PD-1/PD-L1抗体对黑色素瘤等肿瘤具有较好药效，但存在应答率低、易导致自身免疫性疾病等问题；新近研究发现，大黄、金银花等清热解毒中药可重塑肿瘤相关巨噬细胞（将M2转化为M1型），显示了较好的应用前景；鉴于此，项目组基于中医药扶正祛邪理论，提出PD-1/PD-L1抗体联合TAM重塑治疗肿瘤的新思路。本项目拟从肿瘤微环境切入，选择大黄中有效成分-大黄素为代表药物，构建TAM靶向聚唾液酸纳米粒，与aPD1共载于pH敏感长循环脂质体中，形成大黄素/aPD1共载纳米递药系统；采用活体成像、免疫组化和ELISA等方法，以aPD1、大黄素纳米粒、单载脂质体为对照，从整体、组织、细胞及分子水平，以TAM靶向、TAM重塑、T细胞激活、组织靶向与抑瘤率等为指标，全面评价大黄素/aPD1共载纳米递药系统的TAM重塑、“免疫抑制”阻断机制，及其抗肿瘤协同作用。该研究有望为免疫联合治疗肿瘤提供一个新思路。

The application of PD-1/PD-L1 antibody, as single agent, has shown good efficacy in the treatment of tumors such as melanoma, but its response rate is low, which causes side effects such as autoimmune diseases. Recent studies reported that rhubarb, honeysuckle and other heat-clearing and anti-toxicant traditional Chinese medicine can remodel tumor-associated macrophages (converting M2 to M1 phenotype), which showed a good application prospect. Based on the “Fu zheng qu xie” theory of Traditional Chinese medicine, the project proposed a new idea that combined PD-1/PD-L1 antibody therapy with TAM remodeling to treat tumors. In the perspective of tumor microenvironment, emodin, an active ingredient of rhubarb, is used as a representative drug. We would construct polysialic acid -emodin nanoparticles with TAM targeting ability, which co-loaded with aPD1 in pH-sensitive long-circulating liposomes, to construct emodin/aPD1 co-loaded nano-drug delivery system. APD1, emodin nanoparticles and single-loaded liposomes as control, TAM targeting, TAM remodeling, T cells activation, tissue targeting and tumor inhibition rate would be examined from the whole body, tissue, cellular and molecular levels by means of in vivo imaging, immunohistochemistry and ELISA. The TAM remodeling, "immunosuppression" blocking mechanism and the anti-tumor synergy of emodin/aPD1 co-loaded nano-drug system would be comprehensively evaluated. The project would provide a new strategy for tumors combinatorial immunotherapy.