Janus Silica Nanoparticle-Based Tumor Microenvironment Modulator for Restoring Tumor Sensitivity to Programmed Cell...

Area of Science:

• Nanotechnology
• Immunotherapy
• Oncology

Background:

• The tumor microenvironment (TME) often suppresses anti-tumor immunity, limiting the effectiveness of PD-1/PD-L1 immune checkpoint blockade (ICB) therapy.
• Inadequate cytotoxic lymphocytes and abundant immunosuppressors within the TME are key barriers to successful ICB therapy.

Purpose of the Study:

• To develop a Janus silica nanoparticle (JSNP)-based immunomodulator to reshape the TME and improve the therapeutic outcomes of αPD-L1 therapy.
• To investigate the combined effects of targeting myeloid-derived suppressor cells (MDSCs) and enhancing cytotoxic lymphocyte recruitment within the TME.

Main Methods:

• A dual-domain JSNP (IUIPC) was designed, encapsulating a PI3Kγ inhibitor (IPI549) and CXCL9 cDNA.
• IUIPC releases IPI549 in acidic TME to target MDSCs and CXCL9 cDNA in glutathione-rich tumor cells to recruit cytotoxic lymphocytes.
• The strategy was evaluated in combination with αPD-L1 therapy to assess TME remodeling and anti-tumor efficacy.

Main Results:

• IUIPC successfully remodeled the immunosuppressive TME by targeting MDSCs and promoting cytotoxic lymphocyte infiltration.
• Combined therapy significantly boosted systemic anti-tumor immune responses.
• Remarkable suppression of primary tumor growth, prevention of recurrence, and regression of abscopal tumors were observed.

Conclusions:

• The IUIPC-mediated TME-regulating strategy effectively overcomes immunosuppression and enhances anti-tumor immunity.
• This approach offers a promising perspective for improving the efficacy of PD-1/PD-L1 ICB therapy.