Statins as Repurposed Anticancer Agents: Regulated Cell Death, the Tumor Immune Microenvironment, and the Translational Evidence Gap.

Authors

Xu Zhou, Yizhang Chen, Hanxiao Hua, Bo Shen, Shuai Liang, Dong Hua

Published in

Drug development research. Volume 87. Issue 7. Pages e70388.

Abstract

Statins inhibit 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) and reduce flux through the mevalonate pathway, which supplies both cholesterol and the non-sterol isoprenoids required for prenylation of small GTPases. Because this pathway is frequently activated in cancer, statins have become one of the most intensively studied candidates for oncological drug repurposing. Preclinical work indicates that statins can lower the threshold for apoptosis, modulate autophagy in either a pro-death or a cytoprotective direction, induce pyroptosis, and sensitize cells to ferroptosis, while also acting on CD8⁺ T cells, macrophages, dendritic cells, and cancer-associated fibroblasts within the tumor microenvironment. Clinical evidence, however, remains discordant with the strength of these mechanistic claims: favorable observational associations are susceptible to immortal-time bias, healthy-user bias, and confounding by indication, and randomized trials have been largely neutral for tumor-directed endpoints. This narrative review appraises the mechanistic, preclinical, and clinical literature using an explicit five-tier evidence hierarchy, and treats two constraints as analytical tools rather than closing caveats: the pharmacological heterogeneity of individual statins, and the one-to-two order-of-magnitude gap between concentrations used in cancer-cell experiments and free drug concentrations achievable in patients. We conclude that statins are biologically plausible but clinically unproven anticancer agents whose evaluation should proceed through biomarker-selected, pharmacodynamically validated combination trials rather than unselected add-on designs.

PMID:
42763787
Bibliographic data and abstract were imported from PubMed on 20 Sep 2026.

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