CD204-Targeted Liposomal Nanoparticles for Macrophage Repolarization in Cancer Immunotherapy: Current Approaches, Challenges, and Future Perspectives
Mennatallah Abdelmaqsoud
12/08/2026
Tumor-associated macrophages, predominantly exhibiting an M2-like phenotype, are considered a crucial component of the immunosuppressive tumor microenvironment, driving tumor progression, angiogenesis, and metastatic dissemination. CD204 (macrophage scavenger receptor 1, MSR1) is markedly upregulated on M2-like TAMs, functioning not only as a phenotypic marker but also as a critical modulator of immune suppression and tumor-supportive processes. Therapeutic targeting of CD204 offers a strategic way to reprogram TAMs toward a proinflammatory M1-like phenotype, thereby restoring anti-tumor immunity. Liposomal nanoparticles (LPs), engineered with surface functionalization such as anti-CD204 antibodies or mannose ligands, provide a selective and efficient delivery platform for therapeutic payloads. Among these, small interfering RNA (siRNA) enables precise intracellular gene silencing, inhibiting STAT6-mediated M2 polarization and reducing the secretion of immunosuppressive cytokines, including IL-10 and TGF-β. This combinatorial approach of receptor-targeted nanoparticle delivery and gene-silencing payloads effectively modulates TAM phenotype, reshapes the tumor immune milieu, and enhances cytotoxic T-cell-mediated antitumor responses. CD204-directed liposomal immunotherapy represents a promising paradigm in cancer treatment, offering the potential to overcome immune evasion mechanisms and improve clinical outcomes.