In light of the complexity and multifaceted nature of the tumor development, complex effect both on malignant tumor cells and tumor microenvironment is an important therapeutic strategy. Angiogenesis plays a key role in the development of solid tumors and their metastasis. The vascular endothelial growth factor VEGF and its receptors VEGFR are the main targets of modern antiangiogenic tumor therapy. However, adaptive resistance to existing antiangiogenic drugs and their numerous side effects require the identification of additional targets for more specific and effective tumor targeting. In this aspect, activation of the signaling pathways of the TRAIL cytokine, which is involved in the immunobiological surveillance of tumors, is promising. TRAIL surveills and selectively eliminates transformed cells by apoptosis upon binding to death receptors, primarily the DR5 receptor. As a fundamental scientific basis, the authors of the project previously showed that concurrent effects on the DR5 and VEGFR2 receptors can lead to a significant increase in the antitumor effect in vivo due to the suppression of tumor angiogenesis. However, in addition to the activation of VEGFR2, activation of fibroblast growth factor (FGF) receptors, primarily FGFR1, is also known to play an extremely important role in the formation of the tumor microenvironment and vasculature. The goal of this project is comprehensive investigation of the complex effects on tumors and the tumor microenvironment using a set of new multimodal hybrid protein constructs based on the DR5 receptor agonist, a receptor-selective variant of the TRAIL cytokine. In addition to activation of DR5-mediated tumor cell apoptosis and inhibition of the VEGF/VEGFR2 interaction, novel protein constructs will contain an antagonistic peptide that blocks the FGF/FGFR1 interaction. It is expected that simultaneous effects on two signaling pathways involved in angiogenesis and the formation of the tumor microenvironment, along with activation of the DR5 receptor, will lead to dramatic inhibition of the growth of tumors of various origins. It is important that antagonistic anti-VEGFR2 and anti-FGFR1 moieties of the fusion protein constructs will act specifically in tumors due to the TRAIL domain, which selectively binds to the DR5 receptor, overexpressed in tumor cells. This will reduce the frequency and intensity of side effects that limit the use of antiangiogenic drugs. The project will apply a modern integrative approach to studying the biological properties of new multimodal hybrid protein constructs. Antitumor properties will be studied in vitro in co-culture models of tumor cells, fibroblasts and/or endothelial cells, and in vivo in xenograft models of solid tumors of various origin. The antiangiogenic effect of multimodal fusion proteins will be studied using optical coherence tomography (OCT), optoacoustic tomography, immunohistochemistry, and scanning electron microscopy. The metabolic status of drug-treated tumors will be studied using optical metabolic imaging based on endogenous fluorescence of metabolic cofactors (FLIM microscopy) in vivo; oxygenation of tumors – using phosphorescent oxygen sensors (PLIM microscopy). As a result of the project, we plan to evaluate the contribution of inhibition of the VEGF/VEGFR2 and FGF/FGFR1 signaling to antiangiogenic and antitumor effects. A multimodal fusion protein with the best antitumor and antiangiogenic properties will be patented with the possibility of further preclinical and clinical trials as a new therapeutic agent for the treatment of solid tumors. Successful implementation of the project will lay the basis for the development of a new strategy of antitumor therapy.