Simple SummaryIn esophageal cancer, the 5-year survival rate for patients who underwent esophagectomy with chemoradiotherapy is poor, with an estimated rate of 32.4%. One reason for this outcome is the low response rate to preoperative chemotherapy or radiotherapy. In this study, we revealed that low-dose chemotherapy or radiotherapy causes malignant phenotypic changes, such as cancer-associated fibroblasts, in normal fibroblasts. Furthermore, radiotherapy-resistant fibroblasts significantly increased the total number of tumors in the peritoneal cavity compared to the control group in peritoneal-disseminated tumor models. Thus, conventional cancer therapy has anti-therapeutic effects via activation of fibroblasts, and it is important to determine which modality of esophageal cancer treatment is selected or combined, recognizing that inappropriate radiotherapy and chemotherapy can lead to tumor resistance.AbstractEsophageal cancer is one of the most aggressive tumors, and the outcome remains poor. One contributing factor is the presence of tumors that are less responsive or have increased malignancy when treated with conventional chemotherapy, radiotherapy, or a combination of these. Cancer-associated fibroblasts (CAFs) play an important role in the tumor microenvironment. Focusing on conventional cancer therapies, we investigated how CAFs acquire therapeutic resistance and how they affect tumor malignancy. In this study, low-dose chemotherapy or radiotherapy-induced normal fibroblasts showed enhanced activation of CAFs markers, fibroblast activation protein, and α-smooth muscle actin, indicating the acquisition of malignancy in fibroblasts. Furthermore, CAFs activated by radiotherapy induce phenotypic changes in cancer cells, increasing their proliferation, migration, and invasion abilities. In in vivo peritoneal dissemination models, the total number of tumor nodules in the abdominal cavity was significantly increased in the co-inoculation group of cancer cells and resistant fibroblasts compared to that in the co-inoculation group of cancer cells and normal fibroblasts. In conclusion, we demonstrated that conventional cancer therapy causes anti-therapeutic effects via the activation of fibroblasts, resulting in CAFs. It is important to select or combine modalities of esophageal cancer treatment, recognizing that inappropriate radiotherapy and chemotherapy can lead to resistance in CAF-rich tumors.