Current advances and clinical perspectives of anti-angiogenic therapy combined with immune checkpoint inhibitors in digestive system malignancies

High heterogeneity and an immunosuppressive tumor microenvironment (TME) are the core therapeutic bottlenecks of digestive system tumors. Current monotherapies face prominent limitations: immune checkpoint inhibitors (ICIs) yield low overall response rates as single agents, while long-term use of anti-angiogenic drugs (AADs) easily induces tumor resistance. To overcome these drawbacks, AAD-ICI combination therapy has become a research hotspot in this field, whose core synergy lies in coordinated TME modulation. AADs promote vascular normalization and reverse immunosuppressive TME to enhance intratumoral T lymphocyte infiltration, thereby laying a foundation for ICIs to exert anti-tumor effects and reactivating the endogenous anti-tumor immune response. Natural compounds have drawn extensive attention due to their regulatory value in TME remodeling and tumor combination therapy. However, there is still a lack of a comprehensive and systematic summary of their specific roles, molecular mechanisms and latest research progress in anti-angiogenic therapy, ICIs and their combination regimens for digestive system tumors. This deficiency impedes the further development of this research field. To fill this critical void, this review systematically elaborates the underlying mechanisms and clinical advances of AAD-ICI combination therapy for digestive system tumors. It also summarizes the regulatory functions and relevant research evidence of natural compounds in this therapeutic system, including those with dual regulatory effects. Additionally, the review analyzes existing challenges in basic research and clinical application, and outlines future research priorities. This work is expected to provide a valuable reference for the clinical translation and regimen optimization of precision immunotherapy for digestive system tumors.