{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T14:29:32Z","timestamp":1788791372578,"version":"build-2803163510"},"reference-count":159,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,9,6]],"date-time":"2026-09-06T00:00:00Z","timestamp":1788652800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Science Development Fund of the Warsaw University of Life Sciences\u2014SGGW"},{"id":[{"id":"https:\/\/ror.org\/05srvzs48","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>The tumor microenvironment (TME) is an innervated and neurochemically active setting. To date, its cholinergic and GABAergic signaling have largely been analyzed as separate systems, contributing to inconsistent findings across the literature. We propose a Calcium-Gated Excitability (CAGE) model, in which \u03b17 nicotinic acetylcholine receptor (nAChR), \u03b14\u03b22 nAChR, GABA type A (GABAA) and type B (GABAB) receptors, and \u03b12\u03b4-1 converge on a single downstream variable: Ca2+ flux. \u03b17 conducts Ca2+ directly; \u03b14\u03b22 may redirect cholinergic input toward GABA release; GABAA and GABAB set the direction of the calcium response through intracellular chloride-gradient state and opposing intracellular signaling branches; \u03b12\u03b4-1 sets the gain that determines whether depolarization reaches a functional threshold. The resulting calcium-axis configuration, defined by receptor functional state, chloride-gradient status, \u03b12\u03b4-1 gain, and ligand exposure, shapes Ca2+ output and constrains downstream biological responses. Under this framework, some divergent findings on acetylcholine, nicotine, and GABA become testable consequences of distinct calcium-regulatory configurations. CAGE yields testable predictions, including nonlinear nAChR dose\u2013response curves, reversal of GABAA polarity, \u03b12\u03b4-1-dependent signal scaling, and spatially heterogeneous Ca2+ states. Studies evaluating nAChR- and GABA-receptor-targeted therapies without prior calcium-axis stratification may not be underpowered; they may be asking the wrong question.<\/jats:p>","DOI":"10.3390\/ijms27177937","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T13:53:28Z","timestamp":1788789208000},"page":"7937","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The CAGE Framework (Calcium-Gated Excitability): From Single Neurotransmitters to Calcium States in the Tumor Microenvironment"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-0163-1055","authenticated-orcid":false,"given":"Lena M.","family":"Rudy","sequence":"first","affiliation":[{"name":"Scientific Society of Veterinary Medicine Students, Warsaw University of Life Sciences\u2014SGGW, Nowoursynowska 159, 02-776 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5479-207X","authenticated-orcid":false,"given":"Micha\u0142 M.","family":"Godlewski","sequence":"additional","affiliation":[{"name":"Department of Physiological Sciences, Warsaw University of Life Sciences\u2014SGGW, Nowoursynowska 159, 02-776 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1016\/j.ccell.2023.02.016","article-title":"The Evolving Tumor Microenvironment: From Cancer Initiation to Metastatic Outgrowth","volume":"41","author":"Joyce","year":"2023","journal-title":"Cancer Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"R921","DOI":"10.1016\/j.cub.2020.06.081","article-title":"The Tumor Microenvironment","volume":"30","author":"Anderson","year":"2020","journal-title":"Curr. 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