{"gene":"TMPRSS11B","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2014,"finding":"HATL5 (TMPRSS11B) is a catalytically active serine protease that is inhibited by the Kunitz-type serine protease inhibitors HAI-1 and HAI-2, as well as by serpinA1. Full-length HATL5 localizes to the cell surface of cultured mammalian cells.","method":"In vitro protease activity assays with inhibitors (HAI-1, HAI-2, serpinA1); confocal microscopy for cell surface localization","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 1-2 / Weak — in vitro enzymatic activity demonstrated with inhibitor profiling and direct cell surface localization by microscopy, single lab, single study","pmids":["24498351"],"is_preprint":false},{"year":2018,"finding":"TMPRSS11B promotes solubilization (shedding) of Basigin, an obligate chaperone of the lactate monocarboxylate transporter MCT4, thereby enhancing lactate export and glycolytic (Warburg) metabolism to promote lung squamous cell carcinoma tumorigenesis.","method":"TMPRSS11B knockdown/inhibition in HBEC transformation assays and LUSC cell lines; soluble receptor screen; functional lactate export assays; tumor growth assays in vivo","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (cell-based protease activity, substrate identification, metabolic assays, in vivo tumor growth), single lab but mechanistic chain established","pmids":["30463017"],"is_preprint":false},{"year":2025,"finding":"TMPRSS11B knockdown in PDAC cells (Panc1, BxPc3) enhances lactate import through SLC16A1, while TMPRSS11B overexpression in T3M4 cells dampens SLC16A1-driven lactate uptake. These effects depend on both SLC16A1 and Basigin (BSG), placing TMPRSS11B upstream of a BSG–SLC16A1 axis controlling lactate transport.","method":"shRNA-mediated knockdown; TMPRSS11B overexpression; GFP/iLACCO1 fluorescent lactate uptake assay; gene silencing of SLC16A1 and BSG; colony formation and stem cell marker expression assays","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional rescue/epistasis with multiple genetic perturbations and direct lactate transport measurement, single lab","pmids":["40508207"],"is_preprint":false},{"year":2025,"finding":"Tmprss11b depletion in immunocompetent syngeneic mice significantly reduces tumor burden and triggers immune cell infiltration into LUSC tumors. Spatial transcriptomics and RNA FISH localize Tmprss11b expression specifically to Krt13+ hillock-like cells within LUSC tumors. Ultra-pH-sensitive nanoparticle imaging links TMPRSS11B activity to regions of tumor acidification, elevated lactate, and enrichment of immunosuppressive M2-like macrophages.","method":"Syngeneic mouse model with Tmprss11b depletion; RNA FISH; spatial transcriptomics; ultra-pH-sensitive nanoparticle imaging; metabolite analysis","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal in vivo and imaging methods in a single study; immunocompetent mouse model provides functional link to immune suppression","pmids":["41214366"],"is_preprint":false},{"year":2025,"finding":"TMPRSS11B promotes an acidified and immunosuppressive tumor microenvironment in LUSC, with Tmprss11b depletion reducing tumor burden and increasing immune infiltration in immunocompetent mice (preprint corroborating peer-reviewed EMBO reports findings).","method":"Syngeneic mouse model; ultra-pH-sensitive nanoparticle imaging; metabolite analysis; spatial transcriptomics","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — preprint with multiple orthogonal methods, substantially overlapping with peer-reviewed EMBO reports paper from same group","pmids":["40235980"],"is_preprint":true}],"current_model":"TMPRSS11B is a cell-surface type II transmembrane serine protease (inhibited by HAI-1, HAI-2, and serpinA1) that promotes glycolytic metabolism and tumor progression by cleaving and shedding Basigin (BSG), the obligate chaperone of MCT4/SLC16A3 and SLC16A1 lactate transporters, thereby enhancing lactate export in lung squamous cell carcinoma and dampening lactate import in pancreatic cancer; in vivo, TMPRSS11B activity acidifies the tumor microenvironment, enriches immunosuppressive M2-like macrophages, and suppresses anti-tumor immune infiltration."},"narrative":{"mechanistic_narrative":"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.","teleology":[{"year":2014,"claim":"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","pmids":["24498351"],"confidence":"Medium","gaps":["No physiological substrate identified at this stage","Single in vitro study, no in vivo context","No structural basis for catalysis or inhibition"]},{"year":2018,"claim":"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","pmids":["30463017"],"confidence":"High","gaps":["Direct proteolytic cleavage site on Basigin not mapped","Whether other surface substrates are processed remains unaddressed","Single lab"]},{"year":2025,"claim":"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","pmids":["40508207"],"confidence":"Medium","gaps":["Direction of metabolic outcome differs between cancer types and is not fully reconciled","Single lab","Cleavage-dependence not biochemically isolated from co-factor effects"]},{"year":2025,"claim":"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)","pmids":["41214366","40235980"],"confidence":"Medium","gaps":["Causal chain from acidification to M2 macrophage enrichment not mechanistically dissected","Cell-type specificity (Krt13+ hillock cells) origin and regulation unknown","Single group"]},{"year":null,"claim":"How TMPRSS11B activity is regulated in vivo and whether it processes substrates beyond Basigin remains open.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the protease","Cleavage site on Basigin unmapped","Endogenous activating proteases and physiological inhibitor balance undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[1,2]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,3]}],"complexes":[],"partners":["BSG","SLC16A1","HAI-1","HAI-2","SERPINA1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q86T26","full_name":"Transmembrane protease serine 11B","aliases":["Airway trypsin-like protease 5"],"length_aa":416,"mass_kda":46.3,"function":"Serine protease","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q86T26/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TMPRSS11B","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TMPRSS11B","total_profiled":1310},"omim":[],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"cervix","ntpm":105.8},{"tissue":"esophagus","ntpm":382.6},{"tissue":"vagina","ntpm":113.7}],"url":"https://www.proteinatlas.org/search/TMPRSS11B"},"hgnc":{"alias_symbol":["HATL5"],"prev_symbol":[]},"alphafold":{"accession":"Q86T26","domains":[{"cath_id":"3.30.70.960","chopping":"44-170","consensus_level":"high","plddt":94.8059,"start":44,"end":170},{"cath_id":"2.40.10.10","chopping":"188-416","consensus_level":"medium","plddt":94.2552,"start":188,"end":416}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86T26","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q86T26-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q86T26-F1-predicted_aligned_error_v6.png","plddt_mean":91.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TMPRSS11B","jax_strain_url":"https://www.jax.org/strain/search?query=TMPRSS11B"},"sequence":{"accession":"Q86T26","fasta_url":"https://rest.uniprot.org/uniprotkb/Q86T26.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q86T26/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86T26"}},"corpus_meta":[{"pmid":"32649023","id":"PMC_32649023","title":"COVID-19 and human spermatozoa-Potential risks for infertility and sexual transmission?","date":"2020","source":"Andrology","url":"https://pubmed.ncbi.nlm.nih.gov/32649023","citation_count":61,"is_preprint":false},{"pmid":"30463017","id":"PMC_30463017","title":"Transmembrane Protease TMPRSS11B Promotes Lung Cancer Growth by Enhancing Lactate Export and Glycolytic Metabolism.","date":"2018","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/30463017","citation_count":42,"is_preprint":false},{"pmid":"24498351","id":"PMC_24498351","title":"HATL5: a cell surface serine protease differentially expressed in epithelial cancers.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24498351","citation_count":22,"is_preprint":false},{"pmid":"33527022","id":"PMC_33527022","title":"Identification of key miRNA-gene pairs in gastric cancer through integrated analysis of mRNA and miRNA microarray.","date":"2021","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/33527022","citation_count":12,"is_preprint":false},{"pmid":"40508207","id":"PMC_40508207","title":"Transmembrane Protease Serine 11B Modulates Lactate Transport Through SLC16A1 in Pancreatic Ductal Adenocarcinoma-A Functional Link to Phenotype Heterogeneity.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40508207","citation_count":3,"is_preprint":false},{"pmid":"39917297","id":"PMC_39917297","title":"Epithelial and immune transcriptomic characteristics and possible regulatory mechanisms in asthma exacerbation: insights from integrated studies.","date":"2025","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/39917297","citation_count":3,"is_preprint":false},{"pmid":"41214366","id":"PMC_41214366","title":"TMPRSS11B promotes an acidified microenvironment and immune suppression in squamous lung cancer.","date":"2025","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/41214366","citation_count":2,"is_preprint":false},{"pmid":"40686951","id":"PMC_40686951","title":"Machine Learning-Based Analysis of Salivary Proteomic Signatures in Catathrenia.","date":"2025","source":"ACS omega","url":"https://pubmed.ncbi.nlm.nih.gov/40686951","citation_count":2,"is_preprint":false},{"pmid":"40580591","id":"PMC_40580591","title":"Identification of the differences in molecular networks between idiopathic pulmonary fibrosis and lung squamous cell carcinoma using machine learning.","date":"2025","source":"Computational biology and chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/40580591","citation_count":1,"is_preprint":false},{"pmid":"40271514","id":"PMC_40271514","title":"A comprehensive transcriptome based meta-analysis to unveil the aggression nexus of oral squamous cell carcinoma.","date":"2025","source":"Biochemistry and biophysics reports","url":"https://pubmed.ncbi.nlm.nih.gov/40271514","citation_count":1,"is_preprint":false},{"pmid":"40235980","id":"PMC_40235980","title":"Transmembrane Serine Protease TMPRSS11B promotes an acidified tumor microenvironment and immune suppression in lung squamous cell carcinoma.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/40235980","citation_count":0,"is_preprint":false},{"pmid":"41948683","id":"PMC_41948683","title":"Combined Transcriptomic and Proteomic Forecast Analyses for Potential Biomarkers of Smoking-Induced Benign and Malignant Transformation of Vocal Fold Lesions.","date":"2025","source":"World journal of otorhinolaryngology - head and neck surgery","url":"https://pubmed.ncbi.nlm.nih.gov/41948683","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8585,"output_tokens":1428,"usd":0.023588,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8144,"output_tokens":1980,"usd":0.04511,"stage2_stop_reason":"end_turn"},"total_usd":0.068698,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"HATL5 (TMPRSS11B) is a catalytically active serine protease that is inhibited by the Kunitz-type serine protease inhibitors HAI-1 and HAI-2, as well as by serpinA1. Full-length HATL5 localizes to the cell surface of cultured mammalian cells.\",\n      \"method\": \"In vitro protease activity assays with inhibitors (HAI-1, HAI-2, serpinA1); confocal microscopy for cell surface localization\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Weak — in vitro enzymatic activity demonstrated with inhibitor profiling and direct cell surface localization by microscopy, single lab, single study\",\n      \"pmids\": [\"24498351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TMPRSS11B promotes solubilization (shedding) of Basigin, an obligate chaperone of the lactate monocarboxylate transporter MCT4, thereby enhancing lactate export and glycolytic (Warburg) metabolism to promote lung squamous cell carcinoma tumorigenesis.\",\n      \"method\": \"TMPRSS11B knockdown/inhibition in HBEC transformation assays and LUSC cell lines; soluble receptor screen; functional lactate export assays; tumor growth assays in vivo\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (cell-based protease activity, substrate identification, metabolic assays, in vivo tumor growth), single lab but mechanistic chain established\",\n      \"pmids\": [\"30463017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TMPRSS11B knockdown in PDAC cells (Panc1, BxPc3) enhances lactate import through SLC16A1, while TMPRSS11B overexpression in T3M4 cells dampens SLC16A1-driven lactate uptake. These effects depend on both SLC16A1 and Basigin (BSG), placing TMPRSS11B upstream of a BSG–SLC16A1 axis controlling lactate transport.\",\n      \"method\": \"shRNA-mediated knockdown; TMPRSS11B overexpression; GFP/iLACCO1 fluorescent lactate uptake assay; gene silencing of SLC16A1 and BSG; colony formation and stem cell marker expression assays\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional rescue/epistasis with multiple genetic perturbations and direct lactate transport measurement, single lab\",\n      \"pmids\": [\"40508207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Tmprss11b depletion in immunocompetent syngeneic mice significantly reduces tumor burden and triggers immune cell infiltration into LUSC tumors. Spatial transcriptomics and RNA FISH localize Tmprss11b expression specifically to Krt13+ hillock-like cells within LUSC tumors. Ultra-pH-sensitive nanoparticle imaging links TMPRSS11B activity to regions of tumor acidification, elevated lactate, and enrichment of immunosuppressive M2-like macrophages.\",\n      \"method\": \"Syngeneic mouse model with Tmprss11b depletion; RNA FISH; spatial transcriptomics; ultra-pH-sensitive nanoparticle imaging; metabolite analysis\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal in vivo and imaging methods in a single study; immunocompetent mouse model provides functional link to immune suppression\",\n      \"pmids\": [\"41214366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TMPRSS11B promotes an acidified and immunosuppressive tumor microenvironment in LUSC, with Tmprss11b depletion reducing tumor burden and increasing immune infiltration in immunocompetent mice (preprint corroborating peer-reviewed EMBO reports findings).\",\n      \"method\": \"Syngeneic mouse model; ultra-pH-sensitive nanoparticle imaging; metabolite analysis; spatial transcriptomics\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — preprint with multiple orthogonal methods, substantially overlapping with peer-reviewed EMBO reports paper from same group\",\n      \"pmids\": [\"40235980\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"TMPRSS11B is a cell-surface type II transmembrane serine protease (inhibited by HAI-1, HAI-2, and serpinA1) that promotes glycolytic metabolism and tumor progression by cleaving and shedding Basigin (BSG), the obligate chaperone of MCT4/SLC16A3 and SLC16A1 lactate transporters, thereby enhancing lactate export in lung squamous cell carcinoma and dampening lactate import in pancreatic cancer; in vivo, TMPRSS11B activity acidifies the tumor microenvironment, enriches immunosuppressive M2-like macrophages, and suppresses anti-tumor immune infiltration.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #1]. 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 [#0]. 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 [#1]; in pancreatic cancer cells it acts upstream of a BSG\\u2013SLC16A1 axis, with its activity dampening SLC16A1-driven lactate import in a manner dependent on both SLC16A1 and BSG [#2]. 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 [#3]. No structural model of the protease or its catalytic engagement with Basigin has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro protease activity assays with HAI-1, HAI-2 and serpinA1 inhibitors plus confocal localization in cultured mammalian cells\",\n      \"pmids\": [\"24498351\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No physiological substrate identified at this stage\",\n        \"Single in vitro study, no in vivo context\",\n        \"No structural basis for catalysis or inhibition\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"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.\",\n      \"evidence\": \"TMPRSS11B knockdown/inhibition in HBEC transformation and LUSC lines, soluble receptor screen, lactate export assays, and in vivo tumor growth\",\n      \"pmids\": [\"30463017\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct proteolytic cleavage site on Basigin not mapped\",\n        \"Whether other surface substrates are processed remains unaddressed\",\n        \"Single lab\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Genetic epistasis in pancreatic cancer cells generalized the mechanism, placing TMPRSS11B upstream of a BSG\\u2013SLC16A1 axis that controls lactate import as well as export.\",\n      \"evidence\": \"shRNA knockdown and overexpression in PDAC lines with fluorescent lactate uptake assays and SLC16A1/BSG silencing\",\n      \"pmids\": [\"40508207\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direction of metabolic outcome differs between cancer types and is not fully reconciled\",\n        \"Single lab\",\n        \"Cleavage-dependence not biochemically isolated from co-factor effects\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"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.\",\n      \"evidence\": \"Syngeneic Tmprss11b-depletion mouse model, RNA FISH, spatial transcriptomics, ultra-pH-sensitive nanoparticle imaging and metabolite analysis (peer-reviewed plus corroborating preprint)\",\n      \"pmids\": [\"41214366\", \"40235980\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Causal chain from acidification to M2 macrophage enrichment not mechanistically dissected\",\n        \"Cell-type specificity (Krt13+ hillock cells) origin and regulation unknown\",\n        \"Single group\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TMPRSS11B activity is regulated in vivo and whether it processes substrates beyond Basigin remains open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural model of the protease\",\n        \"Cleavage site on Basigin unmapped\",\n        \"Endogenous activating proteases and physiological inhibitor balance undefined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"BSG\", \"SLC16A1\", \"HAI-1\", \"HAI-2\", \"serpinA1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":4,"faith_total":4,"faith_pct":100.0}}