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Background <p>Immune checkpoint inhibitors (ICIs) have fundamentally transformed the treatment of solid tumors. Despite significant advances, limitations remain due to suboptimal patient selection, resistance, and immune-related adverse events (irAEs). Novel strategies aim to enhance the effectiveness of current therapies through more targeted immune modulation, new checkpoint targets, and regulation of the tumor microenvironment (TME).</p> Objectives <p>This review aims to summarize recent developments in the optimization of ICI-based therapies. It focuses on emerging immune checkpoints such as LAG‑3, TIGIT, and TIM‑3, the adenosine signaling pathway, as well as bispecific antibodies, antibody–drug conjugates (ADCs) and tyrosine kinase inhibitor (TKI) combinations in immuno-oncology.</p> Materials and methods <p>A&#xa0;systematic evaluation of current clinical and preclinical studies was conducted using the databases PubMed, Embase, Cochrane Library, and ClinicalTrials.gov, with a&#xa0;focus on ICI-based combination strategies.</p> Results <p>Novel immune checkpoint (IC)-targeting agents demonstrate promising efficacy and tolerability. Further, the combination of approved ICIs with bispecific antibodies, ADCs or TKIs shows significant clinical activity in treatment-resistant tumors<i>.</i> Nonetheless, irAEs remain a&#xa0;relevant clinical challenge. Strategies such as dual checkpoint blockade, subcutaneous administration, and TME modulation offer promising approaches to improve treatment outcomes.</p> Conclusion <p>Despite clinical success, resistance, irAEs, and lack of biomarkers remain key challenges. Novel IC targets, combination strategies, and TME modulation show promise but require improved patient selection and a&#xa0;deeper understanding of immunological mechanisms.</p>

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Neue Immuncheckpointinhibitoren und Kombinationen

  • 期刊论文

  • 发表日期：

    2025年7月31日

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  • U.-U. Yesilyurt,
  • T. Hilser,
  • N. Klümper,
  • M. Al-Nader,
  • A. Isgandarov,
  • M. Wahl,
  • C. Darr,
  • V. Grünwald

摘要

Background

Immune checkpoint inhibitors (ICIs) have fundamentally transformed the treatment of solid tumors. Despite significant advances, limitations remain due to suboptimal patient selection, resistance, and immune-related adverse events (irAEs). Novel strategies aim to enhance the effectiveness of current therapies through more targeted immune modulation, new checkpoint targets, and regulation of the tumor microenvironment (TME).

Objectives

This review aims to summarize recent developments in the optimization of ICI-based therapies. It focuses on emerging immune checkpoints such as LAG‑3, TIGIT, and TIM‑3, the adenosine signaling pathway, as well as bispecific antibodies, antibody–drug conjugates (ADCs) and tyrosine kinase inhibitor (TKI) combinations in immuno-oncology.

Materials and methods

A systematic evaluation of current clinical and preclinical studies was conducted using the databases PubMed, Embase, Cochrane Library, and ClinicalTrials.gov, with a focus on ICI-based combination strategies.

Results

Novel immune checkpoint (IC)-targeting agents demonstrate promising efficacy and tolerability. Further, the combination of approved ICIs with bispecific antibodies, ADCs or TKIs shows significant clinical activity in treatment-resistant tumors. Nonetheless, irAEs remain a relevant clinical challenge. Strategies such as dual checkpoint blockade, subcutaneous administration, and TME modulation offer promising approaches to improve treatment outcomes.

Conclusion

Despite clinical success, resistance, irAEs, and lack of biomarkers remain key challenges. Novel IC targets, combination strategies, and TME modulation show promise but require improved patient selection and a deeper understanding of immunological mechanisms.