Immune checkpoint inhibitors in cancer therapy: what lies beyond monoclonal antibodies?

PMCID: PMC12178997

PMID: 40536609

DOI: 10.1007/s12032-025-02822-1

Journal: Medical oncology (Northwood, London, England)

Publication Date: 2025-6-19

Authors: Zamani MR, Šácha P

Key Points

• Non-antibody immune checkpoint inhibitors represent a promising frontier in cancer immunotherapy, offering more targeted and potentially less toxic treatment approaches
• Multiple novel ICI candidates are currently in clinical trials, including small-molecule inhibitors like CA-170 (Phase 2b/3) and multispecific agents targeting combinations like CTLA-4 and PD-1
• The emerging strategies seek to overcome current limitations of monoclonal antibodies, including resistance mechanisms and high treatment costs

Summary

This comprehensive review explores the evolving landscape of immune checkpoint inhibitors (ICIs) beyond traditional monoclonal antibodies, highlighting emerging strategies to overcome current limitations in cancer immunotherapy. While monoclonal antibodies targeting PD-1, PD-L1, and CTLA-4 have revolutionized cancer treatment, the field is rapidly expanding to include innovative approaches such as small-molecule inhibitors, gene-editing technologies, and novel molecular targeting mechanisms.

The review emphasizes the potential of alternative ICI strategies, including lysosome-targeting chimeras (LYTACs), proteolysis-targeting chimeras (PROTACs), and cell-based therapies like CAR-NK cells. These emerging approaches aim to enhance therapeutic efficacy, reduce adverse events, and provide more personalized treatment options. The clinical pipeline showcases multiple promising candidates across various stages of development, targeting diverse immune checkpoint molecules beyond the traditional PD-1/PD-L1 axis.