中和促肿瘤炎症有望提高化学免疫联合治疗效果。本课题据此提出“三位一体”新策略，同时使用DTX杀肿瘤细胞，免疫检验点IDO抑制剂Indoximod解除肿瘤对T细胞的抑制，Bruton酪氨酸激酶抑制剂依鲁替尼解除促肿瘤炎症对T细胞的抑制。拟利用NGR靶向肿瘤部位，GLA靶向前列腺癌细胞，实现逐级靶向；pH敏感GLA-CA-PAMAM为载体制备载DTX纳米小粒，向肿瘤深层渗透；pH敏感PLH-PLL制备双载Indoximod及依鲁替尼混合胶束；纳米小粒与混合胶束组装构建“一箭三星”集成胶束，实现三药共载；利用电荷翻转、质子化、希夫碱键敏感断裂三种pH敏感模式实现三药依序释放。“一箭三星”集成胶束集三药共载、逐级靶向、依序释药、深层渗透等多功能，通过抑制免疫检验点、中和促肿瘤炎症双通道解除肿瘤免疫抑制，双效增强T细胞免疫，有望提高前列腺癌治疗效果，为临床开展“三位一体”化学免疫联合治疗奠定基础。

Chemoimmunotherapy is now the hot topic in cancer treatment, and it was reported that neutralizing tumor-promoting inflammation would be benefit for improving the efficacy of chemoimmunotherapy. In this project, a novel “three in one” strategy was proposed, in which cytotoxic drugs Docetaxel (DTX) was used to inhibit or kill tumor cells, Indoximod as an immune checkpoint indoleamine 2,3-dioxygenase inhibitor was expected to relieve immune suppression , while Ibrutinib as a Bruton’s tyrosine kinase inhibitor was selected to inhibit the tumor-infiltrating B lymphocytes, thus the immune suppression caused by tumor-promoting inflammation could be relieved. The “one rocket launch three satellites” assembled micelles were creatively designed to accomplish the novel “three in one” strategy. Stepwise-targeting ability is realized due to NGR peptide and GLA could target either tumor tissue or tumor cells, respectively. DTX loaded mini-nanoparticle was firstly prepared by pH sensitive material GLA-CA-PAMAM and achieved the deep penetration into tumor tissue. Meanwhile, Indoximod and Ibrutinib co-loaded hybrid micelles were obtained using pH sensitive materials PLH-PEG-NGR and PLH-PLL as carriers. Subsequently, the creative “one rocket launch three satellites” assembled micelles were formed by combining both mini-nanoparticles and hybrid micelles. All three drugs could be responsively released in sequence in the tumor tissues according to three different pH-sensitive modes, i.e. charge-reverse, protonation and schiff-bond sensitive abscission, respectively. In summary, the creative “one rocket launch three satellites” assembled micelles could integrate the advantages including three drugs co-loading, stepwise-targeting, multi-mode pH-sensitive and deep penetration. Furthermore, the tumor immune inhibitions were relieved in two channels and T cell responses were double reinforced, by means of inhibiting immune checkpoint and neutralizing tumor-promoting inflammation, therefore improve the therapeutic efficacy of prostate cancer. This novel “three in one” strategy would lay the foundation for the clinical development of chemoimmunotherapy.