Table1:

List of plant- and marine-based natural compounds and their TME targeting potential

Natural Agent (chemical category)	Source	Effect on TME	References
Terpenoids
Zerumbone (sesquiterpene)	Zingiber zerumbet Sm. (Ginger)	Downregulation of CD1d Inhibition of angiogenesis via targeting VEGF/VEGFR Inhibition in the colonization of enterotoxigenic Bacteroides fragilis	[252, 253, 255]
Curcumin (curcuminoid)	Curcuma longa (Turmeric plant)	Modulation of immunomodulatory cytokines Modulation of the ECM Disruption of tumor-fibroblast interaction Polarization towards M1 macrophage phenotype Decreased Tregs cells Increased central memory T cell	[221–225, 328, 332–333]
Alkaloids
Berberine (benzylisoquinoline alkaloids)	Berberis plants	Increased M1 macrophage polarization Active in a hypoxic microenvironment Disruption of tumor-fibroblast interaction Decreased Tregs cells Increased NK cell activity	[230, 231, 233, 334–336]
Trabectedin	Ecteinascidia turbinate (Marine ascidian)	Activation of NK cells Inhibition of macrophage polarization Targeting of PD-L1 positive tumor cells and immune cells Induction of CD8+ T cells infiltration	[291,292, 296, 337]
Phenylpropanoids
Honokiol (lignan)	Magnolia species	Activation of immunomodulatory cytokines Inhibition of angiogenesis Inhibition of immunosuppressive Tregs Stimulation of T-lymphocytes Disruption of tumor-fibroblast interaction	[157–160]
Hydroxytyrosol (catechol)	Oleaeuropaea (Olive plant)	Inhibits remodeling of ECM and angiogenesis Modulation of oxidative stress Active in a hypoxic microenvironment Modulation of immunomodulatory cytokines Disruption of tumor-stromal interaction	[167, 168, 343–345]
Resveratrol (stilbenoid)	Pine trees, peanut plants, grapevines, and vaccinium shrubs	Disables immunosuppressive Tregs Active in a hypoxic microenvironment Inhibition of cancer-associated fibroblasts Modulation of oxidative stress Inhibition of M2 polarization of macrophages	[199–203]
Epigallocatechin-3-gallate (EGCG; catechin)	Camellia sine sis (Tea)	Inhibition of metabolic circuitry in fibroblasts Decreased M2 macrophage infiltration Inhibition of tumor angiogenesis Improvement of immunotherapy response via downregulation of PD-L1	[240, 241, 350, 351]
Genistein (isoflavone)	Genistatinctoria	Inhibition of tumor angiogenesis Modulation of the ECM Inhibition of fibroblast growth Disruption of macrophage-tumor cell interaction	[261–263, 266]
Naringenin (flavones)	Grapefruit, bergamot, sour orange, tomatoes, coca and others	Decreased accumulation of ECM AbrogatesTGF-β mediated immunosuppression Inhibitionof VEGF-mediated angiogenesis	[279–281]
Onionin A (flavonoids and phenols)	Allium cepa (Onion)	Inhibition of macophage polarization Inhibition of the MDSCs activity Inhibitionof PDL-1 expression	[268, 270–272]
Others *
Plitidepsin (cyclodepsipeptide)	Aplidiumalbica ns (Mediterranean tunicate)	Inhibition of angiogenesis Activation of immunomodulatory cytokines Induce CD8+T cell infiltraion	[302, 304, 306]
Fucoidan (sulfated polysaccharides )	Brown algae and brown seaweed	Inhibition of M2 macrophage activity Activation of macrophage-induced tumor cell killing Activation of immunomodulatory cytokines	[317, 352, 353]

^*Nonribosomal polypeptides and modified polysaccharides.