肿瘤相关巨噬细胞（TAMs）是实体肿瘤组织中最丰富的免疫细胞，通过释放支持肿瘤生长的细胞因子并削弱吞噬作用来限制抗肿瘤免疫。本研究构建了一种采用嵌合肽工程调控因子（ChiP-RS）的肿瘤免疫治疗方法，通过巨噬细胞极化和吞噬作用恢复来实现。ChiP-RS由巨噬细胞靶向嵌合肽（ChiP）负载Toll样受体激动剂（R848）和Src同源2（SH2）结构域含有型酪氨酸磷酸酶2（SHP-2）抑制剂（SHP099）来制备。其中，ChiP-RS更容易被TAMs内吞，将M2巨噬细胞转化为M1巨噬细胞以扭转免疫抑制微环境。此外，SHP-2的下调也可以促进M1巨噬细胞的吞噬消除作用，同时激活基于T细胞的抗肿瘤免疫，用于治疗转移性肿瘤。体外和体内实验证明ChiP-RS对转移性肿瘤具有优越的抑制作用而不会引起全身副作用。这种简单却有效的纳米平台为免疫治疗提供了复杂的协同作用，有助于促进转化性纳米医学的发展，用于转移性肿瘤治疗。

Tumor-associated macrophages (TAMs) are the most abundant immune cells in solid tumor tissues, which restrict antitumor immunity by releasing tumor-supporting cytokines and attenuating phagocytosis behaviors. In this work, a chimeric peptide engineered bioregulator (ChiP-RS) is constructed for tumor immunotherapy through macrophage polarization and phagocytosis restoration. ChiP-RS is fabricated by utilizing macrophage-targeting chimeric peptide (ChiP) to load Toll-like receptor agonists (R848) and Src homology 2 (SH2) domain-containing protein tyrosine phosphatase 2 (SHP-2) inhibitor (SHP099). Among which, ChiP-RS prefers to be internalized by TAMs, repolarizing M2 macrophages into M1 macrophages to reverse the immunosuppressive microenvironment. In addition, SHP-2 can be downregulated to promote phagocytotic elimination behaviors of M1 macrophages, which will also activate T cell-based antitumor immunity for metastatic tumor therapy. In vitro and in vivo findings demonstrate a superior suppression effect of ChiP-RS against metastatic tumors without systemic side effects. Such a simple but effective nanoplatform provides sophisticated synergism for immunotherapy, which may facilitate the development of translational nanomedicine for metastatic tumor treatment.