National Taiwan University research discovers TXNDC5 regulates key mechanisms of tumor fibrosis and improves immunotherapy response in colorectal cancer

2026/10/03 09:52

National Taiwan University research has discovered that TXNDC5 regulates the key mechanism of tumor fibrosis and improves the response to immunotherapy of colorectal cancer. The picture shows the mechanism by which the endoplasmic reticulum protein TXNDC5 causes the progression of colorectal cancer. (Photo by reporter Lin Xiaoyun)

[Reporter Lin Xiaoyun/Taipei Report] Colorectal cancer receives immunotherapy. Why are some tumors so difficult to attack? The research team of Professor Yang Kai-jian of the Institute of Pharmacology, National Taiwan University School of Medicine found the key mechanism and found that the endoplasmic reticulum protein "TXNDC5" can promote the continuous activation of cancer-related fibroblasts and aggravate tumor fibrosis, like building a barrier to block the entry of T cells responsible for killing cancer cells. Animal experiments have found that deleting TXNDC5 not only inhibits tumor growth, but also significantly improves the effect of PD-1 immunotherapy, providing a new direction for improving the resistance of colorectal cancer immunotherapy in the future.

The research results were published in the international journal "Nature Communications" on June 5, 2026. The research team pointed out that "stromal" colorectal cancer has a highly fibrotic tumor microenvironment. Cancer-associated fibroblasts (CAF) will form a dense fibrosis barrier, which not only compresses blood vessels in the tumor and causes hypoxia, but also prevents toxic T cells from entering the tumor. This is one of the important reasons for immunotherapy resistance.

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After analyzing human and mouse colorectal cancer data, the research team found that TXNDC5 was abnormally expressed in cancer-related fibroblasts. Further investigation of the mechanism revealed that TGFβ1 signaling and endoplasmic reticulum pressure in the tumor microenvironment induce an increase in TXNDC5. TXNDC5 maintains the protein stability of the TGFβ receptor TGFBR1, allowing related signals to continue to act, further promoting fibroblast activation and tumor fibrosis, forming a vicious cycle.

High-grade fibrosis doesn't just make tumors "harder." Research shows that fibrosis can compress blood vessels and cause hypoxia, further creating an immunosuppressive environment and recruiting immune tolerance cells such as bone marrow-derived suppressor cells (MDSCs) and regulatory T cells (Tregs). At the same time, T cells with killing capabilities are excluded from tumors, making it easier for cancer cells to evade immune system attacks.

The research team further specifically deleted Txndc5 in fibroblasts in a mouse model. As a result, the hardness of tumor tissue decreased, blood vessel compression and hypoxia improved. Inflammatory fibroblasts that promote tumors also decreased, and toxic T cells increased into tumors.

More importantly, changing the tumor microenvironment can not only inhibit tumor growth, but also significantly improve the response to blocking PD-1 immunotherapy. The study was jointly completed by the first author Cheng Kailin and the cooperating team, revealing the important role of the TXNDC5-TGFBR1 axis in tumor fibrosis and immunotherapy resistance. In the future, it is expected to become a new research direction for regulating the tumor microenvironment and improving the effect of immunotherapy in stromal colorectal cancer.