Stress granule dynamics orchestrate colitis-to-cancer transition via TOM1-mediated disassembly and driven oncogenesis in response to inflammatory oxidative stress.

Colitis-associated colorectal cancer (CAC) is a serious complication of inflammatory bowel disease. As stress-responsive membraneless organelles, stress granules (SGs) are involved in modulating inflammatory suppression and promoting tumorigenesis, but their role in the pathogenesis of CAC remains unclear. This study reveals that SGs exhibit a stage-specific function during CAC progression, being protective in acute colitis but transitioning to a tumor-promoting role in the dysplasia-carcinoma sequence. We first demonstrate that, during acute colitis, fluctuating oxidative stress drives dynamic SGs assembly. However, despite persistently elevated oxidative stress from chronic colitis to dysplasia, SGs levels paradoxically decline. This decline is attributed to the upregulation of TOM1, a novel negative regulator that binds the NTF2L domain of the core SGs scaffold protein G3BP1 to promote SGs disassembly, thereby counteracting the oxidative stress-driven assembly. The consequent disassembly facilitates the nuclear translocation of the oncogenic transcription factor FUBP1, which in turn promotes c-Myc expression and thereby contributes to tumorigenesis. Our findings establish the regulation of SGs dynamics, particularly via TOM1 and G3BP1, as a promising therapeutic strategy for CAC.