Reprogramming the tumor microenvironment with antibody against membrane-proximal AXL to overcome immune checkpoint blockade resistance

T cells. These cells displayed a transcriptomic profile resembling that of Tregs, characterized by elevated expression of immune checkpoint molecules (including PD-1 and CTLA4), reduced IL-2 production, and increased IL-2 receptor expression, thereby attenuating antitumor immune responses. The combination of 6C5 with dual immune checkpoint blockade (anti-PD-1 plus anti-CTLA-4) or a PD-1-targeted IL-2 fusion protein therapy mitigated this immunosuppression, resulting in potent tumor regression and durable immune memory. Our findings demonstrate that a membrane-proximal AXL-targeting antibody effectively converts the immune-cold tumor microenvironment, overcoming resistance to both conventional and next-generation immune checkpoint inhibitors.

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Publication Details

Journal
Signal Transduction and Targeted Therapy
Published
2026-04-17
DOI
https://doi.org/10.1038/s41392-026-02664-x
Primary Topic
Phagocytosis and Immune Regulation
Type
article
Field-Weighted Citation Impact
0.00

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article

Reprogramming the tumor microenvironment with antibody against membrane-proximal AXL to overcome immune checkpoint blockade resistance

Pengfei Duan, Liyu Zhang, Yang‐Xin Fu, Shuaishuai Cao et al.
Signal Transduction and Targeted Therapy
Phagocytosis and Immune Regulation
article

Reprogramming the tumor microenvironment with antibody against membrane-proximal AXL to overcome immune checkpoint blockade resistance

Pengfei Duan, Liyu Zhang, Yang‐Xin Fu, Shuaishuai Cao, Xueli Kuang, Xuyuan Zhang, Xiaohua Nie, Zuming Yang, Shaojun Yang, Zifan Wei, Liguo Zhang, Zhenhua Ren, Jiaen Zhang, Mingwan Tang, Yong Liang, Xun Lan, Huiming Huang, Jingshu Wang, Xin Sun, Zhimin Wang
article en

Abstract

T cells. These cells displayed a transcriptomic profile resembling that of Tregs, characterized by elevated expression of immune checkpoint molecules (including PD-1 and CTLA4), reduced IL-2 production, and increased IL-2 receptor expression, thereby attenuating antitumor immune responses. The combination of 6C5 with dual immune checkpoint blockade (anti-PD-1 plus anti-CTLA-4) or a PD-1-targeted IL-2 fusion protein therapy mitigated this immunosuppression, resulting in potent tumor regression and durable immune memory. Our findings demonstrate that a membrane-proximal AXL-targeting antibody effectively converts the immune-cold tumor microenvironment, overcoming resistance to both conventional and next-generation immune checkpoint inhibitors.

Signal Transduction and Targeted TherapyVol. 11(1)
Chinese Academy of Sciences (CN), Peking University (CN), Chinese PLA General Hospital (CN), Institute of Biophysics (CN), Peking University First Hospital (CN), Institute of Process Engineering (CN), University of Chinese Academy of Sciences (CN), Tsinghua University (CN)
National Natural Science Foundation of China, Chinese Academy of Sciences, Tsinghua University, National Science and Technology Major Project, Institute of Biophysics, Chinese Academy of Sciences
Zero hunger
Openalex Percentile: Top 23%
Phagocytosis and Immune Regulation
DOIOpen Access PDFOpenAlex
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