{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T11:11:19Z","timestamp":1777979479259,"version":"3.51.4"},"reference-count":46,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T00:00:00Z","timestamp":1777939200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"K-12 grant program","award":["K12CA090628"],"award-info":[{"award-number":["K12CA090628"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Tumor Treating Fields (TTFields) represent a novel, non-invasive therapeutic modality in oncology that employs low-intensity, intermediate-frequency alternating electric fields to disrupt mitotic processes and induce cancer cell death. This review integrates mechanistic, preclinical, and emerging clinical evidence supporting the integration of TTFields with immunotherapeutic strategies in pancreatic ductal adenocarcinoma (PDAC). Although immunotherapy has transformed the treatment landscape across multiple malignancies, its efficacy in PDAC remains limited due to the tumor\u2019s dense stroma, immunosuppressive microenvironment, and low immunogenicity. Preclinical investigations suggest that TTFields may potentiate immune-based therapies by enhancing antigen presentation, modulating the tumor microenvironment (TME), and attenuating mechanisms of immune resistance. We highlight studies evaluating TTFields in combination with immune checkpoint inhibitors (ICI), adoptive cellular therapies, and cancer vaccines, emphasizing their potential synergistic effects in PDAC. Clinically, the phase II PANOVA-2 trial demonstrated feasibility and encouraging survival outcomes with TTFields in combination with gemcitabine and nab-paclitaxel, providing the rationale for the ongoing phase III PANOVA-3 trial and the phase II PANOVA-4 trial, which combines TTFields with chemotherapy and atezolizumab. Additional clinical experiences in glioblastoma (GBM) and non-small-cell lung cancer (NSCLC) further substantiate the broader applicability of TTFields as an immunomodulatory adjunct. Remaining challenges include optimizing treatment sequencing, identifying predictive biomarkers, and managing TTFields-associated toxicities. Collectively, current evidence positions TTFields as a promising strategy to augment immunotherapy in PDAC, warranting further translational and clinical investigation to establish its role in reshaping therapeutic paradigms.<\/jats:p>","DOI":"10.3390\/cells15090845","type":"journal-article","created":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T10:01:30Z","timestamp":1777975290000},"page":"845","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Combining Tumor Treating Fields with Immunotherapy in Pancreatic Ductal Adenocarcinoma: Mechanisms, Preclinical Evidence, and Emerging Therapeutic Synergy"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7899-8438","authenticated-orcid":false,"given":"Douaa","family":"Albelal","sequence":"first","affiliation":[{"name":"Division of Hematology and Oncology, Mayo Clinic College of Medicine and Science, 4500 San Pablo Road South, Jacksonville, FL 32224, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hari Krishnareddy","family":"Rachamala","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, 4500 San Pablo Road South, Jacksonville, FL 32224, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-7881-4971","authenticated-orcid":false,"given":"Ishita","family":"Saha","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Mayo Clinic College of Medicine and Science, 4500 San Pablo Road South, Jacksonville, FL 32224, USA"},{"name":"Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, 4500 San Pablo Road South, Jacksonville, FL 32224, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3579-4317","authenticated-orcid":false,"given":"Santanu","family":"Bhattacharya","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, 4500 San Pablo Road South, Jacksonville, FL 32224, USA"},{"name":"Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine and Science, 4500 San Pablo Road South, Jacksonville, FL 32224, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1858-5054","authenticated-orcid":false,"given":"Debabrata","family":"Mukhopadhyay","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, 4500 San Pablo Road South, Jacksonville, FL 32224, USA"},{"name":"Department of Bioengineering, Mayo Clinic College of Medicine and Sciences, 4500 San Pablo Road South, Jacksonville, FL 32224, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hani M.","family":"Babiker","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Mayo Clinic College of Medicine and Science, 4500 San Pablo Road South, Jacksonville, FL 32224, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1053\/j.gastro.2024.09.009","article-title":"Dual Targeting of Syndecan-1 and Glucose Transporter-1 with a Novel Lipid-Based Delivery System Enhances Therapeutic Efficacy and Overcomes Chemoresistance in Pancreatic Ductal Adenocarcinoma","volume":"168","author":"Rachamala","year":"2025","journal-title":"Gastroenterology"},{"key":"ref_2","unstructured":"NIH (2026, March 01). Cancer Stat Facts: Pancreatic Cancer, Available online: https:\/\/seer.cancer.gov\/statfacts\/html\/pancreas.html."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e2350756","DOI":"10.1001\/jamanetworkopen.2023.50756","article-title":"NALIRIFOX, FOLFIRINOX, and Gemcitabine With Nab-Paclitaxel as First-Line Chemotherapy for Metastatic Pancreatic Cancer: A Systematic Review and Meta-Analysis","volume":"7","author":"Nichetti","year":"2024","journal-title":"JAMA Netw. Open"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1038\/s41392-021-00659-4","article-title":"The molecular biology of pancreatic adenocarcinoma: Translational challenges and clinical perspectives","volume":"6","author":"Wang","year":"2021","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"10152","DOI":"10.1073\/pnas.0702916104","article-title":"Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors","volume":"104","author":"Kirson","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1007\/s00262-020-02534-7","article-title":"Tumor-treating fields (TTFields) induce immunogenic cell death resulting in enhanced antitumor efficacy when combined with anti-PD-1 therapy","volume":"69","author":"Voloshin","year":"2020","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"279","DOI":"10.2478\/raon-2023-0044","article-title":"A review of tumor treating fields (TTFields): Advancements in clinical applications and mechanistic insights","volume":"57","author":"Li","year":"2023","journal-title":"Radiol. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2192","DOI":"10.1016\/j.ejca.2012.04.011","article-title":"NovoTTF-100A versus physician\u2019s choice chemotherapy in recurrent glioblastoma: A randomised phase III trial of a novel treatment modality","volume":"48","author":"Stupp","year":"2012","journal-title":"Eur. J. Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1038\/s41420-018-0130-x","article-title":"Tumor treating fields increases membrane permeability in glioblastoma cells","volume":"4","author":"Chang","year":"2018","journal-title":"Cell Death Discov."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.pan.2018.10.004","article-title":"Tumor treating fields in combination with gemcitabine or gemcitabine plus nab-paclitaxel in pancreatic cancer: Results of the PANOVA phase 2 study","volume":"19","author":"Rivera","year":"2019","journal-title":"Pancreatology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2350","DOI":"10.1200\/JCO-25-00746","article-title":"Tumor treating fields with gemcitabine and nab-paclitaxel for locally advanced pancreatic adenocarcinoma: Randomized, open-label, pivotal phase III PANOVA-3 study","volume":"43","author":"Babiker","year":"2025","journal-title":"J. Clin. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"TPS718","DOI":"10.1200\/JCO.2024.42.3_suppl.TPS718","article-title":"PANOVA-4 (EF-39): Pilot study of tumor treating fields (TTFields) therapy with atezolizumab, gemcitabine (GEM), and nab-paclitaxel (NabP) as first-line (1L) treatment for metastatic pancreatic ductal adenocarcinoma (mPDAC)","volume":"42","author":"Seufferlein","year":"2024","journal-title":"J. Clin. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"103535","DOI":"10.1016\/j.critrevonc.2021.103535","article-title":"Tumor-Treating Fields: A fourth modality in cancer treatment, new practice updates","volume":"168","author":"Arvind","year":"2021","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1158\/1078-0432.CCR-17-1117","article-title":"Tumor-Treating Fields: A Fourth Modality in Cancer Treatment","volume":"24","author":"Mun","year":"2018","journal-title":"Clin. Cancer Res."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Gera, N., Yang, A., Holtzman, T.S., Lee, S.X., Wong, E.T., and Swanson, K.D. (2015). Tumor Treating Fields Perturb the Localization of Septins and Cause Aberrant Mitotic Exit. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0125269"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"65125","DOI":"10.18632\/oncotarget.11372","article-title":"Tumor treating fields inhibit glioblastoma cell migration, invasion and angiogenesis","volume":"7","author":"Kim","year":"2016","journal-title":"Oncotarget"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e2451008","DOI":"10.1002\/eji.202451008","article-title":"Lipid nanoparticle-mediated RNA delivery for immune cell modulation","volume":"54","author":"Kim","year":"2024","journal-title":"Eur. J. Immunol."},{"key":"ref_18","first-page":"189183","article-title":"Pancreatic ductal adenocarcinoma cells reshape the immune microenvironment: Molecular mechanisms and therapeutic targets","volume":"1879","author":"Zhao","year":"2024","journal-title":"Biochim. Biophys. Acta BBA\u2014Rev. Cancer"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Guo, S., and Wang, Z. (2024). Unveiling the immunosuppressive landscape of pancreatic ductal adenocarcinoma: Implications for innovative immunotherapy strategies. Front. Oncol., 14.","DOI":"10.3389\/fonc.2024.1349308"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Qin, D., Zhang, Y., Shu, P., Lei, Y., Li, X., and Wang, Y. (2024). Targeting tumor-infiltrating tregs for improved antitumor responses. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1325946"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Martinez-Paniagua, M., Khan, S., Henning, N.W., Konagalla, S.V., and Patel, C.B. (2025). Optimized Methods to Quantify Tumor Treating Fields (TTFields)-Induced Permeabilization of Glioblastoma Cell Membranes. Methods Protoc., 8.","DOI":"10.3390\/mps8010010"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1007\/s12672-025-02861-0","article-title":"Advancement in tumor treating fields of mechanism, clinical applications, and future directions","volume":"16","author":"Zang","year":"2025","journal-title":"Discov. Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Lin, W., Wang, Y., Li, M., Feng, J., Yue, Y., Yu, J., Hu, Y., and Suo, Y. (2025). Tumor treating fields enhance anti-PD therapy by improving CCL2\/8 and CXCL9\/CXCL10 expression through inducing immunogenic cell death in NSCLC models. BMC Cancer, 25.","DOI":"10.1186\/s12885-025-13859-w"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e149258","DOI":"10.1172\/JCI149258","article-title":"Tumor Treating Fields dually activate STING and AIM2 inflammasomes to induce adjuvant immunity in glioblastoma","volume":"132","author":"Chen","year":"2022","journal-title":"J. Clin. Investig."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e163452","DOI":"10.1172\/JCI163452","article-title":"Understanding and therapeutically exploiting cGAS\/STING signaling in glioblastoma","volume":"134","author":"Low","year":"2024","journal-title":"J. Clin. Investig."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e176962","DOI":"10.1172\/jci.insight.176962","article-title":"Tumor treating fields suppress tumor cell growth and neurologic decline in models of spinal metastases","volume":"9","author":"Ledbetter","year":"2024","journal-title":"JCI Insight"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"202110","DOI":"10.1016\/j.arabjc.2021.103386","article-title":"The therapeutic effects of tumor treating fields on cancer and noncancerous cells","volume":"14","author":"Mahgoub","year":"2021","journal-title":"Arab. J. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"709","DOI":"10.4049\/jimmunol.2100100","article-title":"T Cells Retain Pivotal Antitumoral Functions under Tumor-Treating Electric Fields","volume":"207","author":"Diamant","year":"2021","journal-title":"J. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"100093","DOI":"10.1016\/j.mbm.2024.100093","article-title":"Application of biomechanics in tumor epigenetic research","volume":"2","author":"Wang","year":"2024","journal-title":"Mechanobiol. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.1016\/S1470-2045(23)00344-3","article-title":"Tumor Treating Fields therapy with standard systemic therapy versus standard systemic therapy alone in metastatic non-small-cell lung cancer following progression on or after platinum-based therapy (LUNAR): A randomised, open-label, pivotal phase 3 study","volume":"24","author":"Leal","year":"2023","journal-title":"Lancet Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"821","DOI":"10.2217\/imt-2016-0002","article-title":"Immune checkpoint inhibitor combinations in solid tumors: Opportunities and challenges","volume":"8","author":"Kyi","year":"2016","journal-title":"Immunotherapy"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"115671","DOI":"10.1016\/j.addr.2025.115671","article-title":"Classic versus innovative strategies for immuno-therapy in pancreatic cancer","volume":"225","author":"Formelli","year":"2025","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Mason, W.P., Harrison, R.A., Lapointe, S., Lim-Fat, M.J., MacNeil, M.V., Mathieu, D., Perry, J.R., Pitz, M.W., Roberge, D., and Tsang, D.S. (2025). Canadian Expert Consensus Recommendations for the Diagnosis and Management of Glioblastoma: Results of a Delphi Study. Curr. Oncol., 32.","DOI":"10.3390\/curroncol32040207"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"103645","DOI":"10.1016\/j.critrevonc.2022.103645","article-title":"Effectiveness of different treatment strategies in elderly patients with glioblastoma: An evidence map of randomized controlled trials","volume":"173","author":"Ma","year":"2022","journal-title":"Crit. Rev. Oncol.\/Hematol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"17562864221114355","DOI":"10.1177\/17562864221114355","article-title":"Characteristics and trends of globally registered glioma clinical trials in the past 16 years","volume":"15","author":"He","year":"2022","journal-title":"Ther. Adv. Neurol. Disord."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"30611","DOI":"10.1038\/s41598-025-16341-6","article-title":"Tumor treating fields suppress tumor cell growth and induce immunogenic cell death biomarkers in biliary tract cancer cell lines","volume":"15","author":"Yue","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1159\/000539719","article-title":"Long-Term Survival in Hepatocellular Carcinoma following Second-Line Tumor Treating Fields Therapy and Sorafenib: A Case Report","volume":"17","author":"Peinado","year":"2024","journal-title":"Case Rep. Oncol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3032","DOI":"10.1200\/JCO-25-00618","article-title":"Dual Immune Check Point Blockade in MGMT-Unmethylated Newly Diagnosed Glioblastoma: NRG Oncology BN007, a Randomized Phase II\/III Clinical Trial","volume":"43","author":"Lassman","year":"2025","journal-title":"J. Clin. Oncol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e61","DOI":"10.1016\/j.wneu.2021.12.091","article-title":"Efficacy and Safety of Bevacizumab Combined with Other Therapeutic Regimens for Treatment of Recurrent Glioblastoma: A Network Meta-Analysis","volume":"160","author":"Dongpo","year":"2022","journal-title":"World Neurosurg."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Arimoto, K.-i., Miyauchi, S., Liu, M., and Zhang, D.-E. (2024). Emerging role of immunogenic cell death in cancer immunotherapy. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1390263"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/s13045-024-01544-7","article-title":"Understanding the immunosuppressive microenvironment of glioma: Mechanistic insights and clinical perspectives","volume":"17","author":"Lin","year":"2024","journal-title":"J. Hematol. Oncol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2178791","DOI":"10.1080\/21645515.2023.2178791","article-title":"Biomarkers for predicting tumor response to PD-1 inhibitors in patients with advanced pancreatic cancer","volume":"19","author":"Qiu","year":"2023","journal-title":"Hum. Vaccin. Immunother."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Pan, D., Li, X., Qiao, X., and Wang, Q. (2025). Immunosuppressive tumor microenvironment in pancreatic cancer: Mechanisms and therapeutic targets. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1582305"},{"key":"ref_44","unstructured":"Eleazar, A. (2026, April 27). Daraxonrasib Earns FDA Orphan Drug Designation in Pancreatic Cancer, FDA Briefs, Available online: https:\/\/www.targetedonc.com\/view\/daraxonrasib-earns-fda-orphan-drug-designation-in-pancreatic-cancer."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1606","DOI":"10.1016\/j.ccell.2023.07.002","article-title":"KRASG12D inhibition reprograms the microenvironment of early and advanced pancreatic cancer to promote FAS-mediated killing by CD8+ T cells","volume":"41","author":"Mahadevan","year":"2023","journal-title":"Cancer Cell"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1007\/s11060-018-2858-9","article-title":"Acceptance and compliance of TTFields treatment among high grade glioma patients","volume":"139","author":"Onken","year":"2018","journal-title":"J. Neurooncol."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/9\/845\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T10:16:51Z","timestamp":1777976211000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/9\/845"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,5]]},"references-count":46,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["cells15090845"],"URL":"https:\/\/doi.org\/10.3390\/cells15090845","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,5]]}}}