TXNDC5 as a Dual-Bridge Driver of Oncogenesis: Coupling Intracellular Pro-Tumorigenic Signaling with Extracellular Fibrotic Remodeling and Cold Tumor Formation

Corresponding author: Zhanglin, stepinghuns2@163.com

DOI: 10.12201/bmr.202608.00052

•  

  Abstract: Thioredoxin domain-containing protein 5 (TXNDC5), a member of the protein disulfide isomerase (PDI) family, has emerged as a critical mediator in tumor biology with dual functionality. Beyond its established role in protein folding within the endoplasmic reticulum, TXNDC5 exhibits both cell-autonomous pro-tumorigenic effects and non-cell-autonomous microenvironment remodeling capabilities. Herein, we propose the “Dual-Bridge” paradigm to conceptualize TXNDC5’s oncogenic functions: an intracellular bridge that directly promotes tumor cell proliferation, survival, and stress resistance, and an extracellular bridge wherein CAF-derived TXNDC5 drives fibrotic remodeling, vascular compression, hypoxia, and immune exclusion, culminating in cold tumor formation. This framework positions TXNDC5 as a unique molecular hub that coordinates cancer cell-intrinsic malignancy with microenvironmental immunosuppression. This review systematically integrates recent advances in understanding TXNDC5-mediated tumor microenvironment (TME) remodeling, with particular emphasis on its pivotal role in cancer-associated fibroblast (CAF) activation and the subsequent cascade leading to cold tumor formation and immunotherapy resistance. We delineate the molecular architecture of TXNDC5, its expression regulation through epigenetic modifications including m6A RNA methylation, and its divergent functions in tumor cells versus stromal fibroblasts. Central to our discussion is the "TXNDC5-TGFBR1-TGFβ" signaling axis, whereby TXNDC5 stabilizes TGFBR1 through PDI activity, amplifying TGFβ signaling in CAFs and driving extracellular matrix (ECM) deposition, tumor desmoplasia, vascular compression, and intratumoral hypoxia. This fibrotic cascade culminates in immune exclusion characterized by diminished CD8+ cytotoxic T lymphocyte infiltration, myeloid-derived suppressor cell (MDSC) accumulation, and resistance to immune checkpoint inhibitors (ICIs). We further discuss therapeutic implications, including the potential of TXNDC5-targeted strategies to reverse immunotherapy resistance and enhance drug delivery. This comprehensive framework positions TXNDC5 as a promising target for overcoming the physical and immunological barriers that limit current cancer therapeutics. The Dual-Bridge framework not only unifies the disparate observations of TXNDC5 biology but also provides a mechanistic roadmap for targeting both bridges to reverse immunotherapy resistance.

  Key words: TXNDC5; tumor microenvironment; cancer-associated fibroblasts; desmoplasia; cold tumor; immune checkpoint inhibitor resistance; TGFβ signaling; Dual-Bridge paradigm

  Submit time: 22 September 2026

  Copyright: The copyright holder for this preprint is the author/funder, who has granted biomedRxiv a license to display the preprint in perpetuity.
• html

• 图表

• Tang Jian, Yu Ge. Targeting Tumor Microenvironment Metabolic Reprogramming: A New Strategy to Overcome Treatment Resistance in NSCLCZHI Chuanrui1,TANG Jian2,YU Ge2*. 2026. doi: 10.12201/bmr.202603.00010

  Wang Huan, Ma Ying, Tian Jingnan, Lu Yi. Progress in the Diagnosis and Treatment of Immune Checkpoint Inhibitor-Associated Hypothyroidism from the Perspectives of Traditional Chinese and Western Medicine. 2025. doi: 10.12201/bmr.202505.00004

  Yadian Lei, Haiyan Wang. The Impact of the Tumor Immune Microenvironment on T Cell Function: Focusing on the Limitations of ICB and Combined Treatment Strategies. 2024. doi: 10.12201/bmr.202412.00083

  Yao Jin. The expression of IL-16 in immune and tumor related diseases and its anti-tumor application research. 2026. doi: 10.12201/bmr.202603.00011

  李林星, ZHU Shuxia. Research progress on the relationship between miRNA and tumor-associated macrophages in glioma. 2026. doi: 10.12201/bmr.202609.00007

  Gong Hui, Kong Chao-yang, Luo Shi, Liu Juan, Xiao Yu-jie. A New Strategy for Tumor Treatment Targeting Immunometabolism Reprogramming in Traditional Chinese Medicine. 2026. doi: 10.12201/bmr.202607.00005

  GONG Ping. The Role and Research Progress of CCR8-positive Regulatory T Cells in the Immune Microenvironment of Colorectal Cancer. 2026. doi: 10.12201/bmr.202606.00048

  李果, dongfengjiao, guosiyuan, chentaiquan. Exploration of Diagnosis and Treatment Strategies for Immune Checkpoint Inhibitor-Related Myocarditis Based on the “Toxin-Deficiency-Blood Stasis” Pattern within the Framework of “Stagnation and Accumulation in Collaterals”. 2026. doi: 10.12201/bmr.202609.00009

  WANG Lei. The Role of Gastrointestinal Tumor Markers and Inflammatory Indicators in the Diagnosis and Treatment of Esophageal Cancer. 2025. doi: 10.12201/bmr.202510.00034

  Li Ying, Wang Xiaofei, Lu Shengwei, Dong Danni, Zhang Jingfeng, Zheng Jianjun. CT Findings and Clinical Features of checkpoint Inhibitor-related pneumonitis. 2024. doi: 10.12201/bmr.202407.00008

• ID	Submit time	Number	Download
  1	2026-08-28	10.12201/bmr.202608.00052V1	Download

• Public  Anonymous  To author only Submit Comments