Simple SummaryUVRAG has been identified as being involved in tumor progression and prognosis in various types of cancer. We aimed to find the relationship between UVRAG and the prognosis of colorectal cancer and its potential mechanisms. We found that UVRAG had a negative association with prognosis in colorectal cancer, which was mediated by its ability to enhance migration, stemness, and chemoradiotherapy resistance of cancer cells. Additionally, UVRAG can promote the recruitment of macrophages by upregulating SP1 and enhance PD-L1 expression. This study deepens the understanding of UVRAG from the aspect of tumor immunity and provides more evidence for UVRAG as a novel therapeutic target with or without being combined with immunotherapy or molecular inhibitors.AbstractColorectal cancer (CRC) is the third most common type of cancer. The ultraviolet radiation resistance-associated gene (UVRAG) plays a role in autophagy and has been implicated in tumor progression and prognosis. However, the role of UVRAG expression in CRC has remained elusive. In this study, the prognosis was analyzed via immunohistochemistry, and the genetic changes were compared between the high UVRAG expression group and the low UVRAG expression group using RNA sequencing (RNA-seq) and single-cell RNA-seq (scRNA-seq) data, and genetic changes were then identified by in vitro experiments. It was found that UVRAG could enhance tumor migration, drug resistance, and CC motif chemokine ligand 2 (CCL2) expression to recruit macrophages by upregulating SP1 expression, resulting in poor prognosis of CRC patients. In addition, UVRAG could upregulate the expression of programmed death-ligand 1 (PD-L1). In summary, the relationship between UVRAG expression and the prognosis of CRC patients as well as the potential mechanisms in CRC were explored, providing evidence for the treatment of CRC.