023 
      Dec 25.