From foe to friend: Rewiring oncogenic pathways through artificial selenoprotein to combat immune-resistant tumor

Weiming You; Zhengjun Zhou; Zhanfeng Li; Jin Yan; Yang Wang

doi:10.1016/j.jpha.2025.101322

Volume 15 Issue 12

Dec. 2025

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Weiming You, Zhengjun Zhou, Zhanfeng Li, Jin Yan, Yang Wang. From foe to friend: Rewiring oncogenic pathways through artificial selenoprotein to combat immune-resistant tumor[J]. Journal of Pharmaceutical Analysis, 2025, 15(12): 101322. doi: 10.1016/j.jpha.2025.101322

Citation:

Weiming You, Zhengjun Zhou, Zhanfeng Li, Jin Yan, Yang Wang. From foe to friend: Rewiring oncogenic pathways through artificial selenoprotein to combat immune-resistant tumor[J]. Journal of Pharmaceutical Analysis, 2025, 15(12): 101322. doi: 10.1016/j.jpha.2025.101322

Citation:

Weiming You, Zhengjun Zhou, Zhanfeng Li, Jin Yan, Yang Wang. From foe to friend: Rewiring oncogenic pathways through artificial selenoprotein to combat immune-resistant tumor[J]. Journal of Pharmaceutical Analysis, 2025, 15(12): 101322. doi: 10.1016/j.jpha.2025.101322

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From foe to friend: Rewiring oncogenic pathways through artificial selenoprotein to combat immune-resistant tumor

doi: 10.1016/j.jpha.2025.101322

Weiming You^a,b,
Zhengjun Zhou^c,
Zhanfeng Li^d,
Jin Yan^{a,b
,
,},
Yang Wang^{a,b
,
,}

a. Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, China;
b. National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, China;
c. Department of General Surgery, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, 563000, China;
d. Department of Medical Oncology and Department of Talent Highland, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China

Funds:

This work was supported by the National Natural Science Foundation of China (Grant No.: 82272782) and the Shaanxi Natural Science Foundation Research Program, China (Grant No.: 2024JC-YBMS-795).

Received Date: Jan. 18, 2025
Accepted Date: Apr. 21, 2025
Rev Recd Date: Apr. 14, 2025
Publish Date: Apr. 25, 2025

Abstract

Abstract

Reprogramming oncogenic signaling pathways to generate anti-tumor effects is a promising strategy for targeted cancer intervention, without significant off-target effects. Although reprogramming multi-oncoprotein interactions in a single signaling pathway axis has been shown to achieve sustained efficacy, there are several challenges that limit its clinical application. Herein, we transformed the mouse double minute 2 homolog (MDM2)-heat shock cognate protein 70 (HSC70) axis, a tumor-promoting pathway, into an activator of anti-tumor immunity using the Path-editor, an artificial selenoprotein. Once it enters the cell, Path-editor decomposes into PMI and PPI peptides: PMI inhibits MDM2-mediated p53 degradation and promotes HSC70 expression, while PPI binds to HSC70, enabling its ability to selectively degrade the programmed cell death ligand 1 (PD-L1). As a proof of concept, we tested its performance in microsatellite-stable (MSS) colorectal cancer, which typically displays limited responsiveness to immunotherapy. The results indicated that Path-editor effectively attenuated PD-L1 expression and reversed immune evasion in both CT26 allografts and humanized patient-derived tumor xenograft (PDX) models, thereby inhibiting tumor progression with high biosafety. Therefore, this paper introduces Path-editor as a paradigm for reprogramming oncogenic multi-protein pathways, utilizing selenium-assisted approach to achieve the rapid design of tumor-specific pathway editors. This strategy is expected to reverse immune escape in MSS colorectal cancer and treat difficult malignancies.
- Reprogramming,
- Pro-oncogenic pathways,
- Anti-tumor immunity,
- Artificial microprotein,
- Cancer therapy

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References(56)

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