Natural and Synthetic Coumarins as Tumor Microenvironment-Oriented Immunotherapeutic Agents: A Review

Abstract

The tumor microenvironment (TME) plays a major role in cancer progression, immune evasion, and resistance to immunotherapy. Coumarins, a structurally diverse class of natural and synthetic compounds, have attracted increasing attention because of their anticancer, anti-inflammatory, antioxidant, and immunomodulatory properties, suggesting potential applications in TME-oriented cancer immunotherapy. This review aimed to summarize the immunotherapeutic potential of natural and synthetic coumarin derivatives in modulating TME and enhancing anticancer immune responses. A narrative review of the literature was conducted focusing on the effects of coumarin derivatives on immune-cell regulation, immune checkpoint signaling, angiogenesis, extracellular matrix remodeling, metabolic reprogramming, and hypoxia-related pathways within TME. Evidence from preclinical studies involving natural and synthetic coumarins was critically evaluated. Preclinical findings indicate that coumarin derivatives can modulate several components of TME by promoting M1 macrophage polarization, activating dendritic cells and natural killer cells, enhancing T-cell–mediated immunity, and suppressing immunosuppressive cell populations such as regulatory T cells and M2 macrophages. Several coumarins also demonstrated the ability to inhibit tumor glycolysis, attenuate hypoxia-associated immune resistance, normalize angiogenesis, and regulate inflammatory signaling pathways. Synthetic coumarins showed additional promise through structural optimization and targeted delivery approaches, while their potential complementary effects with immune checkpoint inhibitors remain to be established experimentally. However, available evidence remains limited, and further mechanistic and translational investigations are required. Natural and synthetic coumarins represent promising multifunctional immunomodulators capable of reshaping TME and improving anticancer immune responses. Their diverse biological activities support their future development as adjuncts or enhancers of cancer immunotherapy.