Rationale of using immune checkpoint inhibitors (ICIs) and anti-angiogenic agents in cancer treatment from a molecular perspective.

Combination of immune checkpoint inhibitors (ICIs) and anti-angiogenic drugs (AADs) holds promise in cancer treatment. While ICIs block signals that help cancer cells evade the immune system, anti-angiogenic agents target blood vessels, limiting tumor growth by restricting nutrient and oxygen supplies. Additionally, the judicious use of AADs can normalize the tumor vasculature, alleviate hypoxia, and enhance the antitumor immune response. As the shutdown of a single target does not necessarily eradicate cancer, the use of combinations of molecular-targeted agents has been proposed, and some pioneering research has been conducted to examine the efficacy of this strategy. The combination of these two modalities offers a synergistic approach, enhancing the efficacy of tumor eradication. Recent studies have elucidated the rationale behind this combination therapy, but a limited response rate has been achieved with monotherapy. Clinical trials have demonstrated the potential of this combination, with improved outcomes in various solid tumor types. The dual blockade of angiogenesis and immune checkpoints is poised to become a standard of care, with indications expected to expand as more evidence accumulates. The antitumor efficacy of current therapies is limited, most likely because of the high degree of cancer clonal heterogeneity, intratumor genetic heterogeneity, and cell signal complexity. Although numerous studies have been conducted in this area, this review provides a comprehensive analysis of the molecular rationale for ICIs and AADs in cancer therapy. We not only compare the individual properties and mechanisms of both treatments, but also explore their complementary roles, which are essential for optimizing personalized treatment strategies. By addressing key challenges such as tumor heterogeneity, immune evasion, and resistance to monotherapies, we demonstrate how this combination approach can enhance treatment outcomes. Furthermore, we incorporate the latest preclinical and clinical findings and offer future perspectives on optimizing drug selection, dosing, and treatment design to maximize therapeutic efficacy.