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Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Huayu Wan (HYW), a Traditional Chinese Medicine (TCM) formulation widely used in the clinical treatment of cancer, has demonstrated anti-tumor activity and augments chemotherapy efficacy by improving intratumoral drug delivery in non-small cell lung cancer. However, its efficacy and role in enhancing the response to immune checkpoint inhibitors (ICIs) for the treatment of triple-negative breast cancer (TNBC) remain unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To study the underlying mechanisms of HYW in enhancing the efficacy of ICIs for TNBC treatment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and methods<\/jats:title>\n                    <jats:p>\n                      In the 4T1 TNBC model, tumor growth, vascular structure\/function, immune cell infiltration, angiogenic factors and effector cytokines were evaluated using ultrasound imaging, immunohistochemistry, immunofluorescence, and ELISA. HYW\u2019s effects on angiogenesis were validated via\n                      <jats:italic>in vitro<\/jats:italic>\n                      assays (HUVEC proliferation, tube formation, wound healing and transwell invasion) under normal oxygen\/hypoxic conditions.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      TCGA data and network pharmacology identified VEGFA and the PI3K-Akt\/HIF-1 signaling axis as key targets of HYW. HYW significantly enhanced ICIs efficacy, with a tumor inhibition rate of 36.55% (vs. 5.01% for ICIs alone). Mechanistically, HYW: Normalized tumor vasculature: Restored the balance between proangiogenic and antiangiogenic factors (reduced VEGFA\/bFGF, increased TSP-1\/PF4), enhanced pericyte coverage and improved vascular maturity, and enhanced intratumoral perfusion (ultrasound imaging). Alleviated hypoxia: Inhibited HIF-1\u03b1 and reduced hypoxic regions (Hypoxyprobe staining). Remodeled the TME: Promoted CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell infiltration, increased effector cytokines (GZMB, IFN-\u03b3, TNF-\u03b1), and inhibited CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell exhaustion, downregulated exhaustion markers (Tim3, CD244, CD101, PD-L1). Inhibited PI3K-Akt-mTOR signaling: Reduced downstream HIF-1\u03b1\/VEGFA expression, breaking the hypoxia-angiogenesis-immunosuppression cycle.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>HYW enhances ICIs efficacy in TNBC by normalizing tumor vasculature and remodeling the tumor immune microenvironment (TIME), which provides a novel rationale for combining TCM with ICIs to improve TNBC treatment outcomes.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1824721","type":"journal-article","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T11:48:15Z","timestamp":1779191295000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Huayu Wan enhances immune checkpoint inhibitor efficacy in triple-negative breast cancer by normalizing tumor vasculature and 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