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Cancer cells precisely modulate replication stress to sustain genomic instability without triggering lethal DNA damage, yet regulators enabling this delicate balance remain largely unknown. Here, we identify N-methyl-D-aspartate receptor synaptonuclear signaling and neuronal migration factor (NSMF) as a novel and critical regulator of replication stress in colorectal cancer (CRC). NSMF expression is significantly elevated in CRC tissues and correlates closely with elevated replication stress. In ApcMin/+ mouse models, Nsmf knockout selectively induces replication-dependent DNA damage in tumor tissues, suppressing tumor growth and prolonging survival, without harming normal tissues. Mechanistically, NSMF deficiency impairs replication fork progression under stress conditions, resulting in DNA damage accumulation, growth arrest, and senescence. Conversely, NSMF overexpression provides resistance to oncogene-induced replication stress, enabling cancer cells to evade senescence and sustain proliferation. These findings establish NSMF as an essential safeguard against lethal replication stress and highlight its potential as a promising therapeutic target for CRC treatment.