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Background <p>Macrophages are a major component of the immune infiltrate in brain tumors and play a crucial role in shaping the tumor microenvironment. Their pronounced plasticity makes them attractive targets for therapeutic reprogramming, particularly to enhance antitumor phagocytic activity. Among key immunoregulatory receptors, CSF1R and PD-L1, which are expressed on macrophages, contribute to immunosuppression and tumor progression. Liposomes are well-established multivalent platforms that can present high densities of targeting ligands, increasing binding avidity and specificity; however, they can undergo rapid immune clearance, which limits their utility in brain tumor settings. In contrast, exosomes are biologically derived nanoparticles with inherent biocompatibility and immune-evasive properties; when fused with liposome membranes, they can endow synthetic vesicles with a more physiological surface and enhance circulation. To explore these complementary features in a reductionist in vitro setting, an exosome–liposome hybrid nanoparticle platform was engineered and functionalized with αCSF1R antibodies and αPD‑L1 nanobodies to target tumor‑associated macrophages differentiated from THP-1 monocytes in the presence of glioblastoma- and medulloblastoma‑derived tumor‑conditioned media.</p> Results <p>Hybrids exhibited 22% FRET-confirmed fusion efficiency. Receptor‑targeted Ex‑Lip hNPs modulated macrophage phagocytosis in a tumor-dependent manner under these in vitro conditions. Dual‑targeted hybrids consistently produced the strongest enhancement across responsive models (ONS‑76, DAOY, A172, U373; <i>p</i> &lt; 0.01–0.0001), whereas single‑target effects were variable and cell-line–dependent. No significant response was observed in U87MG‑educated TAMs, indicating that not all tumor‑educated macrophage populations are susceptible to this dual-checkpoint targeting strategy.</p> Conclusion <p>Within the limits of this in vitro THP‑1–derived TAM model and the specific receptor pair tested, these findings support the concept that nanoparticle‑based macrophage reprogramming in brain tumors may benefit from rational selection and combination of checkpoint targets tailored to the inhibitory circuitry associated with different tumor backgrounds.</p> Graphical Abstract <p></p>

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Combinational CSF1R/PD-L1 targeting by BM-MSC-derived exosome–liposome hybrid orchestrates tumor-associated macrophage phagocytosis in an in vitro tumor-microenvironment-dependent manner

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月3日

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  • Ommolbanin Asad Pour,
  • Felipe Opazo,
  • Jalal Rostamzadeh,
  • Jamal Ghanam,
  • Venkatesh Kumar Chetty,
  • Anisa Hila,
  • Ulf Neumann,
  • Susann Hetze,
  • Lennart Barthel,
  • Jan Best,
  • Hartmut H Schmidt,
  • Basant Kumar Thakur

摘要

Background

Macrophages are a major component of the immune infiltrate in brain tumors and play a crucial role in shaping the tumor microenvironment. Their pronounced plasticity makes them attractive targets for therapeutic reprogramming, particularly to enhance antitumor phagocytic activity. Among key immunoregulatory receptors, CSF1R and PD-L1, which are expressed on macrophages, contribute to immunosuppression and tumor progression. Liposomes are well-established multivalent platforms that can present high densities of targeting ligands, increasing binding avidity and specificity; however, they can undergo rapid immune clearance, which limits their utility in brain tumor settings. In contrast, exosomes are biologically derived nanoparticles with inherent biocompatibility and immune-evasive properties; when fused with liposome membranes, they can endow synthetic vesicles with a more physiological surface and enhance circulation. To explore these complementary features in a reductionist in vitro setting, an exosome–liposome hybrid nanoparticle platform was engineered and functionalized with αCSF1R antibodies and αPD‑L1 nanobodies to target tumor‑associated macrophages differentiated from THP-1 monocytes in the presence of glioblastoma- and medulloblastoma‑derived tumor‑conditioned media.

Results

Hybrids exhibited 22% FRET-confirmed fusion efficiency. Receptor‑targeted Ex‑Lip hNPs modulated macrophage phagocytosis in a tumor-dependent manner under these in vitro conditions. Dual‑targeted hybrids consistently produced the strongest enhancement across responsive models (ONS‑76, DAOY, A172, U373; p < 0.01–0.0001), whereas single‑target effects were variable and cell-line–dependent. No significant response was observed in U87MG‑educated TAMs, indicating that not all tumor‑educated macrophage populations are susceptible to this dual-checkpoint targeting strategy.

Conclusion

Within the limits of this in vitro THP‑1–derived TAM model and the specific receptor pair tested, these findings support the concept that nanoparticle‑based macrophage reprogramming in brain tumors may benefit from rational selection and combination of checkpoint targets tailored to the inhibitory circuitry associated with different tumor backgrounds.

Graphical Abstract