TUSC2 (tumor suppressor candidate 2) is a mitochondrial calcium regulator located on chromosome 3.3 that functions as a tumor suppressor across multiple cancer types 1. TUSC2 exerts anti-tumor effects primarily through regulating G1 cell cycle progression, apoptosis, and calcium homeostasis 1. The protein maintains cellular Ca2+ homeostasis by interacting with mitochondrial Ca2+ transport machinery, controlling both apoptosis and senescence 2. TUSC2 expression is reduced or lost in various cancers including lung, breast, glioblastoma, and colorectal cancer, though mRNA levels often remain normal, suggesting post-translational degradation mechanisms 3, 4. NEDD4-mediated polyubiquitination at lysine 71 represents a novel degradation pathway in glioblastoma, with TUSC2 loss promoting progression through Bcl-xL upregulation 3. TUSC2 expression inversely correlates with Ki67 proliferation index and tumor size in breast cancer 4. Therapeutically, TUSC2 restoration shows promise: pseudogene TUSC2P and its 3'-UTR act as microRNA sponges to increase TUSC2 translation 5, while HDAC inhibitors enhance TUSC2 transcription to induce immunogenic cell death 6. Clinical trials combining TUSC2-nanoparticles with erlotinib demonstrate feasibility in lung cancer 1.