{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T13:23:20Z","timestamp":1789046600615,"version":"build-2803163510"},"reference-count":112,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T00:00:00Z","timestamp":1788998400000},"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. Pharmacol."],"abstract":"<jats:p>\n                    Potassium (K\n                    <jats:sup>+<\/jats:sup>\n                    ) channels sustain immune-cell activation by coupling K\n                    <jats:sup>+<\/jats:sup>\n                    flux to membrane potential, Ca\n                    <jats:sup>2+<\/jats:sup>\n                    signaling, migration, and metabolic adaptation. In solid tumors, however, extracellular K\n                    <jats:sup>+<\/jats:sup>\n                    accumulation, adenosine, hypoxia, acidosis, oxidative stress, and lipid stress can disrupt ionic homeostasis and channel function. Here, we define an ionic checkpoint as a context-dependent regulatory state in which K\n                    <jats:sup>+<\/jats:sup>\n                    gradients, channel gating and trafficking, membrane potential, and subcellular channel localization determine whether immune cells cross the electrophysiological thresholds required for Ca\n                    <jats:sup>2+<\/jats:sup>\n                    signaling and effector function. We synthesize evidence across adaptive and innate immunity, emphasizing Kv1.3 and KCa3.1 in T- and natural killer-cell responses and dendritic-cell migration, and Kir and K2P channels in myeloid and NK-cell programs. We further examine plasma-membrane\u2013mitochondrial channel crosstalk, redox regulation, and spatial and temporal heterogeneity in the tumor immune microenvironment. Because the same channel may support lymphocyte function while sustaining tumor-cell survival or immunosuppressive myeloid states, neither universal activation nor universal inhibition is appropriate. Direct channel targeting is constrained by cell and organelle selectivity, whereas upstream tumor-microenvironment-directed strategies, particularly adenosine-axis interventions, are clinically more advanced but have not yet established direct restoration of K\n                    <jats:sup>+<\/jats:sup>\n                    channel-supported immune function. Translation will require functional and spatial biomarkers, precision patient stratification, and cell- or organelle-selective delivery.\n                  <\/jats:p>","DOI":"10.3389\/fphar.2026.1907228","type":"journal-article","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T12:14:51Z","timestamp":1789042491000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Potassium channels as an ionic checkpoint in tumor immunity"],"prefix":"10.3389","volume":"17","author":[{"given":"Huanle","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Gastrointestinal Surgery, The Second Hospital of Dalian Medical University","place":["Dalian, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, The Second Hospital of Dalian Medical University","place":["Dalian, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sufen","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Heze Third People\u2019s Hospital","place":["Heze, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaojiang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Surgery, The Second Hospital of Dalian Medical University","place":["Dalian, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixin","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Surgery, The Second Hospital of Dalian Medical University","place":["Dalian, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukun","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Surgery, The Second Hospital of Dalian Medical University","place":["Dalian, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Dalian No. 3 People\u2019s Hospital","place":["Dalian, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cong","family":"Xia","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Surgery, The Second Hospital of Dalian Medical University","place":["Dalian, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, The Second Hospital of Dalian Medical University","place":["Dalian, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e2518440","DOI":"10.1001\/jamanetworkopen.2025.18440","article-title":"Durvalumab alone or combined with novel agents for unresectable stage III non-small cell lung cancer: update from the COAST randomized clinical trial","volume":"8","author":"Aggarwal","year":"2025","journal-title":"JAMA Netw. 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