Abstract

Tumour metabolic modulation represents a promising adjuvant therapeutic strategy for cancers, including colorectal cancer (CRC). Dapagliflozin, a clinically approved sodium‒glucose cotransporter 2 (SLC5A2/SGLT2) inhibitor, has attracted considerable attention, yet its functional role in CRC remains unclear. Here, we investigated the oncogenic effect of SLC5A2 on the colorectal mucosal epithelium using transgenic rats and an azoxymethane/dextran sulphate sodium (AOM/DSS)-induced tumour model. Multiple immunofluorescence and tissue microarray analyses of clinical samples revealed an inverse correlation between SLC5A2 expression and natural killer (NK) cell infiltration, highlighting the therapeutic potential of dapagliflozin for CRC treatment. Mechanistically, gene expression profiling analysis and coculture experiments demonstrated that SLC5A2 impairs NKG2D-mediated NK cell cytotoxicity. Furthermore, perforated patch‒clamp and calcium imaging revealed that SLC5A2 modulates the membrane potential and calcium influx, enhancing MHC-I-associated MICA/B secretion via extracellular vesicle (EV) formation and thereby enabling CRC cells to evade NK cell surveillance. Our findings reveal a critical oncogenic role of SLC5A2 in CRC progression and suggest dapagliflozin as a novel therapeutic option, particularly for CRC patients with metabolic comorbidities.