{"doi":"10.1016/j.tranon.2025.102309","title":"Timp2 loss-of-function mutation and TIMP2 treatment in a murine model of NSCLC: Modulation of immunosuppression and oncogenic signaling","abstract":"• TIMP2 mutation increases lung tumor growth and mortality in a murine model. • Recombinant TIMP2 reduces primary tumor growth in both mutant and wild-type mice. • TIMP2 normalizes transcriptome; affecting oncogenic mediators and immune modulators. • TIMP2 also reduces cell-stress responses at metastatic sites. • Study highlights TIMP2′s potential as an adjuvant therapy for lung cancer. Mounting evidence suggests that the tissue inhibitor of metalloproteinases-2 (TIMP2) can reduce tumor burden and metastasis. However, the demonstration of such anti-tumor activity and associated mechanisms using in vivo tumor models is lacking. The effects of a Timp2 functional mutation and administration of recombinant TIMP2 were examined in both orthotopic and heterotopic murine models of lung cancer using C57Bl/6 syngeneic Lewis Lung 2-luciferase 2 cells (LL2-Luc2) cells. Mice harboring a functional mutation of TIMP2 (mT2) display markedly increased primary lung tumor growth, increased mortality, enriched vasculature, and enhanced infiltration of pro-tumorigenic, immunosuppressive myeloid cells. Treatment with recombinant TIMP2 reduced primary tumor growth in both mutant and wild-type (wt) mice. Comparison of transcriptional profiles of lung tissues from tumor-free, wt versus mT2 mice reveals only minor changes. However, lung tumor-bearing mice of both genotypes demonstrate significant genotype-dependent changes in gene expression following treatment with TIMP. In tumor-bearing wt mice, TIMP2 treatment reduced the expression of upstream oncogenic mediators, whereas treatment of mT2 mice resulted in an immunomodulatory phenotype. A heterotopic subcutaneous model generating metastatic pulmonary tumors demonstrated that daily administration of recombinant TIMP2 significantly reduces the expression of heat shock proteins, suggesting a reduction of cell-stress responses. In summary, we describe how TIMP2 exerts novel, anti-tumor effects in a murine model of lung cancer and that rTIMP2 treatment supports a normalizing effect on the tumor microenvironment. Our findings show that TIMP2 treatment demonstrates significant potential as an adjuvant in the treatment of NSCLC.","journal":"Translational Oncology","year":2025,"id":561395,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9557,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":670695,"name":"Sarvesh Kumar","orcid":"0000-0001-6904-734X","position":1,"is_corresponding":false},{"id":703186,"name":"Tej Pratap Singh","orcid":"0000-0002-0122-1089","position":2,"is_corresponding":false},{"id":400996,"name":"Yueqin Liu","orcid":null,"position":3,"is_corresponding":false},{"id":1171195,"name":"Sandra Jensen","orcid":null,"position":4,"is_corresponding":false},{"id":706599,"name":"Anandã Chowdhury","orcid":"0000-0002-2016-3697","position":5,"is_corresponding":false},{"id":1058162,"name":"Sasha Coates-Park","orcid":"0009-0005-2291-5337","position":6,"is_corresponding":false},{"id":1170858,"name":"Joshua A. Rich","orcid":"0000-0002-2206-5214","position":7,"is_corresponding":false},{"id":882602,"name":"Sadeechya Gurung","orcid":null,"position":8,"is_corresponding":false},{"id":384684,"name":"Yu Fan","orcid":"0000-0002-7473-6104","position":9,"is_corresponding":false},{"id":418276,"name":"Daoud Meerzaman","orcid":"0000-0002-0129-5256","position":10,"is_corresponding":false},{"id":881695,"name":"William G. Stetler‐Stevenson","orcid":"0000-0002-5500-5808","position":11,"is_corresponding":false},{"id":881693,"name":"David Peeney","orcid":"0000-0002-9126-9923","position":0,"is_corresponding":true}],"reference_count":58,"raw_metadata":null,"created_at":"2026-07-19T02:55:58.259104Z","pmid":"39904284","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}