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Chemotherapy is widely used to treat colorectal cancer (CRC). Despite its substantial benefits, the development of drug resistance and adverse effects remain challenging. This study aimed to elucidate a novel role of glucagon in anti‐cancer therapy. In a series of in vitro experiments, glucagon inhibited cell migration and tube formation in both endothelial and tumor cells. In vivo studies demonstrated decreased tumor blood vessels and fewer pseudo‐vessels in mice treated with glucagon. The combination of glucagon and chemotherapy exhibited enhanced tumor inhibition. Mechanistic studies demonstrated that glucagon increased the permeability of blood vessels, leading to a pronounced disruption of vessel morphology. Signaling pathway analysis identified a VEGF/VEGFR‐dependent mechanism whereby glucagon attenuated angiogenesis through its receptor. Clinical data analysis revealed a positive correlation between elevated glucagon expression and chemotherapy response. This is the first study to reveal a role for glucagon in inhibiting angiogenesis and vascular mimicry. Additionally, the delivery of glucagon‐encapsulated PEGylated liposomes to tumor‐bearing mice amplified the inhibition of angiogenesis and vascular mimicry, consequently reinforcing chemotherapy efficacy. Collectively, the findings demonstrate the role of glucagon in inhibiting tumor vessel network and suggest the potential utility of glucagon as a promising predictive marker for patients with CRC receiving chemotherapy. [ABSTRACT FROM AUTHOR]

[Display omitted] • A tumor microenvironment-activated hollow vanadium-based nanoplatform (pLi-HVMSN-Pt) was developed. • pLi-HVMSN-Pt promoted DNA damage via the formation of Pt-DNA adduct and ERCC1 inhibition. • pLi-HVMSN-Pt decreased cellular GSH level via depleting GSH and inhibiting GCL expression. • pLi-HVMSN-Pt enhanced cellular ROS production and then induced cells oxdative death. • pLi-HVMSN-Pt achieved the precise therapy of lung cancer via reversing CDDP resistance. The resistance and side effect of cisplatin (CDDP) were still great challenges for highly efficient therapy of lung cancer in clinic. The studies indicated that the CDDP resistance mainly involved GSH-mediated inactivation and the damaged DNA repair. Herein, a novel vanadium-based nanoplatform was designed via platelet-derived growth factor receptor-β (PDGFR-β)-recognizing cyclic peptide (PDGFB)-labeled liposomes coating onto the hollow vanadium-doped mesoporous silica nanoparticle (HVMSN) loaded Pt (IV) prodrugs (pLi-HVMSN-Pt). This nanoplatform actively targeted tumor tissue, and then effectively responded to weakly acidic and high GSH of tumor microenvironment, making Pt (IV) prodrugs and vanadium ions be precisely delivered and intelligently released. Moreover, the vanadium ions significantly downregulated the expression of glutamyl cysteine ligase (GCL) and excision repair cross-complementing 1 (ERCC1), which inhibited the synthesis of GSH in cells and the damaged DNA repair. These synergistic actions dramatically increased the sensitivity of tumor cells to Pt-based drug, and then reversed CDDP resistance. Furthermore, in vivo experiment results demonstrated highly efficient suppression of tumor growth induced by the pLi-HVMSN-Pt. Therefore, this work provided a novel strategy for reversing CDDP-resistance and the precise therapy of lung cancer. [ABSTRACT FROM AUTHOR]