ONCOLOGY REPORTS 52: 149, 2024 - The combination of a PTP1B inhibitor, TNFR2 blocker, and PD‑1 antibody suppresses the progression of non-small cell lung cancer tumors by enhancing immunocompetence

Sep 21, 2026

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Lung cancer remains a major cause of cancer-related death, and although PD‑1 inhibitors are widely used, response rates are still suboptimal in non‑small cell lung cancer (NSCLC). Protein tyrosine phosphatase 1B (PTP1B) is implicated in cancer progression through effects on T-cell expansion and cytotoxicity. This study evaluates triple therapy with PD‑1 inhibition plus PTP1B inhibition and TNFR2 blockade. Results in NSCLC mouse models show reduced tumor growth and prolonged survival, alongside remodeling of immune-cell distributions, decreased PD‑L1/PTP1B/TNFR2 in tumors, and altered suppressor and effector cell populations.

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Abstract

Introduction

ONCOLOGY REPORTS 52: 149, 2024 The combination of a PTP1B inhibitor, TNFR2 blocker, and PD‑1 antibody suppresses the progression of non‑small cell lung cancer tumors by enhancing immunocompetence HUAN GUI 1,3 , YUJIE NIE2 , HAOHUA YUAN 1 , QIANYU JING2 , LINZHAO LI 1 , LAN ZHU 1 , SHUANGHUI CHEN 1 , MENGJIAO WANG 1 , QUAN WAN 1,2 , HANG LV2 , YINGJIE NIE 1,4 and XIANGYAN ZHANG 1,2 1School of Medicine, Guizhou University, Guiyang, Guizhou 550025, P.R. China; 2NHC Key Laboratory of Pulmonary Immunological Diseases, Guizhou Provincial People's Hospital, Guiyang, Guizhou 550002, P.R. China; 3Department of Hyperbaric Oxygen, People's Hospital of Qianxinan Prefecture, Xingyi, Guizhou 562400, 4 P.R. China; Shenzhen Key Laboratory for Cancer Metastasis and Personalized Therapy, Department of Clinical Oncology, The University of Hong Kong‑Shenzhen Hospital, Shenzhen, Guangdong 518053, P.R. China Received April 5, 2024; Accepted July 30, 2024 DOI: 10. 3892/or.2024.8808 Abstract. Lung cancer is increasingly recognized as a leading cause of cancer‑related mortality. Immunotherapy has emerged as a promising therapeutic approach for lung cancer, particu‑ larly non‑small cell lung cancer (NSCLC) . Nonetheless, the response rate to programmed cell death 1 (PD‑1) inhibitors remains less than optimal. It has been suggested that protein tyrosine phosphatase 1B (PTP1B) plays a crucial role in the development and progression of cancer by facilitating T cell expansion and cytotoxicity. Our previous research demon‑ strated that the combination of tumor necrosis factor receptor 2 (TNFR2) with immune activity treatments synergistically suppresses tumor growth. This insight led to exploring the efficacy of a combined treatment strategy involving PD‑1 inhibitors, PTP1B inhibitors and TNFR2 antibodies (triple therapy) in NSCLC. In this context, the therapeutic effective‑ ness of these combination immunotherapies was validated in mouse models with NSCLC by analyzing the expansion and function of immune cells, thereby assessing their impact on Correspondence to: Professor Yingjie Nie, Shenzhen Key Laboratory for Cancer Metastasis and Personalized Therapy, Department of Clinical Oncology, The University of Hong Kong‑Shenzhen Hospital, Haiyuan 1st Road, Futian, Shenzhen, Guangdong 518053, P.R. China E‑[mail: nienyj@hotmail.com](mail: nienyj@hotmail.com) Dr Xiangyan Zhang, NHC Key Laboratory of Pulmonary Immunological Diseases, Guizhou Provincial People's Hospital, 83 Zhongshan East Road, Guiyang, Guizhou 550002, P.R. China E‑mail: [zxy35762@126.com](zxy35762@126.com) Key words: non‑small cell lung cancer, combination immunotherapy, protein tyrosine phosphatase 1B, tumor necrosis factor receptor 2, programmed cell death 1, CD8+T cells tumor growth. The results indicated that inhibiting PTP1B decreases the expression of PD‑L1 and TNFR2 on LLC cells, along with an increase in the proportion of CD4+T and CD8+T cells. Compared with other treatment groups, the triple therapy significantly reduced tumor volume in mice with NSCLC and extended their survival. Moreover, this combination therapy altered the distribution of myeloid‑derived suppressor cells, dendritic cells, B cells and M1 macrophages, while increasing the proportion of CD8+T cells and reducing the proportion of Treg cells in the spleens, lymph nodes, and tumors of NSCLC models. The triple therapy also resulted in a decrease in PD‑L1, PTP1B and TNFR2 expression within NSCLC tumor tissues in mice. Overall, the triple therapy effectively suppressed tumor growth and improved outcomes in mice with NSCLC by modulating immune cell distribution and reducing levels of target immune proteins. Introduction As of 2020, lung cancer was responsible for the deaths of ~1.8 million individuals worldwide, making it the leading cause of cancer mortality. Non‑small cell lung cancer (NSCLC) constitutes the majority of these cases, accounting for ~85%(1,2) . The surgical resection, despite its

FAQs

What problem does this study address in NSCLC immunotherapy?

The study targets the limited response rate to PD‑1 inhibitors and the need for strategies that improve outcomes in non‑small cell lung cancer.

What is the triple therapy evaluated in the work?

The triple therapy combines a PD‑1 inhibitor with a PTP1B inhibitor and a TNFR2 blocker (TNFR2 antibody), aiming to jointly enhance antitumor immunity.

What immune and tumor effects were observed in the NSCLC mouse models?

Triple therapy reduced tumor volume and extended survival, decreased PD‑L1/PTP1B/TNFR2 expression in tumor tissues, increased CD4+ and CD8+ T-cell proportions, and shifted suppressor and antigen-presenting cell distributions while reducing Treg proportions.

Sep 21, 2026

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