低剂量抗血管生成疗法已被证明能够增强肿瘤血管的正常化，从而改善缺氧水平、药物输送并促进抗癌免疫反应。肥大细胞已被确定为抵抗抗血管生成治疗的贡献者和异常新血管生成的促进者。在这项研究中，我们证明，通过同时用伊马替尼靶向瘤内肥大细胞并给予低剂量抗 VEGFR2 治疗，可以增强临床前模型中的抗肿瘤功效。因此，联合治疗克服了治疗耐药性，同时促进肿瘤血管正常化。值得注意的是，肿瘤切片的组织形态计量学分析表明，通过抑制肥大细胞可以改善血管灌注，尽管微血管密度显着降低，但与单独的抗 VEGFR2 治疗相比，联合治疗并未导致肿瘤缺氧水平升高。短期伊马替尼应用有效提高了抗肿瘤疗效，并且通过延长伊马替尼应用，肿瘤血管正常化得到进一步改善。肥大细胞耗竭和抗血管生成治疗的结合尚未得到详细研究，有望帮助克服治疗耐药性。需要进一步研究来探索它们对其他治疗方法的影响，并随后在临床环境中验证这些发现。© 2024 作者。约翰·威利出版的《国际癌症杂志》

Low-dose antiangiogenic therapies have demonstrated the ability to enhance normalization of tumor vessels, consequently improving hypoxia levels, drug delivery, and promoting anticancer immune responses. Mast cells have been identified as contributors to resistance against antiangiogenic therapy and facilitators of abnormal neoangiogenesis. In this study, we demonstrate that by simultaneously targeting intratumoral mast cells with Imatinib and administering low-dose anti-VEGFR2 therapy, antitumor efficacy can be enhanced in preclinical models. Thus, combinatory treatment overcomes therapy resistance, while concurrently promoting tumor vessel normalization. Notably, histomorphometric analysis of tumor sections revealed that vessel perfusion could be improved through mast cell inhibition and, despite a significantly reduced microvessel density, the combination treatment did not result in elevated tumor hypoxia levels compared to anti-VEGFR2 therapy alone. Short-term Imatinib application effectively increased antitumor efficacy, and by prolonging the application of Imatinib tumor vessel normalization was additionally improved. The combination of mast cell depletion and antiangiogenic treatments has not been investigated in detail and promises to help overcoming therapy resistance. Further studies will be required to explore their impact on other treatment approaches, and subsequently to validate these findings in a clinical setting.© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.