尽管抗肿瘤免疫疗法取得了显著的成功，但由于效果有限，目前在多种恶性肿瘤中使用免疫检查点阻断抗体仍受到限制。癌细胞对免疫破坏的反应不佳是免疫检查点疗法失败的一个重要原因。我们假设将天然产物化学增敏剂与免疫检查点疗法结合，可能提高免疫反应。本研究中，我们采用温敏脂质体作为载体，将靶向二萜类衍生物与检查点阻断剂（抗CTLA-4）结合，以改善免疫治疗效果。在体内实验中，脂质体使两种药物载荷同时传递到肿瘤中。结果显示，脂质体抑制了调节性T细胞增殖，增强了细胞毒性T细胞浸润，并取得了深远的免疫治疗效果。另外，我们还发现另一种临床常用的免疫检查点抗体抗PD-1也受益于这种二萜类衍生物。值得注意的是，我们的机制研究揭示了靶向二萜类衍生物通过降低THBS1的表达，并破坏THBS1-CD47的相互作用，增加了癌细胞对免疫攻击的敏感性。总的来说，共递送THBS1抑制剂和检查点阻断剂有望提升癌症免疫治疗效果。我们首次发现THBS1抑制能够加强检查点疗法。©2023中国药学会和中国医学科学院药物研究所。由Elsevier B.V.进行制作和托管。

The use of checkpoint-blockade antibodies is still restricted in several malignancies due to the modest efficacy, despite considerable success in anti-tumor immunotherapy. The poor response of cancer cells to immune destruction is an essential contributor to the failure of checkpoint therapy. We hypothesized that combining checkpoint therapy with natural-product chemosensitizer could enhance immune response. Herein, a targeted diterpenoid derivative was integrated with the checkpoint blockade (anti-CTLA-4) to improve immunotherapy using thermosensitive liposomes as carriers. In vivo, the liposomes enabled the co-delivery of the two drug payloads into the tumor. Consequently, the regulatory T cell proliferation was restrained, the cytotoxic T cell infiltration was enhanced, and the profound immunotherapeutic effect was achieved. In addition, the immunotherapeutic effect of another clinically used checkpoint antibody, anti-PD-1, also benefited from the diterpenoid derivative. Of note, our mechanism study revealed that the targeted diterpenoid derivative increased the sensitivity of cancer cells to immune attack via THBS1 downregulation and the resultant destruction of THBS1-CD47 interaction. Collectively, co-delivering THBS1 inhibitor and checkpoint blockade is promising to boost cancer immunotherapy. We first time discovered that THBS1 suppression could strengthen checkpoint therapy.© 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.