{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T22:25:25Z","timestamp":1761171925235,"version":"build-2065373602"},"reference-count":57,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T00:00:00Z","timestamp":1761091200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The tumor microenvironment (TME) is characterized by high lactate and proton accumulation resulting from glycolytic metabolism. While acidosis is known to influence immune and stromal cells, its direct effects on erythrocytes\u2014the most abundant circulating cells\u2014remain underexplored.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>An integrative review of cancer metabolism, erythrocyte physiology, and lactate transport systems was conducted using PubMed and Web of Science. From this synthesis, the CILLO-E hypothesis (Cancer-Induced Lactate Load on Erythrocytes) was formulated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The hypothesis proposes that lactate and protons enter erythrocytes via MCT1, leading to intracellular acidification. This process disrupts glycolytic enzymes, reduces ATP production, and impairs Na\n                      <jats:sup>+<\/jats:sup>\n                      \/K\n                      <jats:sup>+<\/jats:sup>\n                      -ATPase and Ca\u00b2\n                      <jats:sup>+<\/jats:sup>\n                      -ATPase activity. Energy depletion causes Ca\u00b2\n                      <jats:sup>+<\/jats:sup>\n                      overload, which activates scramblase and inhibits flippase, resulting in PS exposure and premature eryptosis. In parallel, reduced 2,3-BPG synthesis alters hemoglobin\u2013oxygen affinity, exacerbating hypoxia. Together, these mechanisms provide a biochemical explanation for the normocytic\u2013normochromic anemia frequently observed in cancer. Importantly, cancer-associated anemia is multifactorial, and CILLO-E should be viewed not as a comprehensive explanation but as a complementary mechanism acting through lactate-induced erythrocyte dysfunction.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The CILLO-E hypothesis reframes erythrocytes as active metabolic targets in the TME rather than passive oxygen carriers. By linking lactate-driven metabolic stress to erythrocyte dysfunction, anemia, and systemic hypoxia, it suggests a feedback loop that promotes tumor progression and highlights opportunities for erythrocyte-based biomarkers and therapeutic strategies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2025.1697588","type":"journal-article","created":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T04:17:49Z","timestamp":1761106669000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["The CILLO-E Hypothesis: Erythrocyte-Driven Acidosis and Early Eryptosis as Drivers of Cancer-Associated Anemia"],"prefix":"10.3389","volume":"15","author":[{"given":"H\u00fcseyin","family":"Ayd\u0131n","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,10,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","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":"B2","doi-asserted-by":"publisher","DOI":"10.3389\/fsurg.2023.1118403","article-title":"The value of lactate dehydrogenase to albumin ratio and immune inflammation biomarkers in colorectal cancer","volume":"10","author":"Wu","year":"2023","journal-title":"Front Surg"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2024.105564","article-title":"Lactate in breast cancer cells is associated with evasion, heterogeneity, and poor prognosis","volume":"300","author":"Liu","year":"2024","journal-title":"J Biol Chem"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1126\/science.abn7293","article-title":"Metabolic reprogramming and cancer progression","volume":"379","author":"Faubert","year":"2023","journal-title":"Science"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2009.358","article-title":"Q\u2019s next: The diverse functions of glutamine in metabolism, cell biology and cancer","volume":"29","author":"DeBerardinis","year":"2010","journal-title":"Oncogene"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1126\/science.123.3191.309","article-title":"On the origin of cancer cells","volume":"123","author":"Warburg","year":"1956","journal-title":"Science"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2015.12.001","article-title":"The Warburg effect: How does it benefit cancer cells? 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