Review
Natural and Synthetic Coumarins as Tumor Microenvironment-Oriented Immunotherapeutic Agents: A Review
Received: 22 July 2026; Revised: 11 August 2026; Accepted: 24 August 2026; Published: 1 September 2026
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.
Keywords
References
- 1. Ling, S.P.; Ming, L.C.; Dhaliwal, J.S.; et al. Role of Immunotherapy in the Treatment of Cancer: A Systematic Review. Cancers 2022, 14, 5205.
- 2. Zhang, M.; Liu, C.; Tu, J.; et al. Advances in cancer immunotherapy: historical perspectives, current developments, and future directions. Mol. Cancer 2025, 24, 136.
- 3. Zeki, N.M.; Mustafa, Y.F. 6,7-Coumarin-heterocyclic hybrids: A comprehensive review of their natural sources, synthetic approaches, and bioactivity. J. Mol. Struct. 2024, 1303, 137601.
- 4. Younes, A.H.; Mustafa, Y.F. Novel coumarins from green sweet bell pepper seeds: Their isolation, characterization, oxidative stress-mitigating, anticancer, anti-inflammatory, and antidiabetic properties. J. Mol. Struct. 2024, 1312, 138629.
- 5. Todorov, L.; Saso, L.; Kostova, I. Antioxidant Activity of Coumarins and Their Metal Complexes. Pharmaceuticals 2023, 16, 651.
- 6. Mustafa, Y.F. Triple coumarin-based 5-fluorouracil prodrugs, their synthesis, characterization, and release kinetics. J. Mol. Struct. 2024, 1301, 137415.
- 7. Zhang, J.; Yuan, Y.; Gao, X.; et al. Scopoletin ameliorates hyperlipidemia and hepatic steatosis via AMPK, Nrf2/HO-1 and NF-κB signaling pathways. Biochem. Pharmacol. 2025, 231, 116639.
- 8. Sharif, N.; Jabeen, H. Natural sources for coumarins and their derivatives with relevance to health-promoting properties: A systematic review. Trends Phytochem. Res. 2024, 8, 1–16.
- 9. Mustafa, Y.F. Natural immune boosters: Coumarins as emerging potentiators of immunity in drug discovery. Phytomedicine Plus 2025, 5, 100880.
- 10. Li, Y.; Wang, G.Q.; Li, Y.B. Therapeutic potential of natural coumarins in autoimmune diseases with underlying mechanisms. Front. Immunol. 2024, 15, 1–15.
- 11. Kubrak, T.P.; Makuch-Kocka, A.; Aebisher, D. Coumarins in anticancer therapy: Mechanisms of action, potential applications and research perspectives. Pharmaceutics 2025, 17, 595.
- 12. Liu, S.; Liu, C.; He, Y.; et al. Benign non-immune cells in tumor microenvironment. Front. Immunol. 2025, 16, 1561577.
- 13. Mustafa, Y.F. Biocompatible chlorocoumarins from harmful chlorophenols, their synthesis and biomedicinal evaluation. J. Mol. Struct. 2024, 1309, 138193.
- 14. Zeki, N.M.; Mustafa, Y.F. Annulated Heterocyclic[g]Coumarin Composites: Synthetic Approaches and Bioactive Profiling. Chem. Biodivers. 2024, 21, e202301855.
- 15. Zhao, Y.; Jing, L.; Han, L.; et al. Coumarins in the tumor-immune application: From molecular mechanisms to therapeutic innovations. Front. Immunol. 2025, 16, 1681892.
- 16. Mellman, I.; Chen, D.S.; Powles, T.; et al. The cancer-immunity cycle: Indication, genotype, and immunotype. Immunity 2023, 56, 2188–2205.
- 17. Kim, S.K.; Cho, S.W. The Evasion Mechanisms of Cancer Immunity and Drug Intervention in the Tumor Microenvironment. Front. Pharmacol. 2022, 13, 868695.
- 18. Shahbaz, M.; Perween, A.; Momal, U.; et al. Recent Perspectives on Anticancer Potential of Coumarin Against Different Human Malignancies: An Updated Review. Food Sci. Nutr. 2025, 13, e4696.
- 19. Tiwari, A.; Trivedi, R.; Lin, S.Y. Tumor microenvironment: Barrier or opportunity towards effective cancer therapy. J. Biomed. Sci. 2022, 29, 83.
- 20. Erasha, A.M.; El-Gendy, H.; Aly, A.S.; et al. The Role of the Tumor Microenvironment (TME) in Advancing Cancer Therapies: Immune System Interactions, Tumor-Infiltrating Lymphocytes (TILs), and the Role of Exosomes and Inflammasomes. Int. J. Mol. Sci. 2025, 26, 2716.
- 21. Peña-Romero, A.C.; Orenes-Piñero, E. Dual Effect of Immune Cells within Tumour Microenvironment: Pro- and Anti-Tumour Effects and Their Triggers. Cancers 2022, 14, 1681.
- 22. Bahrami, M.; Haji Molla Hoseini, M.; Rezaei, M.; et al. Umbelliprenin Increases the M1/M2 Ratio of Macrophage Polarization and Improves the M1 Macrophage Activity in THP-1 Cells Cocultured with AGS Cells. Evid.-Based Complement. Altern. Med. 2021, 2021, 9927747.
- 23. Zeki, N.M.; Mustafa, Y.F. Natural linear coumarin-heterocyclic conjugates: A review of their roles in phytotherapy. Fitoterapia 2024, 175, 105929.
- 24. Younes, A.H.; Mustafa, Y.F. Plant-Derived Coumarins: A Narrative Review of Their Structural and Biomedical Diversity. Chem. Biodivers. 2024, 21, e202400344.
- 25. Tsivileva, O.M.; Koftin, O.V.; Evseeva, N.V. Coumarins as Fungal Metabolites with Potential Medicinal Properties. Antibiotics 2022, 11, 1156.
- 26. Abdulaziz, N.T.; Mustafa, Y.F. Antibacterial and Antitumor Potentials of Some Novel Coumarins. Int. J. Drug Deliv. Technol. 2022, 12, 239–247.
- 27. Nogueira, P.L.; da Nóbrega Alves, D.; Queiroga Gomes da Costa, P.C.; et al. Derivative of 7-hydroxycoumarin has antifungal potential against Candida species and low cytotoxicity against human cells: In silico studies and biological evaluation. Fungal Biol. 2023, 127, 1451–1465.
- 28. Mishra, S.; Pandey, A.; Manvati, S. Coumarin: An emerging antiviral agent. Heliyon 2020, 6, e03217.
- 29. Orioli, R.; Belluti, F.; Gobbi, S.; et al. Naturally Inspired Coumarin Derivatives in Alzheimer’s Disease Drug Discovery: Latest Advances and Current Challenges. Molecules 2024, 29, 3514.
- 30. Jibroo, R.N.; Mustafa, Y.F.; Al-Shakarchi, W. Synthesis and evaluation of linearly fused thiadiazolocoumarins as prospects with broad-spectrum bioactivity. Results Chem. 2024, 7, 101494.
- 31. Citarella, A.; Vittorio, S.; Dank, C.; et al. Syntheses, reactivity, and biological applications of coumarins. Front. Chem. 2024, 12, 1362992.
- 32. Hassanein, E.H.M.; Sayed, A.M.; Hussein, O.E.; et al. Coumarins as modulators of the Keap1/Nrf2 /ARE signaling pathway. Oxid. Med. Cell. Longev. 2020, 2020, 1675957.
- 33. Nan, Z.D.; Shang, Y.; Zhu, Y.D.; et al. Systematic review of natural coumarins in plants (2019–2024): Chemical structures and pharmacological activities. Phytochemistry 2025, 235, 114480.
- 34. Mustafa, Y.F.; Bashir, M.K.; Oglah, M.K.; et al. Bioactivity of Some Natural and Semisynthetic Coumarin Derived Compounds. NeuroQuantology 2021, 19, 129–138.
- 35. Aqib, M.; Khatoon, S.; Ali, M.; et al. Exploring the anticancer potential and mechanisms of action of natural coumarins and isocoumarins. Eur. J. Med. Chem. 2025, 282, 117088.
- 36. Zeki, N.M.; Mustafa, Y.F. Coumarin hybrids for targeted therapies: A promising approach for potential drug candidates. Phytochem. Lett. 2024, 60, 117–133.
- 37. Stefanachi, A.; Leonetti, F.; Pisani, L.; et al. Coumarin: A Natural, Privileged and Versatile Scaffold for Bioactive Compounds. Molecules 2018, 23, 250.
- 38. Gao, X.Y.; Li, X.Y.; Zhang, C.Y.; et al. Scopoletin: a review of its pharmacology, pharmacokinetics, and toxicity. Front. Pharmacol. 2024, 15, 1268464.
- 39. Aslantürk, Ö.S.; Aşkin Çelik, T. Anticancer effect of umbelliferone on MKN-45 and MIA PaCa-2 cell lines. Toxicol. In Vitro 2023, 93, 105694.
- 40. Venugopala, K.N.; Rashmi, V.; Odhav, B. Review on natural coumarin lead compounds for their pharmacological activity. Biomed. Res. Int. 2013, 2013, 963248.
- 41. Hacholli, V.B.; R., S.M.; H., P.B.; et al. Coumarin Derivatives as Anticancer Agents: Mechanistic Landscape with an Emphasis on Breast Cancer. Molecules 2025, 30, 4167.
- 42. Liu, X.; Hoft, D.F.; Peng, G. Senescent T cells within suppressive tumor microenvironments: Emerging target for tumor immunotherapy. J. Clin. Invest. 2020, 130, 1073–1083.
- 43. Jasim, S.F.; Mustafa, Y.F. New fused-coumarin composites: Synthesis, anticancer and antioxidant potentials evaluation. Eurasian Chem. Commun. 2022, 4, 607–619.
- 44. Basak, U.; Sarkar, T.; Mukherjee, S.; et al. Tumor-associated macrophages: an effective player of the tumor microenvironment. Front. Immunol. 2023, 14, 1295257.
- 45. Wu, Y.; Xu, J.; Liu, Y.; et al. A Review on Anti-Tumor Mechanisms of Coumarins. Front. Oncol. 2020, 10, 592853.
- 46. Qian, R.; Ge, J.; Fan, N.; et al. Natural Products in Cancer Prevention and Therapy: Current Challenges and Future Directions. MedComm 2026, 7, e70585.
- 47. Pisani, L.; Catto, M.; Muncipinto, G.; et al. A twenty-year journey exploring coumarin-based derivatives as bioactive molecules . Front. Chem. 2022, 10, 1002547.
- 48. Srirangan, P.; Rathnasooriya, P.S.A.; Ranganathan, A.; et al. Unveiling the Potential of Esculetin in Cancer Models and Chemotherapy-Induced Toxicity: Mechanistic Insights From Preclinical Evidence. J. Biochem. Mol. Toxicol. 2026, 40, e70740.
- 49. Jayasingam, S.D.; Citartan, M.; Thang, T.H.; et al. Evaluating the Polarization of Tumor-Associated Macrophages Into M1 and M2 Phenotypes in Human Cancer Tissue: Technicalities and Challenges in Routine Clinical Practice. Front. Oncol. 2020, 9, 1512.
- 50. Ouyang, X.; Zhao, Z.; Hou, Y.; et al. Scopoletin alleviates cognitive deficits in 5xFAD mice via suppressing microglial inflammatory response. Phytomedicine 2026, 153, 157981.
- 51. Chen, F.; Wang, N.; Liao, J.; et al. Esculetin rebalances M1/M2 macrophage polarization to treat sepsis-induced acute lung injury through regulating metabolic reprogramming. J. Cell. Mol. Med. 2024, 28, e70178.
- 52. Kim, D.J.; Jung, M.S.; Jin, H.U.; et al. Anti-Melanogenic Effects of Umbelliferone: In Vitro and Clinical Studies. Molecules 2024, 29, 5571.
- 53. Li, M.; Wang, J.; Huo, B.; et al. Umbelliferone Enhances Immune Function in Cyclophosphamide-Induced Immunosuppressed Mice via Histidine and Purine Metabolism Regulation. Curr. Drug Metab. 2025, 25, 695–705.
- 54. Kornicka, A.; Balewski, Ł.; Lahutta, M.; et al. Umbelliferone and Its Synthetic Derivatives as Suitable Molecules for the Development of Agents with Biological Activities: A Review of Their Pharmacological and Therapeutic Potential. Pharmaceuticals 2023, 16, 1732.
- 55. Rodrigues, V.D.; Detregiachi, C.R.P.; dos Santos Bueno, M.; et al. Imperatorin: A Furanocoumarin with Potential in Combating Cancer Development and Progression—A Comprehensive Review. Pharmaceuticals 2026, 19, 436.
- 56. Bajaj, P.; Kumar, A.; Singh, B.; et al. Immunomodulatory Phytochemicals in Cancer: Mechanistic Pathways and Translational Potential. Chem. Biodivers. 2026, 23, e02737.
- 57. Chen, Y.; Zhang, Q.; Liu, H.; et al. Esculetin Ameliorates Psoriasis-Like Skin Disease in Mice by Inducing CD4+Foxp3+ Regulatory T Cells. Front. Immunol. 2018, 9, 2092.
- 58. Zhang, Z.; Long, S.; Huang, Z.; et al. Regulatory effect of daphnetin on the balance of Th17 and Treg cells in the peripheral blood mononuclear cells from patients with unexplained recurrent pregnancy loss. Cent. Eur. J. Immunol. 2021, 45, 403–408.
- 59. Mazumder, A.; Lee, J.Y.; Talhi, O.; et al. Hydroxycoumarin OT-55 kills CML cells alone or in synergy with imatinib or Synribo: Involvement of ER stress and DAMP release. Cancer Lett. 2018, 438, 197–218.
- 60. Liu, K.; Huang, H.; Zhang, M.; et al. When therapy-induced senescence meets tumors: A double-edged sword: A review. Medicine 2025, 104, e42886.
- 61. Hosseini, F.; Ahmadi, A.; Sarvi, Z.N.; et al. 7-Geranyloxycoumarin modulated metastatic potential of osteosarcoma cells via interaction with MMPs and JAK1/2. Naunyn Schmiedebergs Arch. Pharmacol. 2025, 398, 10139–10153.
- 62. Ji, H.; Tan, Y.; Gan, N.; et al. Synthesis and anticancer activity of new coumarin-3-carboxylic acid derivatives as potential lactate transport inhibitors. Bioorg. Med. Chem. 2021, 29, 115870.
- 63. Zhou, R.; Yu, Y.H.; Kim, H.; et al. Synthesis of coumarin derivatives and investigation of their inhibitory effects on lung cancer cell motility. Sci. Rep. 2022, 12, 21635.
- 64. Yang, J.; Han, J.; Li, Y.; et al. Esculetin inhibits the apoptosis in H9c2 cardiomyocytes via the MAPK signaling pathway following hypoxia/reoxygenation injury. Biomed. Pharmacother. 2017, 88, 1206–1210.
- 65. Yao, F.; Zhang, L.; Jiang, G.; et al. Osthole attenuates angiogenesis in an orthotopic mouse model of hepatocellular carcinoma via the downregulation of nuclear factor-κB and vascular endothelial growth factor. Oncol. Lett. 2018, 16, 4471–4479.
- 66. Guo, Y.; Xiao, Y.; Guo, H.; et al. The anti-dysenteric drug fraxetin enhances anti-tumor efficacy of gemcitabine and suppresses pancreatic cancer development by antagonizing STAT3 activation. Aging 2021, 13, 18545–18563.
- 67. Ionescu, C.; Oprea, B.; Ciobanu, G.; et al. The Angiogenic Balance and Its Implications in Cancer and Cardiovascular Diseases: An Overview. Medicina 2022, 58, 903.
- 68. Fan, Z.; Gao, J.; Chen, Y.; et al. Psoralen remodels the articular cartilage microenvironment by pharmacologically regulating the Nrf2 pathway in osteoarthritis treatment. Int. Immunopharmacol. 2025, 149, 114221.
- 69. Du, W.; Xia, X.; Hu, F.; et al. Extracellular matrix remodeling in the tumor immunity. Front. Immunol. 2024, 14, 1340634.
- 70. Sakthivel, K.M.; Vishnupriya, S.; Chandramani, L.; et al. Modulation of multiple cellular signalling pathways as targets for anti-inflammatory and anti-tumorigenesis action of Scopoletin. J. Pharm. Pharmacol. 2022, 74, 147–161.
- 71. Ma, J.; Zhang, M.; Mulati, S.; et al. Esculetin inhibits the PI3K/Akt/mTOR pathway and enhances anti-colorectal cancer activity via binding to ENO1. Front. Pharmacol. 2025, 16, 1627114.
- 72. Wei, Z.; Wei, N.; Su, L.; et al. The molecular effects underlying the pharmacological activities of daphnetin. Front. Pharmacol. 2024, 15, 1407010.
- 73. Abd, M.A.; Asiri, M.; Farhan, S.R.; et al. Update on Application of Oncolytic Virus-Based Combination Therapy in the Treatment of Hepatocellular Carcinoma. J. Biochem. Mol. Toxicol. 2025, 39, e70327.
- 74. Aden, D.; Zaheer, S.; Zaheer, S. Unlocking Cancer Immunity: Deciphering the Role of Tumor-Associated Macrophages in Modulating Immunosuppressive Tumor Microenvironment. Cell Biol. Int. 2026, 50, e70156.
- 75. He, L.; Tam, P.K.H.; Deng, C.X. Orchestration of Tumor-Associated Macrophages in the Tumor Cell-Macrophage-CD8+ T Cell Loop for Cancer Immunotherapy. Int. J. Biol. Sci. 2025, 21, 4098–4116.
- 76. Huang, L.; Wu, E.; Liao, J.; et al. Research Advances of Engineered Exosomes as Drug Delivery Carrier. ACS Omega 2023, 8, 43374–43387.
- 77. Ventura, T.; Silva, D.; Lassounskaia, E.; et al. Coumarine Analogues with Antimycobacterial and Immunomodulatory Activity. Curr. Bioact. Compd. 2015, 11, 109–115.
- 78. Di Stasi, L.C. Coumarin derivatives in inflammatory bowel disease. Molecules 2021, 26, 422.
- 79. Al-Attabi, A.; Mohammed, M.S.; Al-Khazali, N.A.Y.; et al. Nettle (Urtica Dioica L.) Modulates Angiogenesis by Targeting the PI3K/AKT/eNOS Pathway in Prostate Cancer. Middle East J. Cancer 2025, 16, 228–237.
- 80. Mustafa, Y.F. 4-Chloroskimmetine-based derivatives as potential anticancer and antibacterial prospects: Their synthesis and in vitro inspections. Results Chem. 2024, 7, 101511.
- 81. Leung, K.N.; Leung, P.Y.; Kong, L.P.; et al. Immunomodulatory effects of esculetin (6,7-dihydroxycoumarin) on murine lymphocytes and peritoneal macrophages. Cell. Mol. Immunol. 2005, 2, 181–188.
- 82. Al-Rashidi, R.R.; Noraldeen, S.A.M.; Kareem, A.K.; et al. Malignant function of nuclear factor-kappaB axis in prostate cancer: Molecular interactions and regulation by non-coding RNAs. Pharmacol. Res. 2023, 194, 106775.
- 83. Al-Warhi, T.; Sabt, A.; Elkaeed, E.B.; et al. Recent advancements of coumarin-based anticancer agents: An up-to-date review. Bioorg. Chem. 2020, 103, 104163.
- 84. Thakur, A.; Singla, R.; Jaitak, V. Coumarins as anticancer agents: A review on synthetic strategies, mechanism of action and SAR studies. Eur. J. Med. Chem. 2015, 101.
- 85. Rawat, A.; Vijaya Bhaskar Reddy, A. Recent advances on anticancer activity of coumarin derivatives. Eur. J. Med. Chem. Rep. 2022, 5, 100038.
- 86. Koley, M.; Han, J.; Soloshonok, V.A.; et al. Latest developments in coumarin-based anticancer agents: Mechanism of action and structure–activity relationship studies. RSC Med. Chem. 2024, 15, 10–54.
- 87. Ghemrawi, R.; Abuamer, L.; Kremesh, S.; et al. Revolutionizing Cancer Treatment: Recent Advances in Immunotherapy. Biomedicines 2024, 12, 2158.
- 88. Singh, A.; Singh, K.; Kaur, K.; et al. Coumarin as an Elite Scaffold in Anti-Breast Cancer Drug Development: Design Strategies, Mechanistic Insights, and Structure–Activity Relationships. Biomedicines 2024, 12, 1192.
- 89. Patra, I.; Ansari, M.J.; Saadoon, N.; et al. Insights into the Electronic Properties of Coumarins: A Comparative Study Photocatalytic Degradation of Methylene Blue. Phys. Chem. Res. 2023, 11, 437–447.
- 90. Xiujuan, Z.; Hengli, Y.; Jinye, W.U.; et al. Synthesis and anti-inflammatory activity of three series of coumarin-based derivatives. J. China Pharm. Univ. 2025, 56, 40–48.
- 91. Flores-Morales, V.; Villasana-Ruíz, A.P.; Garza-Veloz, I.; et al. Therapeutic Effects of Coumarins with Different Substitution Patterns. Molecules 2023, 28, 2413.
- 92. Mohamed-Ezzat, R.A.; Elgemeie, G.H. Synthetic strategies towards benzothiazole-based compounds of therapeutic potency: Experimental, investigational and approved drugs. RSC Adv. 2025, 15, 41724–41832.
- 93. Kumari, S.; Carmona, A.V.; Tiwari, A.K.; et al. Amide Bond Bioisosteres: Strategies, Synthesis, and Successes. J. Med. Chem. 2020, 63, 12290–12358.
- 94. Atia, Y.A.; Bokov, D.O.; Zinnatullovich, K.R.; et al. The role of amino acid functionalization for improvement of adsorption Thioguanine anticancer drugs on the boron nitride nanotubes for drug delivery. Mater. Chem. Phys. 2022, 278, 125664.
- 95. Chavez Alvarez, A.C.; Moreau, E. Coumarin-Based Prodrugs: Therapeutic Promise or Still Confined to Preclinical Exploration? Pharmaceutics 2026, 18, 341.
- 96. Brion, A.; Chaud, J.; Léonard, J.; et al. Red Light‐Responsive Upconverting Nanoparticles for Quantitative and Controlled Release of a Coumarin‐Based Prodrug. Adv. Healthc. Mater. 2023, 12, e2201474.
- 97. Javed, M.; Saade, A.; Jasim, A.; et al. Anticancer Drug-Loading Capacity of Green Synthesized Porous Magnetic Iron Nanocarrier and Cytotoxic Effects Against Human Cancer Cell Line. J. Clust. Sci. 2022, 4, 44–47.
- 98. Zeki, N.M.; Mustafa, Y.F. Digital alchemy: Exploring the pharmacokinetic and toxicity profiles of selected coumarin-heterocycle hybrids. Results Chem. 2024, 10, 101754.
- 99. Rubab, L.; Afroz, S.; Ahmad, S.; et al. An Update on Synthesis of Coumarin Sulfonamides as Enzyme Inhibitors and Anticancer Agents. Molecules 2022, 27, 1604.
- 100. Chen, L.; Lv, Q.; Cai, J.; et al. Design, synthesis and anticancer activity studies of 3-(coumarin-3-yl)-acrolein derivatives: Evidenced by integrating network pharmacology and vitro assay. Front. Pharmacol. 2023, 14, 1141121.
- 101. Zhang, X.; Yu; Zhang, W.Q.; et al. The antitumor activity of a doxorubicin loaded, iRGD-modified sterically-stabilized liposome on B16-F10 melanoma cells: in vitro and in vivo evaluation. Int. J. Nanomed. 2013, 8, 2473.
- 102. Fusco, M.; Picón, C.R.; Diaz, M.A.; et al. 4-Methylumbelliferone Modulates CAIX to Mitigate Hypoxia-Driven Dysregulation and Enhance PD-1 Immunotherapy in Lung Cancer. Int. J. Mol. Sci. 2025, 26, 10427.
- 103. Anupindi, K.; Malachowski, J.; Hodson, I.; et al. The next innovations in chimeric antigen receptor T cell immunotherapies for cancer. Cytotherapy 2025, 27, 795–811.
- 104. Abdelnaby, R.M.; Rateb, H.S.; Ali, O.; et al. Dual PI3K/Akt Inhibitors Bearing Coumarin-Thiazolidine Pharmacophores as Potential Apoptosis Inducers in MCF-7 Cells. Pharmaceuticals 2022, 15, 428.
- 105. Kumari, S.; Sharma, A.; Yadav, S. Pharmacological Potential of Coumarin-Based Derivatives: (A Comprehensive Brief Review). Orient. J. Chem. 2023, 39, 568–576.
- 106. Pallathadka, H.; Khaleel, A.Q.; Zwamel, A.H.; et al. Multi-Drug Resistance and Breast Cancer Progression via Toll-Like Receptors (TLRs) Signaling. Cell Biochem. Biophys. 2024, 82, 3015–3030.
- 107. Saadati, F.; Modarresi Chahardehi, A.; Jamshidi, N.; et al. Coumarin: A natural solution for alleviating inflammatory disorders. Curr. Res. Pharmacol. Drug Discov. 2024, 7, 100202.
- 108. Song, B.; Wang, Z.; Liu, Y.; et al. Immunosuppressive Activity of Daphnetin, One of Coumarin Derivatives, Is Mediated through Suppression of NF-κB and NFAT Signaling Pathways in Mouse T Cells. Rengarajan, J., Ed. PLoS One 2014, 9, e96502.
- 109. Ahmad Bhat, A.; Kaur, G.; Tandon, N.; et al. Current advancements in synthesis, anticancer activity, and structure–activity relationship (SAR) of coumarin derivatives. Inorg. Chem. Commun. 2024, 167, 112605.
- 110. Lin, H.; You, Q.; Wei, X.; et al. Osthole, a Coumarin from Cnidium monnieri: A Review on Its Pharmacology, Pharmacokinetics, Safety, and Innovative Drug Delivery Platforms. Am. J. Chin. Med. 2024, 52, 1397–1425.
- 111. Maashi, M.S.; Al-Mualm, M.; Al-Awsi, G.R.L.; et al. Apigenin alleviates resistance to doxorubicin in breast cancer cells by acting on the JAK/STAT signaling pathway. Mol. Biol. Rep. 2022, 49, 8777–8784.
- 112. Budi, H.S.; Younus, L.A.; Lafta, M.H.; et al. The role of miR-128 in cancer development, prevention, drug resistance, and immunotherapy. Front. Oncol. 2023, 12, 1067974.
- 113. Thomas, V.; Giles, D.; Basavarajaswamy, G.; et al. Coumarin Derivatives as Anti-inflammatory and Anticancer Agents. Anticancer Agents Med. Chem. 2017, 17, 415–423.
- 114. Lv, J.; Ibrahim, Y.S.; Yumashev, A.; et al. A comprehensive immunobiology review of IBD: With a specific glance to Th22 lymphocytes development, biology, function, and role in IBD. Int. Immunopharmacol. 2024, 137, 112486.
- 115. Hosseini, F.; Ahmadi, A.; Hassanzade, H.; et al. Inhibition of melanoma cell migration and invasion by natural coumarin auraptene through regulating EMT markers and reducing MMP-2 and MMP-9 activity. Eur. J. Pharmacol. 2024, 971, 176517.
- 116. Giercuszkiewicz-Haśnik, K.; Morak-Młodawska, B.; Jeleń, M. Molecularly Targeted Therapies in Oncology: Mechanisms, Resistance, and Combination Strategies. Molecules 2026, 31, 1195.
- 117. Aden, D.; Sureka, N.; Zaheer, S.; et al. Metabolic Reprogramming in Cancer: Implications for Immunosuppressive Microenvironment. Immunology 2025, 174, 30–72.
- 118. Abdelaal, H.I.; Mohamed, A.R.; Abo-Ashour, M.F.; et al. Mitigating the resistance of MCF-7 cancer cells to Doxorubicin under hypoxic conditions with novel coumarin based carbonic anhydrase IX and XII inhibitors. Bioorg. Chem. 2024, 152, 107759.
- 119. Jasim, S.A.; Khalaf, O.Z.; Alshahrani, S.H.; et al. An in vitro investigation of the apoptosis-inducing activity of corosolic acid in breast cancer cells. Iran. J. Basic Med. Sci. 2023, 26, 453–460.
- 120. Jin, X.; Zhang, N.; Yan, T.; et al. Lactate-mediated metabolic reprogramming of tumor-associated macrophages: Implications for tumor progression and therapeutic potential. Front. Immunol. 2025, 16, 1573039.
- 121. Mergia Terefe, E.; Catalan Opulencia, M.J.; Rakhshani, A.; et al. Roles of CCR10/CCL27–CCL28 axis in tumour development: Mechanisms, diagnostic and therapeutic approaches, and perspectives. Expert Rev. Mol. Med. 2022, 24, e37.
- 122. Jin, R.; Neufeld, L.; McGaha, T.L. Linking macrophage metabolism to function in the tumor microenvironment. Nat. Cancer 2025, 6, 239–252.
- 123. Singh, A.; Pillai, L.; Danes, D.; et al. 4-fluorophenylacetamide acetyl coumarin induces pro-inflammatory M1 macrophage polarization and suppresses the immunosuppressive M2 phenotype through PI3k/AKT/NF-κB modulation. Mol. Biol. Rep. 2025, 52, 415.
- 124. Rannikko, J.H.; Hollmén, M. Clinical landscape of macrophage-reprogramming cancer immunotherapies. Br. J. Cancer 2024, 131, 627–640.
- 125. Jamiyan, T.; Kuroda, H.; Yamaguchi, R.; et al. CD68- and CD163-positive tumor-associated macrophages in triple negative cancer of the breast. Virchows Arch. 2020, 477, 767–775.
- 126. Redavid, A.R.; Bigliardi, M.; Ciarrocchi, A.; et al. Transcriptional networks weaving natural killer anti-tumor immune response. Mol. Cancer 2026, 25, 113.
- 127. Mukherjee, S.; Ghosh, A.; Chakraborty, S.; et al. Tumor-infiltrating lymphocytes and tumor-associated macrophages in cancer immunoediting: A targetable therapeutic axis. Front. Immunol. 2025, 16, 1655176.
- 128. Long, Z.; Yang, Q.; Wu, Y.; et al. From Demyelination to Intervention: Natural Compounds as Emerging Therapeutic Targets in Multiple Sclerosis Neuroinflammation. Gurumallesh, P., Ed. J. Immunol. Res. 2026, 2026, 6333512.
- 129. Troise, D.; Infante, B.; Mercuri, S.; et al. Dendritic Cells: A Bridge between Tolerance Induction and Cancer Development in Transplantation Setting. Biomedicines 2024, 12, 1240.
- 130. Emam, S.H.; Hassan, R.A.; Osman, E.O.; et al. Coumarin derivatives with potential anticancer and antibacterial activity: Design, synthesis, VEGFR‐2 and DNA gyrase inhibition, and in silico studies. Drug Dev. Res. 2023, 84, 475–499.
- 131. Kim, S.O.; Hwangbo, H.; Hong, S.H.; et al. Esculetin Attenuates the Migration and Invasion of Human Hepatocellular Carcinoma Cells by Attenuating Matrix Metalloproteinase Activity and Strengthening Tight Junctions. J. Cancer Prev. 2025, 30, 111–117.
- 132. Al-Hawary, S.I.S.; Alhajlah, S.; Olegovich, B.D.; et al. Effective extracellular vesicles in glioma: Focusing on effective ncRNA exosomes and immunotherapy methods for treatment. Cell Biochem. Funct. 2024, 42, e3921.
- 133. Cabral-Pacheco, G.A.; Garza-Veloz, I.; Castruita-De la Rosa, C.; et al. The Roles of Matrix Metalloproteinases and Their Inhibitors in Human Diseases. Int. J. Mol. Sci. 2020, 21, 9739.
- 134. Kao, S.J.; Su, J.L.; Chen, C.K.; et al. Osthole inhibits the invasive ability of human lung adenocarcinoma cells via suppression of NF-κB-mediated matrix metalloproteinase-9 expression. Toxicol. Appl. Pharmacol. 2012, 261, 105–115.
- 135. Majnooni, M.B.; Fakhri, S.; Smeriglio, A.; et al. Antiangiogenic Effects of Coumarins against Cancer: From Chemistry to Medicine. Molecules 2019, 24, 4278.
- 136. Liu, Z.L.; Chen, H.H.; Zheng, L.L.; et al. Angiogenic signaling pathways and anti-angiogenic therapy for cancer. Signal Transduct. Target. Ther. 2023, 8, 198.
- 137. Irfan, D.; Ahmad, I.; Patra, I.; et al. Stem cell-derived exosomes in bone healing: focusing on their role in angiogenesis. Cytotherapy 2023, 25, 353–361.
- 138. Schiliro, C.; Firestein, B.L. Mechanisms of Metabolic Reprogramming in Cancer Cells Supporting Enhanced Growth and Proliferation. Cells 2021, 10, 1056.
- 139. Rodrigues, P.; Bangali, H.; Ali, E.; et al. The mechanistic role of NAT10 in cancer: Unraveling the enigmatic web of oncogenic signaling. Pathol. Res. Pract. 2024, 253, 154990.
- 140. Tanimoto, A.; Witaicenis, A.; Caruso, Í.P.; et al. 4-Methylesculetin, a natural coumarin with intestinal anti-inflammatory activity, elicits a glutathione antioxidant response by different mechanisms. Chem. Biol. Interact. 2020, 315, 108876.
- 141. Puiggros, A.; Collado, R.; Calasanz, M.J.; et al. Patients with chronic lymphocytic leukemia and complex karyotype show an adverse outcome even in absence of TP53/ATM FISH deletions. Oncotarget 2017, 8, 54297–54303.
- 142. Pliszka, M.; Szablewski, L. Glucose Transporters as a Target for Anticancer Therapy. Cancers 2021, 13, 4184.
- 143. Li, S.; Gong, J.; Kang, B.; et al. Targeting Glycolytic Metabolism in Cancer Therapy: Current Approaches and Future Perspectives. Cells 2026, 15, 362.
- 144. Draoui, N.; Schicke, O.; Fernandes, A.; et al. Synthesis and pharmacological evaluation of carboxycoumarins as a new antitumor treatment targeting lactate transport in cancer cells. Bioorg. Med. Chem. 2013, 21, 7107–7117.
- 145. Mosa, A.I.; Emara, A.A.A.; Yousef, J.M.; et al. Novel transition metal complexes of 4-hydroxy-coumarin-3-thiocarbohydrazone: Pharmacodynamic of Co(III) on rats and antimicrobial activity. Spectrochim. Acta A Mol. Biomol. Spectrosc. 2011, 81, 35–43.
- 146. Wang, Y.; Shelton, S.E.; Kastrunes, G.; et al. Preclinical models for development of immune–oncology therapies. Immuno-Oncol. Insights 2022, 3, 396–398.
- 147. Kenoosh, H.A.; Pallathadka, H.; Hjazi, A.; et al. Recent advances in mRNA‐based vaccine for cancer therapy; bench to bedside. Cell Biochem. Funct. 2024, 42, e3954.
- 148. Yadav, A.K.; Maharjan Shrestha, R.; Yadav, P.N. Anticancer mechanism of coumarin-based derivatives. Eur. J. Med. Chem. 2024, 267, 116179.
- 149. Gupta, R.; Radhakrishnan, R.; Kabekkodu, S.P.; et al. Application of in vitro and in vivo cancer models to study the impact of the tumor immune microenvironment on anticancer therapy. Biochim. Biophys. Acta Rev. Cancer 2026, 1881, 189504.
- 150. Wu, S.; Hu, Y.; Sui, B. Promotion Mechanisms of Stromal Cell-Mediated Lung Cancer Development within Tumor Microenvironment. Cancer Manag. Res. 2025, 17, 249–266.
- 151. Zamani Taghizadeh Rabe, S.; Iranshahi, M.; Mahmoudi, M. In vitro anti-inflammatory and immunomodulatory properties of umbelliprenin and methyl galbanate. J. Immunotoxicol. 2016, 13, 209–216.
- 152. Jung, H.S.; Park, Y.J.; Gu, B.H.; et al. Coumarin derivatives ameliorate the intestinal inflammation and pathogenic gut microbiome changes in the model of infectious colitis through antibacterial activity. Front. Cell. Infect. Microbiol. 2024, 14, 1362773.
- 153. Kim, S.; Abikenari, M.; Bergsneider, B.; et al. Biomarkers for predicting immunotherapy response and resistance in glioblastoma. Front. Immunol. 2026, 17, 1823338.
- 154. Passaro, A.; Al Bakir, M.; Hamilton, E.G.; et al. Cancer biomarkers: Emerging trends and clinical implications for personalized treatment. Cell 2024, 187, 1617–1635.
- 155. Holder, A.M.; Dedeilia, A.; Sierra-Davidson, K.; et al. Defining clinically useful biomarkers of immune checkpoint inhibitors in solid tumours. Nat. Rev. Cancer 2024, 24, 498–512.
- 156. Petroni, G.; Buqué, A.; Zitvogel, L.; et al. Immunomodulation by targeted anticancer agents. Cancer Cell 2021, 39, 310–345.
- 157. Gangopadhyay, A. Plant-derived natural coumarins with anticancer potentials: future and challenges. J. Herb. Med. 2023, 42, 100797.
- 158. Hanh, N.T.; Van, C.A.; Son, N.T. Recent advances in bioactive coumarin scoparone: A comprehensive review. Fitoterapia 2026, 188, 106966.
- 159. Lake, B.G.; Evans, J.G.; Lewis, D.F.V.; et al. Studies on the acute effects of coumarin and some coumarin derivatives in the rat. Food Chem. Toxicol. 1994, 32, 357–363.
- 160. Olatunde, A.; Tijjani, H.; Aremu, A.O.; et al. Editorial: Chemistry, toxicity, synthesis, biological and pharmacological activities of coumarins and their derivatives: Recent advances and future perspectives. Front. Pharmacol. 2024, 15.
- 161. Di Stasi, L.C. Natural Coumarin Derivatives Activating Nrf2 Signaling Pathway as Lead Compounds for the Design and Synthesis of Intestinal Anti-Inflammatory Drugs. Pharmaceuticals 2023, 16, 511.
- 162. Mohamed, F.A.M. A current summary of coumarin-based compounds and their therapeutic applications. Egypt. J. Chem. 2024, 67, 1417–1437.
- 163. Niinivehmas, S.; Pentikäinen, O. Coumarins as Tool Compounds to Aid the Discovery of Selective Function Modulators of Steroid Hormone Binding Proteins. Molecules 2021, 26, 5142.