Nanoparticles-mediated SLAMF7 overexpression regulates TME for enhanced immunotherapy of solid tumors

• A glutathione-responsive nanoplatform (NP pSLAMF7 ) was developed to deliver SLAMF7 plasmid DNA into solid tumor cells, enabling macrophage-mediated anti-tumor immunity by overcoming the absence of endogenous SLAMF7 expression. • SLAMF7 overexpression markedly enhanced macrophage phagocytosis and induced secretion of CXCL9/10, which promoted robust CD8 + T cell recruitment and reprogrammed the immunosuppressive tumor microenvironment into an immuneactivating niche. • NP pSLAMF7 accumulated selectively in tumors, suppressed growth in both orthotopic and metastatic models, and achieved maximal tumor inhibition when combined with PD-1 blockade, demonstrating strong synergistic efficacy. Compared to hematologic malignancies, solid tumors respond poorly to immunotherapy, largely due to their immunosuppressive microenvironment and lack of effective immune regulatory molecules. Signaling Lymphocyte Activation Molecule Family Member 7 (SLAMF7), a macrophage-activating receptor highly expressed in hematologic cancers, is scarcely present in solid tumors. While tumor-associated macrophages (TAMs) in the tumor microenvironment (TME) possess anti-tumor potential, their phagocytic capacity remains untapped in solid tumors. We herein developed a glutathione (GSH)-responsive nanoparticle platform based on PLGA 10k -S-S-mPEG 5k to deliver plasmid DNA encoding SLAMF7 (NP pSLAMF7 ) into solid tumor cells. Successful SLAMF7 expression effectively reprogrammed these cells to mimic hematopoietic cancer cells, thereby inducing potent macrophage phagocytosis. RNA-seq and KEGG pathway analysis revealed that upon phagocytosis, macrophages activated phagocytosis-related and cytokine-cytokine receptor interaction pathways, leading to increased secretion of CXCL9 and CXCL10, driving CD8 + T cell recruitment. In both orthotopic and metastatic breast tumor models, NP pSLAMF7 synergized with anti-PD-1 antibody therapy, achieving maximal tumor suppression. Our work establishes NP pSLAMF7 as the first nanoplatform to induce SLAMF7 expression in solid tumors, thereby enhancing macrophage-mediated phagocytosis and CD8 + T cell infiltration. This strategy reprograms the TME and acts synergistically with PD-1 blockade, offering a promising strategy for next-generation solid tumor immunotherapy.