Enhancing Tumor Targeting of Antitumor Drugs through Anlotinib-Mediated Modulation of Extracellular Matrix and RhoA/ROCK Signaling Pathway

In this study, our research focused on investigating the impact of Anlotinib in enhancing the tumor targeting of antitumor drugs in vivo. Through RNA-sequencing and Label-free quantitative proteomics analysis, we discovered that Anlotinib effectively regulated the expression of extracellular matrix (ECM) genes and proteins, leading to a significant reduction in ECM stiffness. Our bioinformatic analysis indicated a potential positive relationship between the ECM pathways and gefitinib resistance, poor PD-1 treatment outcomes, as well as unfavorable prognosis in lung cancer patients following chemotherapy. To evaluate the efficacy of Anlotinib, we administered it in combination with anti-PD-1/PD-L1 agents, chemotherapeutic drugs, and gefitinib, and visualized their distribution using fluorescent labeling in various tumor types. Notably, our results demonstrated that Anlotinib substantially improved the drug targeting process by prolonging the retention time of antitumor drugs at the tumor site. Moreover, the combination therapy induced a notable loosening of the tumor tissue structure compared to the control group. This reduction in stiffness was further associated with decreased interstitial fluid pressures and tumor solid pressure. Additionally, we observed that Anlotinib effectively suppressed the RhoA/ROCK signaling pathway, inhibiting the formation of stress fibers. These findings strongly suggest that Anlotinib enhances the distribution and retention of antitumor drugs in tumors by modulating ECM expression and physical properties through the RhoA/ROCK signaling pathway. These valuable insights contribute to the development of combination therapies aimed at improving tumor targeting in cancer treatment.