Simple SummaryGastrointestinal (GI) cancers are the leading cancer-related deaths worldwide. Despite improved survival rates with current treatments, recurrence remains a clinical challenge for patients with GI cancers. The unmet gap still needs to be further investigated. The tumor microenvironment (TME) is associated with the dormancy and awakening of tumor cells. Among them, the reciprocal regulation of cytokines/chemokines between cancer-associated fibroblasts (CAFs) and TME is a key driver of tumor progression, metastasis, and resistance to chemotherapy. In this review, we discuss the involvement of cytokines/chemokines produced by CAFs in the development of resistance to gastrointestinal cancer therapy, including tumor dormancy and tumor regeneration. Deciphering the crosstalk of CAFs and TME thus reduces the therapeutic recurrence of GI cancers.AbstractGastrointestinal (GI) cancers remain a major cause of cancer-related deaths worldwide. Despite the progress made in current treatments, patients with GI cancers still have high recurrence rates after initial treatment. Cancer dormancy, which involves the entry and escape of cancer cells from dormancy, is linked to treatment resistance, metastasis, and disease relapse. Recently, the role of the tumor microenvironment (TME) in disease progression and treatment has received increasing attention. The crosstalk between cancer-associated fibroblasts (CAF)-secreted cytokines/chemokines and other TME components, for example, extracellular matrix remodeling and immunomodulatory functions, play crucial roles in tumorigenesis. While there is limited direct evidence of a relationship between CAFs and cancer cell dormancy, this review explores the potential of CAF-secreted cytokines/chemokines to either promote cancer cell dormancy or awaken dormant cancer cells under different conditions, and the therapeutic strategies that may be applicable. By understanding the interactions between cytokines/chemokines released by CAFs and the TME, and their impact on the entry/escape of cancer dormancy, researchers may develop new strategies to reduce the risk of therapeutic relapse in patients with GI cancers.