TMPRSS11D (transmembrane serine protease 11D), also known as human airway trypsin-like protease (HAT), is a type II transmembrane serine protease with critical roles in viral infection and cancer progression. Primary Function: TMPRSS11D functions as a cell surface protease involved in proteolytic processing of viral and cellular substrates 1. It preferentially cleaves at the C-terminal side of arginine residues and exhibits optimum activity at pH 8.6 [UniProt]. Mechanism: The protease undergoes spontaneous autocleavage activation of its zymogen, which broadens its substrate specificity 2. TMPRSS11D activates viral spike proteins through proteolytic cleavage, facilitating cellular entry for SARS-CoV-2, influenza, rotaviruses, and coronavirus 229E 34. Additionally, it regulates immune function by inducing endoplasmic reticulum stress in myeloid-derived suppressor cells through ALR interaction 5. Disease Relevance: TMPRSS11D expression is significantly elevated in non-small cell lung cancer and cervical cancer, where it promotes cell proliferation, migration, and invasion via the PI3K/Akt pathway 67. Elevated oxygen exposure upregulates TMPRSS11D in respiratory epithelial cells, potentially increasing SARS-CoV-2 susceptibility 8. Clinical Significance: High TMPRSS11D expression independently predicts poor overall survival in lung cancer patients 6, making it a potential therapeutic target for both viral infections and cancer treatment.