Exploration of the Antitumor Mechanism of Fruquintinib in Colorectal Cancer via Autophagy Regulation

Colorectal cancer (CRC) ranks as the second leading cause of cancer-related mortality worldwide, with treatment challenges largely attributed to late-stage diagnoses, frequent recurrences, and resistance to therapy. In recent years, Fruquintinib, a selective vascular endothelial growth factor receptor (VEGFR) inhibitor, has shown notable effectiveness in advanced CRC by targeting angiogenesis. However, CRC cells often activate autophagy in response to hypoxia and nutrient deprivation caused by anti-angiogenic therapy, which diminishes the therapeutic efficacy of Fruquintinib. Autophagy plays a dual role in CRC by suppressing tumorigenesis through the removal of damaged organelles, while facilitating tumor progression and therapeutic resistance through metabolic adaptation in advanced stages. This complexity underscores the therapeutic promise of strategies targeting autophagy. Current studies reveal that Fruquintinib induces autophagy by inhibiting VEGFR signaling, activating AMPK, and suppressing mTOR, while interacting synergistically with other cell death mechanisms such as apoptosis, ferroptosis, and pyroptosis to enhance its antitumor activity. However, excessive autophagy activation may enable tumor cell survival and promote resistance, highlighting the necessity of precise modulation of autophagy in combination therapies. Moreover, preclinical studies indicate that combining Fruquintinib with autophagy modulators significantly enhances its antitumor effects and delays resistance emergence. This review offers a systematic analysis of Fruquintinib's antitumor mechanisms via autophagy modulation and its potential clinical implications. Based on the reviewed evidence, we propose strategies to optimize Fruquintinib-based combination therapies, including the use of autophagy-related biomarkers, autophagy modulators, and precision medicine approaches tailored to tumor genomic profiles, aiming to enhance treatment outcomes for CRC patients.