The mechanism of MMP14-positive tumor-associated fibroblast subsets in inhibiting PD-1 immunotherapy for esophageal cancer through exosomal tsRNA-10522.

Esophageal cancer (EC) continues to pose a significant health risk. Cancer-associated fibroblasts (CAFs), an essential part of the tumor microenvironment (TME), are viewed as potential therapeutic targets. However, their role in tumor mechanisms specific to esophageal cancer remains to be elucidated. This study identified MMP14 CAFs and MMP14 CAFs using immunofluorescence staining. The cytotoxic activity of CD8 T cells was assessed via western blot and ELISA. Using a transwell test, the migratory potential of MMP14 CAFs was evaluated. Using flow cytometry, apoptosis was found in the esophageal squamous cell carcinoma cell line KYSE30. To determine the important tsRNAs released by MMP14 CAFs, tsRNA-seq was used. Two subgroups of EC receiving PD-1 immunotherapy were identified by our research: MMP14 CAFs and MMP14 CAFs. MMP14 CAFs showed improved migratory capacity and released more inflammatory factors linked to cancer. Through exosomes, these CAFs may prevent anti-PD-1-treated CD8 T cells from being cytotoxic. Furthermore, exosomal tsRNA from MMP14 CAFs primarily targeted signaling pathways connected with cancer. Notably, it was discovered that tsRNA-10522 plays a critical role within inhibiting CD8 T cell tumor cell death. The tumor cell killing of CD8 T cells by exosomal tsRNA-10522 is inhibited by a subgroup of cells called MMP14 CAFs inside the EC microenvironment during PD-1 immunotherapy. This reduces the effectiveness of PD-1 immunotherapy for EC. Our findings demonstrate the inhibitory function of MMP14 CAFs within EC receiving PD-1 immunotherapy, raising the prospect that MMP14 CAFs might serve as predictive indicators in EC receiving PD-1 immunotherapy.