以成纤维细胞TXNDC5为靶点，以间充质为特征，解决癌症中的肿瘤结缔组织增生和PD-1耐药性
Targeting fibroblast TXNDC5 resolves tumor desmoplasia and PD-1 resistance in colorectal cancer with mesenchymal traits.
摘要(中文译文)
间质型结直肠癌常对免疫治疗耐药，其耐药性在很大程度上由癌相关成纤维细胞介导的纤维化屏障和免疫排斥所驱动。在此，我们发现TXNDC5——一种在人和小鼠结直肠癌相关成纤维细胞中均上调的蛋白质二硫键异构酶——是该免疫抑制微环境的关键调控因子。机制上，TXNDC5通过稳定成纤维细胞中的TGFβ受体TGFBR1来增强TGFβ信号传导，从而驱动成纤维细胞活化及促肿瘤信号通路。成纤维细胞特异性敲除Txndc5可减轻肿瘤硬度、解除肿瘤血管受压并降低瘤内缺氧，同时抑制促肿瘤性炎症成纤维细胞极化并增强细胞毒性T细胞募集。这种基质重塑可抑制肿瘤生长，并显著增强肿瘤对PD-1阻断治疗的敏感性。我们的研究结果确立了TXNDC5-TGFBR1轴是恶性微环境中纤维化屏障的关键协调者，并提示靶向成纤维细胞中的TXNDC5可能有助于克服间质型结直肠癌患者的免疫治疗耐药。
Abstract
Mesenchymal-type colorectal cancer is frequently refractory to immunotherapy, with resistance largely driven by a cancer-associated fibroblast-mediated fibrotic barrier and immune exclusion. Here, we show that TXNDC5, a protein disulfide isomerase upregulated in both human and mouse colorectal cancer-associated fibroblasts, is a critical regulator of this immunosuppressive niche. Mechanistically, TXNDC5 enhances TGFβ signaling by stabilizing the TGFβ receptor TGFBR1 in fibroblasts, thereby driving fibroblast activation and pro-tumor signaling pathways. Fibroblast-specific Txndc5 deletion attenuates tumor stiffness, decompresses tumor vessels, and reduces intratumoral hypoxia while inhibiting pro-tumorigenic inflammatory fibroblast polarization and augmenting cytotoxic T-cell recruitment. This stromal remodeling restrains tumor growth and markedly sensitizes tumors to PD-1 blockade therapy. Our findings identify the TXNDC5-TGFBR1 axis as a key orchestrator of the fibrotic shield within the malignant microenvironment and suggest that targeting TXNDC5 in fibroblasts could help overcome immunotherapy resistance in patients with mesenchymal-type colorectal cancer.
如何引用
AMA
Kai-Lin Cheng, Chih-I Chen, Shu-Han Yu, Huai-Wen Liang, Yi-Wei Tsai, Chen-Ting Hung, et al. Targeting fibroblast TXNDC5 resolves tumor desmoplasia and PD-1 resistance in colorectal cancer with mesenchymal traits.. Nature communications. 2026; doi:10.1038/s41467-026-74073-1.
APA
Kai-Lin Cheng, Chih-I Chen, Shu-Han Yu, Huai-Wen Liang, Yi-Wei Tsai, Chen-Ting Hung, et al (2026). Targeting fibroblast TXNDC5 resolves tumor desmoplasia and PD-1 resistance in colorectal cancer with mesenchymal traits.. Nature communications. https://doi.org/10.1038/s41467-026-74073-1
GB/T 7714
Kai-Lin Cheng, Chih-I Chen, Shu-Han Yu, Huai-Wen Liang, Yi-Wei Tsai, Chen-Ting Hung, et al. Targeting fibroblast TXNDC5 resolves tumor desmoplasia and PD-1 resistance in colorectal cancer with mesenchymal traits.[J]. Nature communications, 2026 doi:10.1038/s41467-026-74073-1.
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