CALML6 (calmodulin-like 6) is an EF-hand calcium-binding protein that functions as a negative regulator of innate immune signaling and a modulator of cancer cell behavior. Mechanistically, CALML6 suppresses antiviral immunity by directly binding to phosphorylated IRF3 and impairing its dimerization and nuclear translocation, thereby reducing type I interferon production 1. Additionally, CALML6 negatively regulates NF-κB signaling by interacting with TAK1 and recruiting deubiquitylating enzymes to suppress K63-linked polyubiquitination, conferring protection against acute inflammation 2. In cancer contexts, CALML6 demonstrates conflicting roles: in oral squamous cell carcinoma, CALML6 mediates EP4-induced mitochondrial localization and cell migration via the CaMKK2 pathway, promoting metastasis 3; however, in papillary thyroid carcinoma, CALML6 knockdown reduces cell growth and blocks cell cycle progression, suggesting tumor-suppressive functions 4. CALML6 is identified as a prognostic gene in colorectal cancer pyroptosis signatures, with high expression correlating with poor survival 5. These findings position CALML6 as a context-dependent regulator with potential clinical significance as a diagnostic marker and therapeutic target across multiple cancer types, particularly regarding immune checkpoint modulation and metastatic potential.