{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T11:30:53Z","timestamp":1791545453702,"version":"4.3.4"},"reference-count":45,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T00:00:00Z","timestamp":1775606400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Median overall survival remains a central endpoint in oncology, but it can obscure a clinically meaningful long tail of patients with advanced solid tumors who survive well beyond the median. One biological context in which this pattern may be relevant is tumor microenvironment (TME) acidosis. Driven by aerobic glycolysis, hypoxia, impaired perfusion, and proton-export programs, acidic TME is increasingly implicated in invasion, therapeutic resistance, and immune suppression. This narrative review examines TME acidosis as the primary biological framework and considers long-tail survival as a clinical lens through which its implications may be interpreted. We summarize the biological basis and heterogeneity of acidic TME, review current approaches to clinical and translational assessment of tumor acidity, including acidoCEST magnetic resonance imaging (MRI) and positron emission tomography (PET)-based approaches, and discuss the potential and limitations of alkalization-oriented interventions such as buffering and diet-based strategies. Particular attention is given to the distinction between direct measurements of tumor acidity and clinically feasible but indirect markers such as urinary pH, which should not be interpreted as a direct surrogate for local tumor extracellular pH. From a science-based medicine perspective, long-tail survival is treated here as a hypothesis-generating clinical signal rather than proof of causality. Overall, alkalization-oriented interventions appear biologically plausible and clinically testable, but current clinical evidence remains limited and context-dependent. Future progress will require mechanistically informed biomarkers, careful safety evaluation, and trial designs capable of detecting delayed separation of survival curves and tail-oriented patterns of benefit.<\/jats:p>","DOI":"10.3390\/cancers18081193","type":"journal-article","created":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T11:41:18Z","timestamp":1775648478000},"page":"1193","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Tumor Microenvironment Acidosis and Alkalization-Oriented Interventions in Advanced Solid Tumors: A Narrative Review and Science-Based Medicine Perspective on Long-Tail Survival"],"prefix":"10.3390","volume":"18","author":[{"given":"Kazuyuki","family":"Suzuki","sequence":"first","affiliation":[{"name":"Department of Informatics, The University of Electro-Communications, 1-5-1 Chofugaoka, Chofu, Tokyo 182-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9856-9681","authenticated-orcid":false,"given":"Shion","family":"Kachi","sequence":"additional","affiliation":[{"name":"Japanese Society on Inflammation and Metabolism in Cancer, 119 Nishioshikouji-cho, Nakagyo-ku, Kyoto 604-0842, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiromi","family":"Wada","sequence":"additional","affiliation":[{"name":"Japanese Society on Inflammation and Metabolism in Cancer, 119 Nishioshikouji-cho, Nakagyo-ku, Kyoto 604-0842, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of Cancer: The Next Generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1158\/2159-8290.CD-21-1059","article-title":"Hallmarks of Cancer: New Dimensions","volume":"12","author":"Hanahan","year":"2022","journal-title":"Cancer Discov."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1889","DOI":"10.1200\/JCO.2014.56.2736","article-title":"Pooled Analysis of Long-Term Survival Data from Phase II and Phase III Trials of Ipilimumab in Unresectable or Metastatic Melanoma","volume":"33","author":"Schadendorf","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"4102","DOI":"10.1200\/JCO.2016.67.2477","article-title":"Programmed Death-Ligand 1 Expression and Response to the Anti\u2013PD-1 Antibody Pembrolizumab in Melanoma","volume":"34","author":"Daud","year":"2016","journal-title":"J. Clin. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1038\/nrc.2017.77","article-title":"Tumour Acidosis: From the Passenger to the Driver\u2019s Seat","volume":"17","author":"Corbet","year":"2017","journal-title":"Nat. Rev. Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1007\/s10555-019-09787-4","article-title":"Acidosis and Cancer: From Mechanism to Neutralization","volume":"38","author":"Estrella","year":"2019","journal-title":"Cancer Metastasis Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1126\/science.1160809","article-title":"Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation","volume":"324","author":"Cantley","year":"2009","journal-title":"Science"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1038\/nrc1478","article-title":"Why Do Cancers Have High Aerobic Glycolysis?","volume":"4","author":"Gatenby","year":"2004","journal-title":"Nat. Rev. Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1002\/jcp.22400","article-title":"pH Control Mechanisms of Tumor Survival and Growth","volume":"226","author":"Parks","year":"2011","journal-title":"J. Cell. Physiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1016\/j.cmet.2016.08.011","article-title":"LDHA-Associated Lactic Acid Production Blunts Tumor Immunosurveillance by T and NK Cells","volume":"24","author":"Brand","year":"2016","journal-title":"Cell Metab."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3812","DOI":"10.1182\/blood-2006-07-035972","article-title":"Inhibitory Effect of Tumor Cell\u2013Derived Lactic Acid on Human T Cells","volume":"109","author":"Fischer","year":"2007","journal-title":"Blood"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/j.bbcan.2019.01.003","article-title":"Targeting Acidity in Cancer and Diabetes","volume":"1871","author":"Gillies","year":"2019","journal-title":"Biochim. Biophys. Acta Rev. Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1524","DOI":"10.1158\/0008-5472.CAN-12-2796","article-title":"Acidity Generated by the Tumor Microenvironment Drives Local Invasion","volume":"73","author":"Estrella","year":"2013","journal-title":"Cancer Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2746","DOI":"10.1158\/0008-5472.CAN-11-1272","article-title":"Modulation of Microenvironment Acidity Reverses Anergy in Human and Murine Tumor-Infiltrating T Lymphocytes","volume":"72","author":"Calcinotto","year":"2012","journal-title":"Cancer Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1381","DOI":"10.1158\/0008-5472.CAN-15-1743","article-title":"Neutralization of Tumor Acidity Improves Antitumor Responses to Immunotherapy","volume":"76","author":"Kodumudi","year":"2016","journal-title":"Cancer Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"20130099","DOI":"10.1098\/rstb.2013.0099","article-title":"The Chemistry, Physiology and Pathology of pH in Cancer","volume":"369","author":"Swietach","year":"2014","journal-title":"Philos. Trans. R. Soc. Lond. B Biol. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Wada, H., Hamaguchi, R., and Uemoto, S. (2024). How Does Cancer Occur? How Should It Be Treated? Treatment from the Perspective of Alkalization Therapy Based on Science-Based Medicine. Biomedicines, 12.","DOI":"10.3390\/biomedicines12102197"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Hamaguchi, R., Narui, R., Morikawa, H., Okamoto, T., Uemoto, S., and Wada, H. (2022). Meaning and Significance of \u201cAlkalization Therapy for Cancer\u201d. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.1003588"},{"key":"ref_19","unstructured":"Prigogine, I. (1980). From Being to Becoming: Time and Complexity in the Physical Sciences, W.H. Freeman."},{"key":"ref_20","unstructured":"Nicolis, G., and Prigogine, I. (1977). Self-Organization in Nonequilibrium Systems: From Dissipative Structures to Order Through Fluctuations, Wiley."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1662","DOI":"10.1126\/science.1069492","article-title":"Systems Biology: A Brief Overview","volume":"295","author":"Kitano","year":"2002","journal-title":"Science"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1038\/nrc2329","article-title":"Integrative Mathematical Oncology","volume":"8","author":"Anderson","year":"2008","journal-title":"Nat. Rev. Cancer"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1038\/s41571-020-0411-1","article-title":"Integrating Evolutionary Dynamics into Cancer Therapy","volume":"17","author":"Gatenby","year":"2020","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Pollard, A.C., de la Cerda, J., Schuler, F.W., Pollard, T.R., Kotrotsou, A., Pisaneschi, F., and Pagel, M.D. (2022). Radiometal-Based PET\/MRI Contrast Agents for Sensing Tumor Extracellular pH. Biosensors, 12.","DOI":"10.3390\/bios12020134"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1017\/S0007114507862350","article-title":"Urine pH Is an Indicator of Dietary Acid-Base Load, Fruit and Vegetables and Meat Intakes: Results from the EPIC-Norfolk Population Study","volume":"99","author":"Welch","year":"2008","journal-title":"Br. J. Nutr."},{"key":"ref_26","unstructured":"Waddington, C.H. (1957). The Strategy of the Genes, Allen & Unwin."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Huang, S. (2010). Cell Lineage Determination in State Space: A Systems View Brings Flexibility to Dogmatic Canonical Rules. PLoS Biol., 8.","DOI":"10.1371\/journal.pbio.1000380"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1093\/jnci\/djab223","article-title":"Survivorship for Individuals Living with Advanced and Metastatic Cancer: A Synopsis and Call for Research","volume":"114","author":"Mollica","year":"2022","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Hamaguchi, R., Uemoto, S., and Wada, H. (2024). Editorial: The Impact of Alkalizing the Acidic Tumor Microenvironment to Improve Efficacy of Cancer Treatment, Volume II. Front. Oncol., 14.","DOI":"10.3389\/fonc.2024.1542787"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Rahman, M.A., Yadab, M.K., and Ali, M.M. (2024). Emerging Role of Extracellular pH in Tumor Microenvironment as a Therapeutic Target for Cancer Immunotherapy. Cells, 13.","DOI":"10.3390\/cells13221924"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1515\/oncologie-2024-0673","article-title":"Cancer Can Be Suppressed by Alkalizing the Tumor Microenvironment: The Effectiveness of \u201cAlkalization Therapy\u201d in Cancer Treatment","volume":"27","author":"Kachi","year":"2025","journal-title":"Oncologie"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1038\/s41416-025-02962-1","article-title":"Potentiation of Immune Checkpoint Blockade with a pH-Sensitizer as Monitored in Two Pre-Clinical Tumor Models with acidoCEST MRI","volume":"132","author":"Tran","year":"2025","journal-title":"Br. J. Cancer"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1186\/s12943-023-01900-0","article-title":"Acidosis-Mediated Increase in IFN-\u03b3-Induced PD-L1 Expression on Cancer Cells as an Immune Escape Mechanism in Solid Tumors","volume":"22","author":"Knopf","year":"2023","journal-title":"Mol. Cancer"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2260","DOI":"10.1158\/0008-5472.CAN-07-5575","article-title":"Bicarbonate Increases Tumor pH and Inhibits Spontaneous Metastases","volume":"69","author":"Robey","year":"2009","journal-title":"Cancer Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1016\/j.jconrel.2022.08.031","article-title":"Oral Administration of Sodium Bicarbonate Can Enhance the Therapeutic Outcome of Doxil\u00ae via Neutralizing the Acidic Tumor Microenvironment","volume":"350","author":"Ando","year":"2022","journal-title":"J. Control. Release"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1248\/bpb.b21-00076","article-title":"Increasing Tumor Extracellular pH by an Oral Alkalinizing Agent Improves Antitumor Responses of Anti-PD-1 Antibody: Implication of Relationships between Serum Bicarbonate Concentrations, Urinary pH, and Therapeutic Outcomes","volume":"44","author":"Ando","year":"2021","journal-title":"Biol. Pharm. Bull."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2623","DOI":"10.21873\/invivo.12080","article-title":"Effects of Alkalization Therapy on Chemotherapy Outcomes in Advanced Pancreatic Cancer: A Retrospective Case-Control Study","volume":"34","author":"Hamaguchi","year":"2020","journal-title":"In Vivo"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Isowa, M., Hamaguchi, R., Narui, R., Morikawa, H., Okamoto, T., and Wada, H. (2024). Potential of Alkalization Therapy for the Management of Metastatic Pancreatic Cancer: A Retrospective Study. Cancers, 16.","DOI":"10.20944\/preprints202310.1343.v1"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"eaaw5473","DOI":"10.1126\/science.aaw5473","article-title":"Metabolic Reprogramming and Cancer Progression","volume":"368","author":"Faubert","year":"2020","journal-title":"Science"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1007\/s11307-016-1029-7","article-title":"Clinical Translation of Tumor Acidosis Measurements with AcidoCEST MRI","volume":"19","author":"Jones","year":"2017","journal-title":"Mol. Imaging Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"4042","DOI":"10.1021\/acssensors.3c00851","article-title":"Clinically Translatable Hyperpolarized 13C Bicarbonate pH Imaging Method for Use in Prostate Cancer","volume":"8","author":"Mu","year":"2023","journal-title":"ACS Sens."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1158\/0008-5472.CAN-17-0492","article-title":"Lactic Acid Accumulation in the Tumor Microenvironment Suppresses 18F-FDG Uptake","volume":"79","author":"Kiru","year":"2019","journal-title":"Cancer Res."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Hosonuma, M., and Yoshimura, K. (2023). Association between pH regulation of the tumor microenvironment and immunological state. Front. Oncol., 13.","DOI":"10.3389\/fonc.2023.1175563"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"102677","DOI":"10.1016\/j.tranon.2026.102677","article-title":"Five-year survival of patients with non-small cell lung cancer treated with alkalization therapy","volume":"65","author":"Kachi","year":"2026","journal-title":"Transl. Oncol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e010438","DOI":"10.1136\/bmjopen-2015-010438","article-title":"Systematic Review of the Association between Dietary Acid Load, Alkaline Water and Cancer","volume":"6","author":"Fenton","year":"2016","journal-title":"BMJ Open"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/8\/1193\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T09:53:36Z","timestamp":1775728416000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/8\/1193"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,8]]},"references-count":45,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["cancers18081193"],"URL":"https:\/\/doi.org\/10.3390\/cancers18081193","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,8]]}}}