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In this article, we show that introducing deoxygenated SSRBCs into tumor microvessels treated with CA-4 and sublethal radiation (SR) produces a massive surge of tumor vaso-occlusion and broadly propagated tumor infarctions that engulfs treatment-resistant hypoxic niches and eradicates established lung tumors. Tumor regression was histologically corroborated by significant treatment effect. Treated tumors displayed disseminated microvessels occluded by tightly packed SSRBCs along with widely distributed pimidazole-positive hypoxic tumor cells. Humanized HbS-knockin mice (SSKI) but not HbA-knockin mice (AAKI) showed a similar treatment response underscoring SSRBCs as the paramount tumoricidal effectors. Thus, CA-4-SR\u2013remodeled tumor vessels license SSRBCs to produce an unprecedented surge of tumor vaso-occlusion and infarction that envelops treatment-resistant tumor niches resulting in complete tumor regression. Strategically deployed, these innovative tools constitute a major conceptual advance with compelling translational potential.<\/jats:p>","DOI":"10.1172\/jci.insight.125535","type":"journal-article","created":{"date-parts":[[2019,4,3]],"date-time":"2019-04-03T13:41:59Z","timestamp":1554298919000},"source":"Crossref","is-referenced-by-count":4,"title":["Exogenous sickle erythrocytes combined with vascular disruption trigger disseminated tumor vaso-occlusion and lung tumor regression"],"prefix":"10.1172","volume":"4","author":[{"given":"Chiao-Wang","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics, University of Alabama School of Medicine at Birmingham, Birmingham, Alabama, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Chen","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics, University of Alabama School of Medicine at Birmingham, Birmingham, 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