TMPRSS11B

TMPRSS11B (HATL5) is a cell-surface type II transmembrane serine protease that drives glycolytic metabolism and tumor progression by controlling lactate transport through the Basigin axis (PMID:24498351, PMID:30463017). It is a catalytically active protease held in check by the Kunitz-type inhibitors HAI-1 and HAI-2 and by serpinA1, and localizes to the cell surface (PMID:24498351). Mechanistically, TMPRSS11B promotes shedding (solubilization) of Basigin, the obligate chaperone of the lactate transporter MCT4, thereby enhancing lactate export and Warburg-type glycolysis to fuel lung squamous cell carcinoma (PMID:30463017); in pancreatic cancer cells it acts upstream of a BSG–SLC16A1 axis, with its activity dampening SLC16A1-driven lactate import in a manner dependent on both SLC16A1 and BSG (PMID:40508207). In vivo, TMPRSS11B activity is expressed in Krt13+ hillock-like cells and acidifies the tumor microenvironment, enriching immunosuppressive M2-like macrophages and restricting anti-tumor immune infiltration, such that its depletion reduces tumor burden (PMID:41214366). No structural model of the protease or its catalytic engagement with Basigin has been characterized in the available corpus.

1. 2014 Medium

   Establishing that TMPRSS11B is an enzymatically active, inhibitor-regulated cell-surface protease was the necessary first step before any substrate or physiological role could be assigned.

   Evidence In vitro protease activity assays with HAI-1, HAI-2 and serpinA1 inhibitors plus confocal localization in cultured mammalian cells

   PMID:24498351

   Open questions at the time

   • No physiological substrate identified at this stage
   • Single in vitro study, no in vivo context
   • No structural basis for catalysis or inhibition
2. 2018 High

   Identification of Basigin as a shed substrate connected the protease to lactate transport and the Warburg effect, defining its tumor-promoting mechanism in lung squamous cell carcinoma.

   Evidence TMPRSS11B knockdown/inhibition in HBEC transformation and LUSC lines, soluble receptor screen, lactate export assays, and in vivo tumor growth

   PMID:30463017

   Open questions at the time

   • Direct proteolytic cleavage site on Basigin not mapped
   • Whether other surface substrates are processed remains unaddressed
   • Single lab
3. 2025 Medium

   Genetic epistasis in pancreatic cancer cells generalized the mechanism, placing TMPRSS11B upstream of a BSG–SLC16A1 axis that controls lactate import as well as export.

   Evidence shRNA knockdown and overexpression in PDAC lines with fluorescent lactate uptake assays and SLC16A1/BSG silencing

   PMID:40508207

   Open questions at the time

   • Direction of metabolic outcome differs between cancer types and is not fully reconciled
   • Single lab
   • Cleavage-dependence not biochemically isolated from co-factor effects
4. 2025 Medium

   In vivo work in immunocompetent mice linked TMPRSS11B-driven acidification to immune evasion, extending its role from cell-intrinsic metabolism to remodeling of the tumor microenvironment.

   Evidence Syngeneic Tmprss11b-depletion mouse model, RNA FISH, spatial transcriptomics, ultra-pH-sensitive nanoparticle imaging and metabolite analysis (peer-reviewed plus corroborating preprint)

   PMID:40235980 PMID:41214366

   Open questions at the time

   • Causal chain from acidification to M2 macrophage enrichment not mechanistically dissected
   • Cell-type specificity (Krt13+ hillock cells) origin and regulation unknown
   • Single group

• How TMPRSS11B activity is regulated in vivo and whether it processes substrates beyond Basigin remains open.
• No structural model of the protease
• Cleavage site on Basigin unmapped
• Endogenous activating proteases and physiological inhibitor balance undefined