Liu Zefan, Zhang Yajun, Huang Jinyu, Wang Yan, Kang Xin
Department of General Surgery, First People's Hospital of Shuangliu District, Chengdu, China.
Front Pharmacol. 2023 May 9;14:1154392. doi: 10.3389/fphar.2023.1154392. eCollection 2023.
Small molecule drugs are the next-generation of immune checkpoint inhibitors (ICIs), but their therapeutic outcomes remain unsatisfactory for a long time. Herein, we proposed a combinatory regimen that delivered a small molecule ICI and an immunogenic cell death inducer in an formed hydrogel scaffold based on thermosensitive materials (Pluronic F127). This platform increased the tumor retention of administrated small molecules, creating more opportunities for the interaction between drugs and tumor cells. We found that atorvastatin (ATO) effectively downregulated the expression of programmed death ligand 1 (PD-L1) and reversed compensative PD-L1 upregulation after cyclophosphamide (CTX) chemotherapy on CT26 colon tumors. CTX not only killed tumor cells to reduce the tumor burden, but also release damage-associated molecular patterns (DAMPs) to stimulate T cell immunity, therefore amplifying statin-mediated immunotherapy. The platform reported in this study might be promising to overcome the limitation of small molecule ICIs with short retention time and potentiate tumor chemo-immunotherapy.
小分子药物是下一代免疫检查点抑制剂（ICI），但其治疗效果长期以来仍不尽人意。在此，我们提出了一种联合方案，该方案基于热敏材料（泊洛沙姆F127）在形成的水凝胶支架中递送小分子ICI和免疫原性细胞死亡诱导剂。该平台增加了给药小分子在肿瘤中的滞留时间，为药物与肿瘤细胞之间的相互作用创造了更多机会。我们发现，阿托伐他汀（ATO）可有效下调程序性死亡配体1（PD-L1）的表达，并逆转环磷酰胺（CTX）化疗后CT26结肠肿瘤中PD-L1的代偿性上调。CTX不仅杀死肿瘤细胞以减轻肿瘤负担，还释放损伤相关分子模式（DAMP）以刺激T细胞免疫，从而增强他汀介导的免疫治疗。本研究报道的平台可能有望克服小分子ICI保留时间短的局限性，并增强肿瘤化学免疫治疗。
