Photocaged Chloroquine Derivatives for the Light-Dependent Inhibition of Autophagy in Cancer Stem Cells

Chloroquine (CQ) and hydroxychloroquine (HCQ) inhibit autophagy and have shown promise as adjuvant anticancer agents, particularly for targeting therapy-resistant cancer stem cells (CSCs). However, their clinical utility is limited by systemic toxicity and poor tumor selectivity. Here, we report the design, synthesis, and photochemical evaluation of [7-(diethylamino)coumarin-4-yl]methyl (DEACM)-caged CQ and HCQ derivatives as visible-light-activated autophagy inhibitors. Selective caging of the aliphatic amine suppressed biological activity in the dark and enabled rapid release of the parent drugs upon illumination. The lead compound <b>1C</b> displayed robust light-dependent cytotoxicity across multiple cancer cell lines and, upon photoactivation, recapitulated CQ's effects on LC3-II accumulation. In CSC-enriched tumorspheres, <b>1C</b> completely abolished sphere formation only if illuminated. Ex vivo and in vivo studies confirmed that visible light penetrates tumor tissue sufficiently to activate <b>1C</b> and locally release CQ within the tumor. These findings establish the first proof of concept for light-controlled autophagy inhibition and provide a blueprint for spatiotemporally confined anticancer therapies based on photopharmacological modulation of CSCs.