Anthelmintic Drugs as Emerging Immune Modulators in Cancer

Abstract

Despite recent advances in treatment approaches, cancer is still one of the leading causes of death worldwide. Restoration of tumor immune surveillance represents a valid strategy to overcome the acquired resistance and cytotoxicity of conventional therapies in oncology and immunotherapeutic drugs, such as immune checkpoint inhibitors and immunogenic cell death inducers, and has substantially progressed the treatment of several malignancies and improved the clinical management of advanced disease. Unfortunately, because of tumor-intrinsic and/or -extrinsic mechanisms for escaping immune surveillance, only a fraction of patients clinically respond to and benefit from cancer immunotherapy. Accumulating evidence derived from studies of drug repositioning, that is, the strategy to identify new uses for approved or investigational drugs that are outside the scope of the original medical indication, has suggested that some anthelmintic drugs, in addition to their antineoplastic effects, exert important immunomodulatory actions on specific subsets of immune cell and related pathways. In this review, we report and discuss current knowledge on the impact of anthelmintic drugs on host immunity and their potential implication in cancer immunotherapy.

Keywords: PD-1; PD-L1; STAT3; Th17; cancer immunotherapy; drug repositioning; immune checkpoint inhibitors; immunogenic cell death; niclosamide; rafoxanide.

Figure 1

Some putative molecular mechanisms that underlie the ability of certain anthelmintic drugs to improve cancer immunotherapy. (I) Niclosamide and flubendazole suppress STAT3 phosphorylation/activation, thus, impairing the expression of PD-L1 and PD-1. (II) Albendazole negatively affects ubiquilin-4 expression/interaction with PD-L1, thus, promoting its degradation by the proteasome. (III) Rafoxanide and ivermectin promote bona fide immunogenic cell death in cancer cells and prime antitumor immune responses. Abbreviations: STAT- signal transducer and activator of transcription; PD-1: programmed cell death protein-1; PD-L1: programmed death-ligand 1; Ub: ubiquitin; ICD: immunogenic cell death; DC: dendritic cells. Created with Biorender.com.