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

Abstract

Immune checkpoints are critical in modulating immune responses and maintaining self-tolerance. Cancer cells can exploit these mechanisms to evade immune detection, making immune checkpoints attractive targets for cancer therapy. The introduction of immune checkpoint inhibitors (ICIs) has transformed cancer treatment, with monoclonal antibodies targeting CTLA-4, PD-1, and PD-L1 demonstrating clinical success. However, challenges such as immune-related adverse events, primary and acquired resistance, and high treatment costs persist. To address these challenges, it is essential to explore alternative strategies, including small-molecule and peptide-based inhibitors, aptamers, RNA-based therapies, gene-editing technologies, bispecific and multispecific agents, and cell-based therapies. Additionally, innovative approaches such as lysosome-targeting chimeras, proteolysis-targeting chimeras, and N-(2-hydroxypropyl) methacrylamide copolymers are emerging as promising options for enhancing treatment effectiveness. This review highlights significant advancements in the field, focusing on their clinical implications and successes.

Keywords: Cancer therapy; Immune checkpoint inhibitors; Immunotherapy; Monoclonal antibodies; Small molecules.

Fig. 1

Alternatives to monoclonal antibodies for targeting inhibitory immune checkpoints in cancer immunotherapy (Created with bioRender.com)

Fig. 2

Emerging approaches for targeting and degrading membrane immune checkpoints (ICs). The mechanisms of action are not fully understood. Cation-independent mannose 6-phosphate receptor (CR-M6PR). (Created with bioRender.com)