Background <p>One of the leading causes of poor prognosis in colorectal cancer (CRC) patients is the presence of colorectal cancer-initiating cells (CCICs). The tumor microenvironment (TME) plays a role in the acquisition of CCICs characteristics. However, the underlying mechanisms remain unclear.</p> Methods <p>Candidate molecules were identified by analyzing the differentially expressed genes (DEGs) between spheroid and planar cells, as well as between CD24⁺CD44⁺ cells and CD24^-CD44^- cells. The relationship between prognosis and ARRDC4 was assessed using RT-qPCR and Western blot assays. Mitochondrial analysis was conducted to examine the role of ARRDC4 in metabolic reprogramming. Coimmunoprecipitation (co-IP) assays with exosomes were performed to investigate the downstream molecule WWP1. Clinical samples were collected for validation.</p> Results <p>We identified a novel TME-responsive protein involved in the reprogramming of CRC cells. ARRDC4 was upregulated in CCICs and responsive to the TME. In CCICs, ARRDC4 translocated to the mitochondrial matrix, where it reprogrammed lipid metabolism. Upregulation of ARRDC4 promoted exosome secretion. WWP1 primarily binds to ARRDC4 and is released through exosomes. Released WWP1 is taken up by surrounding CRC cells, inhibiting epithelial-mesenchymal transition (EMT) and migration.</p> Conclusion <p>TME-responsive ARRDC4 inhibits CRC progression by regulating metabolic reprogramming and exosome secretion. Increased WWP1 in ARRDC4⁺ CCIC-derived exosomes suppresses CRC metastasis. We identified ARRDC4/WWP1 pathway as a novel mechanism and potential therapeutic target for CRC progression.</p>