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Life sciences · Journal article
Pharmaceutics · October 28, 2026
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Cancer therapy remains challenged by recurrence, metastasis, acquired drug resistance, and tumor heterogeneity, underscoring the need for safe multitarget agents and adjuvant strategies. Citrus fruits, widely used as medicinal and edible resources, provide abundant bioactive constituents in their peels, pulp, seeds, and processing by-products, including flavonoids, terpenoids, coumarins, polysaccharides, and pectin. Increasing preclinical evidence shows that Citrus-derived bioactive compounds modulate multiple processes involved in tumor initiation and progression. They inhibit proliferation; induce cell-cycle arrest, apoptosis, autophagy, and ferroptosis; suppress invasion, metastasis, and angiogenesis; attenuate oxidative stress and inflammation; reverse therapeutic resistance; and regulate the tumor immune microenvironment. These effects are associated with key signaling networks, including PI3K/Akt/mTOR, MAPK, NF-κB, STAT3, Wnt/β-catenin, Nrf2, PD-L1, and galectin-3. Owing to their pleiotropic mechanisms and generally favorable safety profiles, Citrus-derived compounds have potential as anticancer leads, therapeutic sensitizers, resistance modulators, and tumor-microenvironment regulators for integrated cancer therapy. However, translation is hindered by poorly defined active constituents in complex Citrus preparations and insufficiently characterized direct molecular targets, poor aqueous solubility, limited oral bioavailability, rapid metabolism, inconsistent quality control, weak pharmacokinetic–pharmacodynamic correlations, and insufficient clinical evidence. This review summarizes the chemical features, anticancer mechanisms, combination therapy potential, and translational barriers of citrus-derived bioactive compounds, providing guidance for candidate selection, formulation optimization, and anticancer drug development.