Tumor recurrence poses a significant challenge for prognosis following tumor resection surgery. Recently, cancer immunotherapy has emerged as a promising therapeutic strategy with potential to combat tumor relapse. Current tumor immunotherapies mainly rely on antibodies to achieve immune regulation. The intrinsic issues of antibodies, such as high manufacturing costs and long development time, limit their applications in immunotherapy. Here, we present a bi-specific nanoparticle-based engager (BiNE) as an antibody alternative to regulate the cell-cell interactions for better cancer immunotherapy. BiNE is designed as a small-sized nanoparticle with two types of surface groups, mannose (Man) and phenylboronic acid (PBA), which bind to receptors on macrophages and tumor cells respectively. This enhances intercellular interactions, leading to the polarization of tumor-associated macrophages from an immunosuppressive phenotype (M2) to an inflammatory type (M1), and activates anti-tumor immune responses. Animal studies demonstrated that treatment with BiNE effectively inhibited tumor growth. Furthermore, applying BiNE at the surgical site after tumor removal reshaped the tumor microenvironment and prevented tumor recurrence, offering a promising strategy for improving surgical outcomes. In addition, by changing the functional groups on the surface, BiNE can regulate the interactions between various cells, becoming a novel platform for regulating biological processes alternative to antibodies.