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The long-term survival of osteosarcoma has remained unchanged in the last several decades. Immunotherapy is proved to be a promising therapeutic strategy against osteosarcoma, especially for those with metastasis. Our previous study explored the sensibilization of zoledronate (ZOL) in γδ T cell-mediated cytotoxicity against osteosarcoma, but we have not yet elucidated the specific mechanism. Besides, high concentration is required to achieve these effects, whereas plasma ZOL concentration declines rapidly in the circulation. Valproic acid (VPA), a histone deacetylase inhibitor commonly used as the antiepileptic drug, has attracted much attention due to its synergistic antitumor efficacy with chemotherapy or immunotherapy. Here, we demonstrated that VPA combined with ZOL revealed the synergistic effect in enhancing antitumor efficacy of γδ T cells against osteosarcoma cells. This enhancement was mainly TCR-mediated and largely dependent on granule exocytose pathway. Of note, our findings indicated that ZOL sensitized osteosarcoma cells to γδ T cells by increasing the accumulation of the mevalonate pathway intermediates, which could be facilitated by VPA. We also found that this combination had similar effects on primary osteosarcoma cells. All the results suggested that VPA combined with ZOL could reduce the dose required to achieve a significant antitumor effect of γδ T cells, promoting it to be a novel therapy against osteosarcoma.

近年来，骨肉瘤的长期生存率未发生显著变化。免疫疗法已被证实是针对骨肉瘤的一种有潜力的治疗策略，尤其对发生转移的患者而言。本研究之前探讨了唑来膦酸（ZOL）在γδ T细胞介导的细胞毒性对骨肉瘤的敏化作用，然而，我们尚未阐明其具体机制。此外，为实现这些效果，需要高浓度的药物，而血浆中ZOL的浓度在循环中迅速下降。丙戊酸（VPA），作为一种常用作抗癫痫药物的组蛋白脱乙酰化酶抑制剂，因其与化疗或免疫疗法的协同抗肿瘤效应而备受关注。在本研究中，我们证明了VPA与ZOL的联合使用在增强γδ T细胞对骨肉瘤细胞的抗肿瘤效应方面表现出协同作用。这种增强主要是由T细胞受体介导的，并且很大程度上依赖于颗粒外排途径。值得注意的是，我们的研究结果表明，ZOL通过增加异戊二酸途径中间体的积累来敏化骨肉瘤细胞对γδ T细胞的反应，而这种作用可以由VPA促进。我们还发现，这种联合治疗对原发骨肉瘤细胞也具有类似效果。所有这些结果均表明，VPA与ZOL的联合使用可以降低实现显著的抗肿瘤效应所需的剂量，从而使其成为治疗骨肉瘤的一种新型疗法。