The majorities of colorectal cancer (CRC) cases are sporadic in origin and a large proportion of etiologies are associated with environmental stress responses. In response to external and internal stress, the ribosome stands sentinel and stress-driven ribosomal dysfunction triggers the cellular decision pathways via transcriptional reprogramming. In the present study, PR domain zinc finger protein (PRDM) 1, a master transcriptional regulator, was found to be closely associated with ribosomal actions in patients with CRC and the murine models. Stress-driven ribosomal dysfunction enhanced PRDM1 levels in intestinal cancer cells, which contributed to their survival and enhanced cancer cell stemness against cancer treatment. Mechanistically, PRDM1 facilitated clustering modulation of insulin-like growth factor (IGF) receptor-associated genes, which supported cancer cell growth and stemness-linked features. Ribosomal dysfunction-responsive PRDM1 facilitated signaling remodeling for the survival of tumor progenitors, providing compelling evidence for the progression of sporadic CRC.