免疫检查点阻断(ICB)单药治疗对于肝细胞癌(HCC)的生存益处较差，原因是免疫抑制性肿瘤微环境(TME)引起的ICB抗药性和免疫相关副作用导致的药物停用。因此，迫切需要同时重塑免疫抑制性TME和改善副作用的新策略。我们利用体外和原位HCC模型探索和展示了常规临床用药曲普利，显著征服免疫抑制性TME的新作用。我们确定了TA对肿瘤相关巨噬细胞(TAMs)和髓系来源的抑制细胞(MDSCs)中M2极化和多胺代谢的影响。在明确了TA的免疫调节效应后，我们引入了基于纳米医学的以肿瘤为靶点的药物传递策略，更好地利用TA，以逆转免疫抑制性TME并克服ICB抗药性用于HCC免疫疗法。我们发展了一种双pH敏感的纳米药物，同时携带TA和编程细胞死亡受体1抗体(aPD-1)，并在原位的HCC模型中评估了其肿瘤靶向药物传递和TME响应性药物释放的能力。最后，分析了我们结合TA和aPD-1的纳米药物的免疫调节效应、抗肿瘤治疗效应以及副作用。TA通过抑制TAMs和MDSCs中的M2极化和多胺代谢，发挥了征服免疫抑制性TME的新作用。成功合成了双pH敏感的纳米药物，同时携带TA和aPD-1。一方面，该纳米药物通过结合循环编程细胞死亡受体1阳性T细胞实现了肿瘤靶向药物传递，随后这些T细胞渗透到肿瘤中。另一方面，该纳米药物促进了酸性TME中的有效肿瘤内药物释放，释放aPD-1用于ICB，将TA包裹的纳米药物留在肿瘤组织中，以双重调节TAMs和MDSCs。由于TA和aPD-1的联合应用，以及高效的肿瘤靶向药物传递，我们的纳米药物有效地抑制了TAMs和MDSCs中的M2极化和多胺代谢，征服了免疫抑制性TME，这有助于在HCC上获得显著的ICB治疗疗效并降低副作用。 我们的新型肿瘤靶向纳米药物扩展了TA在肿瘤治疗中的应用，并具有打破ICB基础HCC免疫疗法僵局的巨大潜力。 ©作者(s)(或其雇主(s))2023年。在CC BY-NC下允许再利用。无商业再利用。由BMJ出版。

Immune checkpoint blockade (ICB) monotherapy provides poor survival benefit in hepatocellular carcinoma (HCC) due to ICB resistance caused by immunosuppressive tumor microenvironment (TME) and drug discontinuation resulting from immune-related side effects. Thus, novel strategies that can simultaneously reshape immunosuppressive TME and ameliorate side effects are urgently needed.Both in vitro and orthotopic HCC models were used to explore and demonstrate the new role of a conventional, clinically used drug, tadalafil (TA), in conquering immunosuppressive TME. In detail, the effect of TA on M2 polarization and polyamine metabolism in tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) was identified. After making clear the aforementioned immune regulatory effect of TA, we introduced a nanomedicine-based strategy of tumor-targeted drug delivery to make better use of TA to reverse immunosuppressive TME and overcome ICB resistance for HCC immunotherapy. A dual pH-sensitive nanodrug simultaneously carrying both TA and programmed cell death receptor 1 antibody (aPD-1) was developed, and its ability for tumor-targeted drug delivery and TME-responsive drug release was evaluated in an orthotopic HCC model. Finally, the immune regulatory effect, antitumor therapeutic effect, as well as side effects of our nanodrug combining both TA and aPD-1 were analyzed.TA exerted a new role in conquering immunosuppressive TME by inhibiting M2 polarization and polyamine metabolism in TAMs and MDSCs. A dual pH-sensitive nanodrug was successfully synthesized to simultaneously carry both TA and aPD-1. On one hand, the nanodrug realized tumor-targeted drug delivery by binding to circulating programmed cell death receptor 1-positive T cells and following their infiltration into tumor. On the other hand, the nanodrug facilitated efficient intratumoral drug release in acidic TME, releasing aPD-1 for ICB and leaving TA-encapsulated nanodrug to dually regulate TAMs and MDSCs. By virtue of the combined application of TA and aPD-1, as well as the efficient tumor-targeted drug delivery, our nanodrug effectively inhibited M2 polarization and polyamine metabolism in TAMs and MDSCs to conquer immunosuppressive TME, which contributed to remarkable ICB therapeutic efficacy with minimal side effects in HCC.Our novel tumor-targeted nanodrug expands the application of TA in tumor therapy and holds great potential to break the logjam of ICB-based HCC immunotherapy.© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.