Here, we report that NRIP3 (nuclear receptor interacting protein 3) promotes ESCC tumor cell growth and resistance to CRT in ESCC cells by increasing and binding to DDI1 (DNA-damage inducible 1 homolog 1) and RTF2 (homologous to Schizosaccharomycespombe Rtf2), and accelerating the removal of RTF2, which is a key determinant for the ability of cells to manage replication stress. Here, NRIP3 is linked to esophageal squamous cell carcinoma.