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<p>Programmed Cell Death Protein 1 (PD-1) / Programmed Cell Death Ligand 1 (PD-L1) inhibitors have revolutionized cancer immunotherapy but are limited by low response rates and drug resistance. Interleukin-2 (IL-2), a potent T-cell activator, is clinically restricted due to regulatory T&#xa0;cell (Treg) activation and severe systemic toxicity. PD1-IL2 bispecific drugs, integrating PD-1 blockade and engineered IL-2 variants (IL-2v) into a single molecule, precisely regulate tumor microenvironment immunity to overcome these limitations. This review summarizes their latest progress, including the synergistic mechanism of PD-1/PD-L1 and IL-2 signaling, molecular designs (e.g., βγ-biased IL-2v and Innovent’s α-biased IBI363), and ‘cis delivery’ for targeted activation. Preclinical and clinical data (e.g., IBI363) show encouraging anti-tumor activity and improved safety in advanced tumors, benefiting PD-1-resistant patients. Challenges remain, such as unclear mechanisms, drug resistance, and long-term safety. Future advancements rely on optimized molecular design, combination therapies, and predictive biomarkers, driving PD1-IL2 bispecific drugs toward more precise and effective tumor immunotherapy for broader patient populations.</p>

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Programmed Cell Death Protein 1-Interleukin-2 Bispecific Agents for Cancer Therapy

  • 期刊论文

  • 发表日期：

    2026年4月13日

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  • Chang Xu,
  • Tingxu Yan,
  • Shuo Wen,
  • Can Wu,
  • Tingmin Chang,
  • Eryan Kong,
  • Huicong Liu

摘要

Programmed Cell Death Protein 1 (PD-1) / Programmed Cell Death Ligand 1 (PD-L1) inhibitors have revolutionized cancer immunotherapy but are limited by low response rates and drug resistance. Interleukin-2 (IL-2), a potent T-cell activator, is clinically restricted due to regulatory T cell (Treg) activation and severe systemic toxicity. PD1-IL2 bispecific drugs, integrating PD-1 blockade and engineered IL-2 variants (IL-2v) into a single molecule, precisely regulate tumor microenvironment immunity to overcome these limitations. This review summarizes their latest progress, including the synergistic mechanism of PD-1/PD-L1 and IL-2 signaling, molecular designs (e.g., βγ-biased IL-2v and Innovent’s α-biased IBI363), and ‘cis delivery’ for targeted activation. Preclinical and clinical data (e.g., IBI363) show encouraging anti-tumor activity and improved safety in advanced tumors, benefiting PD-1-resistant patients. Challenges remain, such as unclear mechanisms, drug resistance, and long-term safety. Future advancements rely on optimized molecular design, combination therapies, and predictive biomarkers, driving PD1-IL2 bispecific drugs toward more precise and effective tumor immunotherapy for broader patient populations.