Restoration of tumor vascular integrity by P188 improves chemotherapy and immunotherapy efficacy in triple negative breast cancer

Tumor-associated vascular dysfunction is a major barrier limiting the efficacy of cancer therapies by impairing drug delivery, restricting immune-cell infiltration, and promoting hypoxia within the tumor microenvironment (TME). While anti-angiogenic therapies aim to suppress abnormal vessel formation, excessive vascular inhibition may further worsen hypoxia and therapeutic resistance. Here, we investigated whether restoration of endothelial integrity using Poloxamer 188 (P188), a membrane-stabilizing triblock copolymer, could improve vascular function and enhance therapeutic efficacy in triple-negative breast cancer (TNBC). In vitro, P188 prevented and reversed endothelial leakiness, restoring endothelial barrier integrity and enhancing tight junction formation, as demonstrated by increased Zonula occludens-1 (ZO-1) expression, a tight-junction protein, and sealed endothelial morphology. In vivo, fluorescently labeled P188 accumulated in TNBC tumors and significantly enhanced Dextran delivery, indicating improved vascular function and tumor perfusion. Although P188 showed no direct cytotoxic effect on TNBC cells and did not enhance Doxorubicin activity in vitro, combination treatment significantly suppressed tumor progression in vivo, while simultaneously reducing treatment-associated weight loss. Importantly, P188 also enhanced antitumor immunity. While P188 did not directly activate T cells or increase their cytotoxicity in vitro, it significantly increased T-cell infiltration into tumors in vivo and enhanced the therapeutic efficacy of adoptively transferred human normal peripheral blood mononuclear cell (PBMCs). Collectively, these findings demonstrate that restoration of tumor vascular integrity using P188 improves both chemotherapy and immunotherapy efficacy by enhancing therapeutic delivery and immune-cell infiltration. This study highlights vascular restoration as a promising therapeutic strategy for overcoming TME-mediated resistance in solid tumors.