Network Medicine-Based Strategy Identiﬁes Maprotiline asa Repurposable Drug by Inhibiting PD-L1 Expression via Targeting SPOP in Cancer

Sep 21, 2026

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Immune checkpoint inhibitors can restore antitumor activity but face limitations and adverse effects, creating a need for new agents with checkpoint inhibitory activity. A network-based computational framework, Mnet-DRI, was developed to repurpose novel ICIs from about 3000 FDA-approved or investigational drugs. Applied to PD-L1, the antidepressant maprotiline is proposed as a PD-L1 modifier for colorectal and lung cancers. Experiments show MAP reduces PD-L1 expression by targeting SPOP E3 ubiquitin ligase and, combined with anti-CTLA4, enhances antitumor effects in vivo.

LanguageEnglish

CategoryResearch & Report

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Pages23

Reading Time58 min

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Introduction

Network-based computational drug repositioning framework

PD-L1 targeting and experimental validation

Combination with anti-CTLA4 in vivo

RESEARCH ARTICLE [www.advancedscience.com](www.advancedscience.com) Network Medicine-Based Strategy Identiﬁes Maprotiline asa Repurposable Drug by Inhibiting PD-L1 Expression via Targeting SPOP in Cancer Saisai Tian, Mengting Xu, Xiangxin Geng, Jiansong Fang, Hanchen Xu, Xinying Xue, Hongmei Hu, Qing Zhang, Dianping Yu, Mengmeng Guo, Hongwei Zhang, Jinyuan Lu, Chengyang Guo, Qun Wang,* Sanhong Liu,* and Weidong Zhang* Immune checkpoint inhibitors (ICIs) are drugs that inhibit immune checkpoint (ICP) molecules to restore the antitumor activity of immune cells and eliminate tumor cells. Due to the limitations and certain side eﬀects of current ICIs, such as programmed death protein-1, programmed cell death-ligand 1, and cytotoxic T lymphocyte-associated antigen 4 (CTLA4) antibodies, there is an urgent need to ﬁnd new drugs with ICP inhibitoryeﬀects. In this study, a network-based computational framework called multi-network algorithm-driven drug repositioning targeting ICP (Mnet-DRI) is developed to accurately repurpose novel ICIs from ≈3000 Food and Drug Administration-approved or investigational drugs. By applying Mnet-DRI to PD-L1, maprotiline (MAP), an antidepressant drug is repurposed, as a potential PD-L1 modiﬁer for colorectal and lung cancers. Experimental validation revealed that MAP reduced PD-L1 expression by targeting E3 ubiquitin ligase speckle-type zinc ﬁnger structural protein (SPOP), and the combination of MAP and anti-CTLA4 in vivo signiﬁcantly enhanced the antitumor eﬀect, providing a new alternative for the clinical treatment of colorectal and lung cancer. 1. Introduction Recently, tumor immunotherapy has become a focus in cancer treatment and has achieved a series of breakthroughs. [1] Unlike traditional cancer treatment methods, such as radiotherapy and chemotherapy, immunotherapy aims to stimulate or enhance the immune system’s ability to recognize and destroy cancer cells. Immunotherapy comprises various cancer therapies, including cell-based therapies, immune checkpoint inhibitors (ICIs), cancer vaccines, and oncolytic viruses. ICIs are eﬀective immunotherapies that can activate immune checkpoint (ICP) molecules, including programmed death protein-1 (PD- 1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA4)-related signaling pathways, thereby blocking the inﬂammatory response. Brieﬂy, tumor cells achieve immune escape by activating signaling S. Tian, J. Lu, C. Guo, W. Zhang Department of Phytochemistry School of Pharmacy Second Military Medical University Shanghai 200433, China [E-mail:](E-mail: wdzhangy@smmu.edu.cn)[ wdzhangy@smmu.edu.cn](E-mail: wdzhangy@smmu.edu.cn) M. Xu, X. Geng, H. Hu, Q. Zhang, D. Yu, M. Guo, H. Zhang, Q. Wang, S. Liu Shanghai Frontiers Science Center of TCM Chemical Biology Institute of Interdisciplinary Integrative Medicine Research Shanghai University of Traditional Chinese Medicine Shanghai 201203, China E-mail: [qunwang@shutcm.edu.cn](qunwang@shutcm.edu.cn); [liush@shutcm.edu.cn](liush@shutcm.edu.cn) J. Fang Science and Technology Innovation Center Guangzhou University of Chinese Medicine Guangzhou 510006, China The ORCID identiﬁcation number(s) for the author(s) of this article can be found under [https://doi.org/10.1002/advs.202410285](https://doi.org/10.1002/advs.202410285)[ ](https://doi.org/10.1002/advs.202410285)© 2024 The Author(s). Advanced Science published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. DOI: 10.1002/advs.202410285 H. Xu Institute of Digestive Diseases Longhua Hospital Shanghai University of Traditional Chinese Medicine Shanghai 200032, China X. Xue Department of Respiratory and Critical Care Emergency and Critical Care Medical Center Beijing Shijitan Hospital Capital Medical University Beijing 100038, China W. Zhang State Key La

FAQs

What problem does the study address about current immune checkpoint inhibitors?

Current ICIs, including PD-1/PD-L1 and CTLA4 antibodies, have limitations and side effects, motivating the search for new ICP inhibitory drugs.

How does the proposed method find repurposable candidates?

The study introduces Mnet-DRI, a multi-network computational framework that repurposes novel ICIs by analyzing drug candidate relationships around checkpoint targets such as PD-L1.

What did experimental validation show for maprotiline in cancer models?

Maprotiline reduced PD-L1 expression by targeting the E3 ubiquitin ligase SPOP, and the combination of maprotiline with anti-CTLA4 significantly enhanced antitumor effects in vivo.

Sep 21, 2026

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