Ion channels play essential roles in cellular signaling, yet achieving precise, on-demand activation within the tumor microenvironment (TME) remains challenging. In this study, we develop a pH-responsive supramolecular assembly composed of a water-soluble cationic oligophenylenevinylene derivative (OPV-hex) and an acid-cleavable molecule (DMMA). Under physiological pH, OPV-hex and DMMA form a host–guest complex that shields the cationic surface charge of OPV-hex. In an acidic tumor-mimicking environment, DMMA undergoes hydrolysis, leading to disassembly of the complex and release of positively charged OPV-hex, which subsequently targets the plasma membrane and activates calcium ion channels. This leads to an influx of Ca2+ in HCT116 tumor cells and RAW264.7 macrophages. Inhibitor and electrophysiological experiments confirm the involvement of TRPV1 and voltage-gated Ca2+ channels. Transcriptomic analysis shows the enrichment of apoptosis and calcium-related pathways. Additionally, the system also has the potential to induce macrophage polarization, enhancing antitumor immune responses. This work presents a molecular conformation-driven strategy for pH-triggered ion channel modulation and offers a promising platform for targeted cancer therapy.
Song et al. (Wed,) studied this question.