TMPRSS2 (transmembrane serine protease 2) is a cell surface serine protease that serves dual roles in viral entry and cancer progression. As a viral entry factor, TMPRSS2 functions as a functional receptor for human coronavirus HKU1, where it binds to the viral spike protein with high affinity (Kd 334-137 nM) and works synergistically with sialoglycan receptors to facilitate viral entry 1. The protease also cleaves viral spike proteins of multiple coronaviruses including SARS-CoV-2 at the S1/S2 site, enabling membrane fusion and cellular infection 2. Critical residues D417 and Y469 in TMPRSS2's serine peptidase domain determine host range specificity for HKU1 entry 3. Beyond viral interactions, TMPRSS2 is implicated in cancer progression through the AhR-TMPRSS2-IL18 pathway, where PM2.5 exposure activates AhR to upregulate TMPRSS2 expression, promoting lung cancer cell proliferation and tumor growth 4. The protein is expressed in salivary glands and can be found in human saliva, potentially contributing to SARS-CoV-2 transmission 5. TMPRSS2's proteolytic activity is inhibited by compounds like nafamostat, making it an attractive therapeutic target for viral infections 2.