化疗抵抗是癌症患者治疗失败和死亡的主要原因。间充质基质细胞（MSCs）作为肿瘤微环境的一个重要组成部分，被认为能促进药物抵抗。然而，详细的机制尚待阐明。在这里，我们发现MSCs通过减少其肿瘤内积累使乳腺癌对阿霉素产生抵抗性。发现MSCs生成的主要细胞外基质产物透明质酸（HA）介导着其化疗抵抗效应。当透明质酸合成酶2（HAS2）被耗尽或抑制时，MSCs的化疗抵抗效应被废除。外源性透明质酸也能保护肿瘤移植物免受阿霉素的影响。分子动力学模拟分析表明，透明质酸主要通过疏水作用和氢键与阿霉素结合，从而减少其进入乳腺癌细胞。这一机制与透明质酸通过其细胞表面受体的化疗抵抗效应不同。发现血清中透明质酸水平与乳腺癌患者的化疗抵抗性呈正相关。我们的研究结果表明，透明质酸和阿霉素的结合动力学能赋予癌细胞化疗抵抗性。降低透明质酸的含量可能增强化疗的疗效。© 2023。作者在Springer Nature Limited的独家许可下。

Chemotherapy resistance represents a major cause of therapeutic failure and mortality in cancer patients. Mesenchymal stromal cells (MSCs), an integral component of tumor microenvironment, are known to promote drug resistance. However, the detailed mechanisms remain to be elucidated. Here, we found that MSCs confer breast cancer resistance to doxorubicin by diminishing its intratumoral accumulation. Hyaluronan (HA), a major extracellular matrix (ECM) product of MSCs, was found to mediate the chemoresistant effect. The chemoresistant effect of MSCs was abrogated when hyaluronic acid synthase 2 (HAS2) was depleted or inhibited. Exogenous HA also protected tumor grafts from doxorubicin. Molecular dynamics simulation analysis indicates that HA can bind with doxorubicin, mainly via hydrophobic and hydrogen bonds, and thus reduce its entry into breast cancer cells. This mechanism is distinct from the reported chemoresistant effect of HA via its receptor on cell surface. High HA serum levels were also found to be positively associated with chemoresistance in breast cancer patients. Our findings indicate that the HA-doxorubicin binding dynamics can confer cancer cells chemoresistance. Reducing HA may enhance chemotherapy efficacy.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.