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Sialic acid derivatives (SA-derivatives) provide a nanomedicine platform for tumor-targeted delivery and treatment, and allow modulation of immunosuppressive tumor microenvironments with excellent therapeutic effects. Further, the multi-reactive groups of sialic acid (SA) contribute to the diversity of SA derivatives, which inevitably has implications for drug delivery systems and tumor therapy. However, relevant research remains lacking at present. Therefore, this study aimed to explore the effects of SA derivatives on SA-mediated drug delivery systems. Four SA-derivatives with different linking bonds (ester and amide bonds), different linking groups (hydroxyl and carboxyl), and different linking objects (cholesterol, octadecanoic acid, and octadecylamine) were synthesized and the respective SA derivative-modified doxorubicin liposomes were prepared. In-depth research was conducted using both cells and animals. We found that an SA-cholesterol conjugate (SA-CH; linking bond, amide bond; linking group, carboxyl; linking object, cholesterol) could improve liposome stability, reduce liposome adsorption to plasma proteins, and enhance the targeting of liposomes for killing tumor-associated macrophages (TAMs). Reduced TAMs in the immunosuppressive tumor microenvironment lead to enhanced tumor infiltration of CD8+ T cells. The results of this experiment provide clarity for research and development on SA-derivatives and a theoretical basis for clinical trials of SA-derivative-modified nanoparticles. [Display omitted] • Sialic acid-derivatives modified liposomes modulated immunosuppressive tumor microenvironment. • Sialic acid-derivatives linking bonds, linking groups, and linking objects influenced sialic acid mediated drug delivery systems. • Sialic acid-cholesterol conjugate could improve the stability of liposomes. • Sialic acid-cholesterol conjugate enhanced the targeting and killing of liposomes to tumor-associated macrophages. • The carboxyl group of sialic acid was not the key to affecting the anti-tumor therapeutic effect of sialic acid modified liposomes. [ABSTRACT FROM AUTHOR]