¹³¹I-Labeled Dual Immune Checkpoint Inhibitors for Tumor Microenvironment Improvement To Enhance Antitumor Efficacy

Area of Science:

• Oncology
• Immunotherapy
• Radiochemistry

Background:

• Bispecific immune checkpoint inhibitors (ICIs) offer potential for radioimmunotherapy (RIT).
• Cadonilimab (AK104) is a tetravalent bispecific antibody targeting PD-1 and CTLA-4.

Purpose of the Study:

• To evaluate ¹³¹I-labeled cadonilimab ([¹³¹I]I-AK104) as a novel RIT agent for non-small-cell lung cancer (NSCLC).
• To elucidate the therapeutic mechanisms of [¹³¹I]I-AK104 in the tumor microenvironment (TME).

Main Methods:

• SPECT/CT imaging for biodistribution of [¹³¹I]I-AK104.
• Tumor growth monitoring and histopathology in tumor-bearing mice.
• Imaging mass cytometry and single-cell RNA sequencing to analyze TME changes.

Main Results:

• [¹³¹I]I-AK104 demonstrated effective tumor targeting, retention, and antitumor activity.
• Treatment promoted CD8⁺ T cell infiltration and clonal expansion in the TME.
• It induced immunogenic cell death (ICD) via neutrophil recruitment and reactive oxygen species (ROS)/nitric oxide (NO) release.
• Enhanced immune cell interactions, forming neutrophil-CD8⁺ T cell-dendritic cell neighborhoods (CN).

Conclusions:

• ¹³¹I-based RIT combined with bispecific ICIs effectively remodels the TME in NSCLC.
• CD8⁺ T cell activation and neutrophil-mediated ROS/NO release are crucial for enhanced tumor cell killing.