TNK2 (tyrosine kinase non-receptor 2), also known as ACK1, is a cytoplasmic non-receptor tyrosine kinase with multifaceted roles in cell signaling and cancer biology. Functionally, TNK2 mediates cell spreading, migration, survival, and proliferation through phosphorylation of key substrates including AKT1, AR, MCF2, and WASL 1. TNK2 regulates clathrin-mediated endocytosis and EGFR trafficking by binding ubiquitinated cargo at early endosomes 1. The kinase acts as a CDC42 effector promoting CDC42-dependent cell migration via BCAR1 phosphorylation 1. In disease contexts, TNK2 drives cancer progression across multiple malignancies. In prostate cancer, TNK2 phosphorylates ATP5F1A to enhance mitochondrial ATP synthase activity and promote cancer cell survival, while TNK2 inhibition induces mitophagy-based autophagy 2. In pancreatic cancer, TNK2 activates STAT5A to induce immune checkpoint HVEM expression, suppressing CD8⁺ T cells; TNK2 inhibitors combined with immunotherapy or chemotherapy enhance antitumor efficacy 3. In osteosarcoma, transcription factor ZNF692 drives TNK2 expression to activate MEK/ERK signaling, promoting proliferation and invasion 4. Clinically, TNK2 represents an emerging therapeutic target, with multiple small-molecule inhibitors (AIM-100, (R)-9b, XMD8-87) demonstrating promise in preclinical cancer models 13.