Targeted protein degradation with small molecules for cancer immunotherapy

Abstract

Immunotherapy has transformed cancer treatment, marked by the approval of numerous antibody-based drugs. However, the limitations of antibodies in pharmacokinetics including long half-lives, limited oral bioavailability and immunogenicity, have prompted the pursuit of small molecule-based immunotherapy. Traditional drug discovery strategies, which focus on blocking protein activity through inhibitors, face persistent hurdles, such as reliance on accessible binding pockets, poor selectivity, and the emergence of drug resistance. Targeted protein degradation (TPD) technologies have emerged as powerful tools to address these limitations, offering significant therapeutic advantages over conventional inhibition strategies, particularly for historically ''undruggable'' targets. In recent years, small molecule-based protein degraders have rapidly advanced in cancer immunotherapy. In this review, we highlight recent progress in TPD-driven small-molecule drug discovery and summarize the application of these technologies in cancer immunotherapy, including degraders targeting PD-1/PD-L1, chemokine receptors, IDO1, AhR, and others.

Keywords

Cancer immunotherapy / Small molecules / Targeted protein degradation / Degraders

Conflicts of interest

The authors declare that there are no conflicts of interest. The authors alone are responsible for the content and writing of this article.

Acknowledgment

This work was supported by the National Natural Science Foundation of China (No. 82173668, 82373706).

Supplementary materials

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.ajps.2025.101058. The figures with "S" before the serial number are included in the Supplementary data.

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