TABLE 5.

Natural antitumor terpenoids and their sources, experimental models, and mechanisms of targeting regulatory immune cells.

Category	Name	Source	Tumor type	Clinical/experimental	Targeted regulatory immune cell mechanisms	Reference
Triterpenoids	23-Hydroxybetulinic acid	Pulsatilla chinensis (Bge.) Regel	Colon cancer	In vitro and in vivo	Inhibiting MDSC immunosuppressive function by the inhibition of MDSC differentiation, thereby restoring the antitumor activity of CD8+ T cells (7.5, 15, and 30 mg/mL, respectively, once a day for 18 days, i.v.)	He et al. (2024)
			Colorectal cancer	In vitro and in vivo	Promoting the polarization of TAMs from the M1 type to the M2 type by activating the JAK/STAT3/NF-κB/STAT1 pathway (15 and 30 mg/kg, respectively, once a day for 20 days, i.p.; 80 mg/kg once a day for 20 days, i.g.)	Liu (2023)
	Madecassic acid	Centella asiatica (L.) Urb	Colorectal cancer	In vivo	Increasing the population of antitumor immune cells in the tumor microenvironment by blocking the recruitment of MDSCs via the inhibition of the activation of γδT17 cells (6.25, 12.5, and 25 mg/kg, respectively, i.g.)	Yun et al. (2022)
	Oleanolic acid	Pseudocydonia sinensis (Dum.Cours.) C.K.Schneid	Gastric cancer	In vivo	Promoting the balance of Treg/Th17 cells by promoting the expression of miR-98–5 (NA)	Xu et al. (2021)
	Ursolic acid	Basil, apples, prunes, and cranberries	Breast cancer	In vivo	Modulating CD4+ CD25+ FoxP3+ T cells in 4T1 tumor-bearing mice by inhibiting STAT5 phosphorylation and IL-10 secretion (10 mg/kg once every other day for five times, i.v.)	Zhang et al. (2020)
	Glycyrrhizic acid	Glycyrrhiza glabra	Melanoma	In vitro	Inhibiting B16F10 cell proliferation by STAT3-mediated Treg and MDSC downregulation (NA)	Kumar et al. (2020)
	Ganoderic acid Me	Ganoderma lucidum	Lung cancer	In vitro	Enhancing Treg-mediated immunosuppression by directly inducing T-cell apoptosis and restraining CD8+ T-cell activation (NA)	Que et al. (2014)
	Obacunone	Dictamnus dasycarpus Turcz	Oral squamous cell carcinoma	In vivo	Suppressing tumor by promoting M1 macrophage polarization (50 and 100 mg/kg, respectively)	Zou et al. (2023)
Diterpenoids	Triptolide	Tripterygium wilfordii Hook. f	Liver cancer	In vitro and in vivo	Reducing the proportion of Tregs and inhibiting the secretion of anti-inflammatory factors such as IL-10 and TGF-β (0.157 and 0.314 mg/kg, respectively, once a day for 14 days, i.g.)	Liu (2011)
			Lung cancer	In vitro and in vivo	Inhibiting lung cancer by activating endoplasmic reticulum stress in MDSCs and promoting MDSC apoptosis (1 μg/mL once a day for 14 days, i.p.)	Sun et al. (2019)
			Ovarian cancer	In vitro and in vivo	Inhibiting the polarization of M2 macrophages and promoting M1 polarization by inhibiting the PI3K/AKT/NF-κB pathways (0.15 mg/kg of 0.2 mL once a day for 14 days, i.p.)	Hu (2020)
			Tumor-bearing mice	In vivo	Downregulation of Tregs, IL-10, TGF-β, and VEGF levels (0.15 mg/kg once a day for 7 days, i.p.)	Liu et al. (2013)
	Oridonin	Rabdosia rubescens	Breast cancer	In vitro and in vivo	Inhibiting Treg differentiation by decreasing TGF-β receptor expression (5 mg/kg once every 3 days for 24 days, i.p.)	Guo et al. (2020)
	Sclareol	Salvia sclarea	Breast cancer	In vivo	Decreasing the rate of tumor growth by increasing IFN-γ and decreasing IL-4 (7.85 µg once a day for 6 days)	Shokoofe et al. (2010)
	Paclitaxel	Taxus brevifolia Nutt	Advanced non-small-cell lung cancer	Clinical	Inducing Treg apoptosis by upregulating CD95 (30 ng/mL)	Zhang et al. (2008)
			Melanoma	In vitro	Suppressing tumor by inhibiting MDSC differentiation into dendritic cells (0.2 and 1 nM)	Tillmann et al. (2012)
	Carnosol	Rosmarinus officinalis L.	Fibrosarcoma	In vivo	Reducing the relative level of immunosuppressive Tregs and shifting toward increasing IFN-γ expression (5 and 10 mg/kg, respectively, once a day, i.p.)	Maryam et al. (2015)
Sesquiterpenoids	Artemisinin	Artemisia annua L.	Breast cancer	In vitro and in vivo	Inhibiting the in vivo growth of breast cancer by promoting T-cell activation and inhibiting the expression of Tregs and MDSCs in the tumor microenvironment (100 mg/kg once a day for 20 days, i.p.)	Cao et al. (2019)
	Fraxinellone	Dictamnus dasycarpus Turcz	Oral squamous cell carcinoma	In vivo	Suppressing tumor by promoting M1 macrophage polarization (50 and 100 mg/kg, respectively)	Zou et al. (2023)
	Tehranolide	Artemisia annua L.	Breast cancer	In vivo	Inhibiting tumor growth by reducing the number of CD4+ CD25+ FoxP3+ T lymphocytes (5.64 µg once a day for 6 days, i.p.)	Noori et al. (2010)
					Suppressing tumors by attenuating CD4+ CD25+ FoxP3+ Treg-mediated immune suppression and eliciting persistent antitumor immunity against cancer (5.64 μg once a day for 25 days, i.p.)	Noori et al. (2009)