Isoguanosine-Induced ER Stress via AMPK Enhances Chemosensitivity in OSCC

Oral squamous cell carcinoma (OSCC) is the most common malignancy of the head and neck; however, the efficacy of existing treatment is limited and new effective strategies need to be explored. Our previous work demonstrates that isoguanosine (isoG) is a promising nucleoside molecule with superior self-assembly capability and significant anti-OSCC potential. However, the antitumor mechanism of isoG remains unclear. In this study, we reveal that the antiproliferative effect of isoG is mediated by its cellular metabolite, isoguanosine 5′-monophosphate (isoGMP), which induces excessive endoplasmic reticulum (ER) stress and cell death through adenosine monophosphate–activated protein kinase (AMPK) activation. IsoG activates AMPK and induces ER stress at low concentrations, with minimal impact on cell viability at these concentrations. To further explore the therapeutic potential of isoG, we investigated its role in modulating chemosensitivity. Our findings show that AMPK activation enhances the sensitivity of OSCC cells to 5-fluorouracil (5-FU), and the combination of isoG and 5-FU exhibits a synergistic anticancer effect. Building on the self-assembly characteristics of isoG, we developed an innovative treatment platform by introducing dynamic borate ester bonds to form an isoguanosine-phenylenediboronic acid-isoguanosine (isoGPBisoG) structure. When combined with 5-FU, this platform achieved remarkable therapeutic efficacy in 2 OSCC cell-derived xenograft models, with tumor inhibition rates of 71.0% and 56.6%, respectively, compared with control. These findings establish isoG as a potent enhancer of chemotherapeutic efficacy in OSCC via AMPK activation. More importantly, the isoGPBisoG and 5-FU combination represents a significant paradigm of a synergistic therapy platform. This novel approach offers a promising direction for the development of more effective OSCC treatments.