Abstract
Helminths are parasitic worms that secrete a plethora of immune regulatory molecules which allow them to moderate inflammatory responses by their host's immune system to ensure their survival within the host. This ability to drive a compatible existence with their host has led to research into the potential therapeutic effects of helminth-derived molecules the regulation of overactive immune and inflammatory responses in a wide variety of diseases. This systematic review with cross-study quantitative data analysis aims to synthesize the published data on helminth-derived immunomodulatory peptides/polypeptides/proteins (HDIPs) with a focus on determining the extent to which they modulate the inflammatory response in in vitro cellular models of inflammation. In accordance with PRISMA 2020 guidelines, a predefined systematic search of the PubMed, Web of Science and Medline databases identified relevant studies published up to September 2025, and 79 articles were included after screening. We found that most published studies used LPS or Concanavalin A stimulated macrophages, peripheral blood mononuclear cells or dendritic cells as the cellular model of inflammation. Twenty helminth species from which > 60 isolated HDIPs were derived were tested in these models, with the nematodes, Haemonchus contortus and Acanthocheilonema viteae, and the trematode, Fasciola hepatica, the most explored species. A common property of these molecules was the ability to significantly reduce the expression or production of pro-inflammatory cytokines such as IL-12, IL-1β, IL-6 and TNF, and significantly increase the expression or production of anti-inflammatory cytokines such as IL-10, TGFβ and IL-4. The effects on other cytokines, including IFNγ which is known to have both pro- and anti-inflammatory effects, were less consistent, with HDIPs either decreasing or increasing the levels of this cytokine. This systematic review with cross-study quantitative data analysis synthesizes the existing literature in this field and shows that the HDIPs secreted by several helminth species have consistently demonstrated effects though modification of cytokine levels and, as such, have therapeutic potential in conditions in which overactive immune and inflammatory responses play a pathogenic role.