DOI：10.12201/bmr.202608.00052

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

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  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

  提交时间：2026-09-22

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• 序号	提交日期	编号	操作
  1	2026-08-28	10.12201/bmr.202608.00052V1	下载

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