CLCA2 (chloride channel accessory 2) is a calcium-dependent chloride channel regulator and tumor suppressor with multifaceted roles in epithelial homeostasis and cancer prevention. Mechanistically, CLCA2 enhances store-operated calcium entry by interacting with ORAI-1 and STIM-1, thereby amplifying calcium-activated chloride currents through TMEM16A 1. Beyond ion channel regulation, CLCA2 functions as an adhesion molecule through interactions with EVA1 at cell-cell junctions and β-catenin in cytosolic signaling complexes 2. Nuclear-localized CLCA2, transported via extracellular vesicles, activates Wnt/β-catenin signaling and promotes keratinocyte survival under stress 3. CLCA2 expression is significantly downregulated in colorectal, breast, cervical, and prostate cancers, predominantly through promoter hypermethylation rather than mutation 4 5. In cervical cancer, CLCA2 loss correlates with advanced tumor stage, larger size, and poor prognosis 6. Functionally, CLCA2 suppresses cancer cell proliferation, migration, and invasion while inhibiting epithelial-to-mesenchymal transition via ERK/JNK/p38-MAPK pathway inactivation 7. Transcriptional repression of CLCA2 involves CTBP1-mediated complexes with HDACs, ZEB1, and EP300, as well as miR-196b-5p targeting 8. These findings establish CLCA2 as a clinically relevant tumor suppressor and potential therapeutic target across multiple cancer types.