<p>Immune checkpoint inhibitor (ICI) therapy has become a hopeful treatment for triple-negative breast cancer (TNBC). However, most patients exhibit a low immune response. Tumor-associated fibroblasts (TAFs) suppress anti-tumor immune responses by encouraging the polarization of M2 macrophages, which diminishes the therapeutic efficacy of ICIs. Inhibiting TAFs can reduce the levels of M2 macrophages in the tumor microenvironment, thereby stimulating anti-tumor immune responses. Here, we developed a hybrid membrane-encapsulated biomimetic nanoparticle for inhibiting M2 macrophage polarization. Salvianolic acid B (SAB) was encapsulated in poly(L-lactide-co-glycolide) (PLGA) nanoparticles and coated with a mixed membrane of red blood cells (RBCs) and TAFs on its surface. Nanoparticles coated with RBC membrane possess an “invisible” function that allows them to evade immune clearance and prolong circulation time. When encapsulated by TAF cell membranes, these nanoparticles can precisely target TAFs. By inhibiting TAFs, the released SAB reduced the secretion of CXCL12, thereby interfering with M2 macrophage polarization. In addition, biomimetic nanoparticles increased the levels of CD4⁺ and CD8⁺ T cells within tumors, while reducing the recruitment of myeloid-derived inhibitory cells (MDSCs), ultimately triggering an immune response. When combined with ICIs, biomimetic nanoparticles can extend the survival of mice and dramatically slow the growth of tumors. Our research findings suggest that biomimetic nanoparticles coated with mixed membranes represent an optimal strategy for enhancing the immune response to ICIs.</p>