Synergistic anticancer immunity in metastatic triple-negative breast cancer through an in situ amplifying...

Area of Science:

• Oncology
• Immunotherapy
• Drug Delivery

Background:

• Triple-negative breast cancer (TNBC) treatment faces challenges from tumor heterogeneity and metastasis.
• Combining chemotherapy and immunotherapy shows promise but requires improved targeting and reduced systemic toxicity.

Purpose of the Study:

• To develop a tumor-specific immunogenic agent (TPD1) for enhanced TNBC treatment.
• To investigate TPD1's ability to induce immunogenic cell death and modulate the tumor microenvironment.

Main Methods:

• TPD1, a peptide-drug conjugate targeting integrin αvβ3, was designed for caspase-3-mediated activation.
• Doxorubicin accumulation and immune cell recruitment were assessed in xenograft and metastatic models.
• The impact of TPD1 on the tumor microenvironment and susceptibility to immune checkpoint inhibition was evaluated.

Main Results:

• TPD1 achieved tumor-specific doxorubicin accumulation via caspase-3-mediated amplification.
• The treatment induced immunogenic cell death and recruited immune cells, converting the tumor microenvironment to a 'hot' state.
• TPD1 demonstrated significant anti-metastatic and anti-cancer efficacy, bypassing systemic doxorubicin immunotoxicity.

Conclusions:

• Caspase-3 cleavable peptide-drug conjugates represent a promising strategy for TNBC therapy.
• TPD1 enhances anti-cancer immunotherapy by improving tumor targeting and immune cell engagement.
• This approach holds potential for overcoming challenges in treating metastatic and heterogeneous TNBC.