{"doi":"10.3390/ijms262412086","title":"Pro-Inflammatory Macrophage Phenotype Skewing Induced by Tumor Treating Fields (TTFields)","abstract":"<jats:p>Tumor-associated macrophages (TAMs) are abundant in the tumor microenvironment (TME) and often adopt an M2-like immunosuppressive phenotype that promotes tumor growth. Reprogramming TAMs toward an M1-like pro-inflammatory state is an attractive therapeutic strategy. Tumor Treating Fields (TTFields), an FDA-approved, electric-field–based therapy, has recently been suggested to modulate immune responses in addition to its established anti-mitotic activity. Here, we investigated the direct effects of TTFields on macrophage activation and function. Murine bone marrow–derived macrophages (BMDMs) were polarized toward a pro-inflammatory M1-like phenotype or an anti-inflammatory M2-like phenotype and exposed to TTFields. TTFields rapidly activated guanine nucleotide exchange factor-H1 (GEF-H1), and downstream nuclear factor kappa B (NF-κB) and activator protein-1 (AP-1, via c-Jun N-terminal kinase [JNK]) signaling. Functionally, TTFields reprogrammed M2-like macrophages by increasing major histocompatibility complex class II (MHC-II) and cluster of differentiation 80 (CD80); reducing arginase-1 (Arg1); and elevating secretion of chemokine (C-X-C motif) ligand 1 (CXCL1), interleukin-6 (IL-6), IL-1β, and IL-12 subunit p70 (IL-12p70). In interferon gamma (IFN-γ)-primed macrophages, TTFields provided a secondary signal, driving myeloid differentiation primary response 88 (MyD88)-dependent expression of inducible nitric oxide synthase (iNOS). In vivo, TTFields reduced tumor burden in an orthotopic murine lung cancer model and increased iNOS expression in both M1-like and a subset of M2-like TAMs. These findings demonstrate that TTFields directly reprogram macrophages toward a pro-inflammatory phenotype, suggesting a novel immunomodulatory mechanism that may enhance anti-tumor immunity in the TME.</jats:p>","journal":"International Journal of Molecular Sciences","year":2025,"id":675407,"datarank":0.24141568686511508,"base_score":1.6094379124341003,"endowment":1.6094379124341003,"self_citation_contribution":0.24141568686511508,"citation_network_contribution":0.0,"self_endowment_contribution":0.24141568686511508,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":4,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1764674,"name":"Yiftah Barsheshet","orcid":"0000-0003-0883-8425","position":1,"is_corresponding":false},{"id":1764676,"name":"Tharwat Haj Khalil","orcid":"0000-0003-4258-0923","position":2,"is_corresponding":false},{"id":659997,"name":"Boris Brant","orcid":"0000-0001-9086-3368","position":3,"is_corresponding":false},{"id":1764677,"name":"Tali Voloshin","orcid":null,"position":4,"is_corresponding":false},{"id":1764678,"name":"Kerem Ben-Meir","orcid":"0000-0002-4834-641X","position":5,"is_corresponding":false},{"id":1764679,"name":"Simona Zisman Rosen","orcid":null,"position":6,"is_corresponding":false},{"id":787984,"name":"Moshe Giladi","orcid":"0000-0002-8589-6920","position":7,"is_corresponding":false},{"id":1764680,"name":"Uri Weinberg","orcid":null,"position":8,"is_corresponding":false},{"id":1764681,"name":"Yoram Palti","orcid":"0000-0003-4076-2184","position":9,"is_corresponding":false},{"id":1764672,"name":"Tal Kan","orcid":"0000-0002-9895-697X","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Pro-Inflammatory Macrophage Phenotype Skewing Induced by Tumor Treating Fields (TTFields)","abstract":"<jats:p>Tumor-associated macrophages (TAMs) are abundant in the tumor microenvironment (TME) and often adopt an M2-like immunosuppressive phenotype that promotes tumor growth. Reprogramming TAMs toward an M1-like pro-inflammatory state is an attractive therapeutic strategy. Tumor Treating Fields (TTFields), an FDA-approved, electric-field–based therapy, has recently been suggested to modulate immune responses in addition to its established anti-mitotic activity. Here, we investigated the direct effects of TTFields on macrophage activation and function. Murine bone marrow–derived macrophages (BMDMs) were polarized toward a pro-inflammatory M1-like phenotype or an anti-inflammatory M2-like phenotype and exposed to TTFields. TTFields rapidly activated guanine nucleotide exchange factor-H1 (GEF-H1), and downstream nuclear factor kappa B (NF-κB) and activator protein-1 (AP-1, via c-Jun N-terminal kinase [JNK]) signaling. Functionally, TTFields reprogrammed M2-like macrophages by increasing major histocompatibility complex class II (MHC-II) and cluster of differentiation 80 (CD80); reducing arginase-1 (Arg1); and elevating secretion of chemokine (C-X-C motif) ligand 1 (CXCL1), interleukin-6 (IL-6), IL-1β, and IL-12 subunit p70 (IL-12p70). In interferon gamma (IFN-γ)-primed macrophages, TTFields provided a secondary signal, driving myeloid differentiation primary response 88 (MyD88)-dependent expression of inducible nitric oxide synthase (iNOS). In vivo, TTFields reduced tumor burden in an orthotopic murine lung cancer model and increased iNOS expression in both M1-like and a subset of M2-like TAMs. These findings demonstrate that TTFields directly reprogram macrophages toward a pro-inflammatory phenotype, suggesting a novel immunomodulatory mechanism that may enhance anti-tumor immunity in the TME.</jats:p>","is_dataset_classified":null,"base_score":1.6094379124341003,"endowment":1.6094379124341003,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"41465516","pmcid":"PMC12733770","openalex_id":"https://openalex.org/W4417360781","authors":[],"funders":[{"funder_name":"Novocure Ltd.","grant_id":"","title":null}],"total_grants":1,"fwci":1.6082,"citation_percentile":0.85209019,"influential_citations":0,"citation_trend":[{"year":2026,"count":4}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://www.mdpi.com/1422-0067/26/24/12086/pdf?version=1765881885","host_type":"journal"},{"url":"https://www.mdpi.com/1422-0067/26/24/12086/pdf?version=1765881885","host_type":"publisher"},{"url":"https://www.mdpi.com/1422-0067/26/24/12086/pdf","host_type":"publisher"},{"url":"https://doi.org/10.3390/ijms262412086","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/41465516","host_type":"repository"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC12733770/","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC12733770","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC12733770?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":["Immune cells in cancer","Cancer Cells and Metastasis","Cancer Research and Treatments","Animals","Mice","Tumor Microenvironment","Phenotype","Macrophages","Macrophage Activation","Mice, Inbred C57BL","Tumor-Associated Macrophages","Inflammation","Cytokines","NF-kappa B"],"mesh_terms":["Tumor-Associated Macrophages","Animals","Inflammation","Macrophage Activation","Macrophages","Mice, Inbred C57BL","Phenotype","Cytokines","NF-kappa B","Mice","Tumor Microenvironment"],"keywords":["Tumor microenvironment","Chemokine","Phenotype","Tumor-associated macrophage","Reprogramming","Myeloid","Macrophage","M2 Macrophage","Immune system","CXCL10","Macrophage polarization","Immunomodulation","NF-κB","Non-small cell lung cancer (NSCLC)","MyD88","Gef-h1","Tumor Treating Fields (Ttfields)"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"cellosaurus"},{"name":"nct"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-17T00:20:03.939776Z","pmid":null,"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":[]}