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Comprehensive bioinformatics analyses have demonstrated that highly hypoxic TNBC tumors exhibited elevated T cell exhaustion, increased immune checkpoint molecule expression, and diminished responsiveness to immune checkpoint blockade (ICB). Consequently, strategies aimed at alleviating tumor hypoxia may effectively augment ICB therapy. Although ultrasound-targeted microbubble cavitation (UTMC) has been shown to reduce tumor hypoxia, the precise molecular mechanisms remain unclear. Here, we provide evidence that UTMC activated endothelial nitric oxide synthase (eNOS) through G protein\u2013coupled signaling, resembling pathways induced by fluid shear stress. UTMC-induced eNOS activation was largely Ca\n                    <jats:sup>2+<\/jats:sup>\n                    dependent and resulted in increased nitric oxide production. Enhanced nitric oxide generation was associated with improved tumor perfusion and reduced hypoxia. Combining UTMC with anti\u2013PD-L1 therapy markedly improved the tumor immune microenvironment, characterized by increased CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell infiltration, reduced T cell exhaustion, diminished regulatory T cell infiltration, increased macrophage polarization from an M2 to M1 phenotype, and elevated production of proinflammatory cytokines. Collectively, our findings identified UTMC as a promising adjunctive therapeutic approach to mitigate hypoxia and enhance the efficacy of anti\u2013PD-L1 immunotherapy in TNBC. These results support further translational evaluation of UTMC-based combination strategies in hypoxic TNBC.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.198349","type":"journal-article","created":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T16:01:01Z","timestamp":1775577661000},"source":"Crossref","is-referenced-by-count":0,"title":["Ultrasound-targeted microbubble cavitation enhances anti\u2013PD-L1 therapy in TNBC via eNOS-mediated reoxygenation"],"prefix":"10.1172","volume":"11","author":[{"given":"Zhiyu","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Ultrasound, First Affiliated Hospital of Harbin Medical University, Harbin, China."},{"name":"Laboratory of Medical Genetics, Harbin Medical University, Harbin, China."},{"name":"Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China, Ministry of Education, Harbin Medical University, Harbin, 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