Chemotherapy combined with immunotherapy (chemo-immunotherapy) has emerged as a critical strategy in tumor treatment. However, chemotherapy induced immune tolerance and the immunosuppressive tumor microenvironment limit its effectiveness. Secondary necrosis can generate additional immunogenic substances, enhancing the immunogenicity of tumor cells, but macrophage-mediated clearance of apoptotic cells inhibits the occurrence of secondary necrosis. In this study, a tumor-associated macrophage (TAM)-targeting nanohybrid system, SC@P@U, is designed by combining poly (lactic-co-glycolic acid) (PLGA)-loaded MerTK inhibitor UNC2025 (P@U) with saccharomyces cerevisiae-derived β-glucan (SC shell). This nanohybrid system specifically targets TAMs, preventing them from clearing apoptotic tumor cells induced by chemotherapy and inhibiting their polarization into immune-suppressive M2 macrophages. More importantly, it activates the macrophage STING pathway, further stimulating dendritic cells and initiating T cell-mediated immune responses. In vivo experiments demonstrated that SC@P@U, when combined with paclitaxel (PTX), significantly suppressed tumor growth, activated anti-tumor immunity, and, when used in conjunction with the immune checkpoint inhibitor αPD-1, markedly enhanced the anti-tumor effect. This strategy overcomes chemotherapy immune tolerance in traditional chemo-immunotherapy, reverses the immunosuppressive tumor microenvironment, and offers a promising approach to tumor treatment.