Long-term combined blockade of CXCR4 and PD-L1 with in vivo reassembly for intensive tumor interference

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Cancer Immunotherapy

Background:

• Cancer cells evade immune detection via negative immunoregulatory signals like PD-L1 and CXCR4.
• Blocking CXCR4 enhances T cell infiltration and sensitivity to anti-PD-L1 therapy.
• Developing effective combination strategies is crucial for overcoming tumor immune evasion.

Purpose of the Study:

• To construct pH-responsive reassembled nanomaterials (APAB) for combined PD-L1 and CXCR4 blockade.
• To synergize APAB with photothermal therapy (ICG) for enhanced tumor inhibition.
• To evaluate the efficacy of the combined therapy (ICG@APAB) in melanoma and breast cancer models.

Main Methods:

• Grafting anti-PD-L1 peptide and CXCR4 antagonists onto pH-responsive nanomaterials (APAB).
• Utilizing the aggregation-induced retention (AIR) effect for sustained drug delivery.
• Employing indocyanine green (ICG) for photothermal therapy to induce immunogenic cell death (ICD).
• Assessing tumor growth inhibition, metastasis suppression, and survival rates in mouse models.

Main Results:

• APAB nanoparticles transformed into nanofibers in the acidic tumor microenvironment, enabling long-term blockade.
• ICG@APAB therapy significantly inhibited primary tumor growth (~83.52%) and distant tumor growth (~76.24%).
• The treatment prolonged survival time over 42 days in melanoma-bearing mice.
• ICG@APAB suppressed lung metastasis and reduced angiogenesis markers (CD31, MMP-9, VEGF) in a 4T1 model.

Conclusions:

• The in vivo reassembly strategy with ICG@APAB offers a potent combination therapy for cancer.
• This approach enhances tumor immunogenicity and overcomes immune evasion mechanisms.
• The developed strategy provides novel perspectives for future immunotherapies and clinical translation.