Targeting fibroblast TXNDC5 resolves tumor desmoplasia and PD-1 resistance in colorectal cancer with mesenchymal traits

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. Cancer-associated fibroblasts can induce immune tolerance in mesenchymal colorectal cancer through fibrosis. This study identifies TXNDC5 as a TGFβ-dependent regulator of fibrosis whose targeting remodels the tumor stroma and sensitizes tumors to immunotherapy.