Table 3.

Effects of curcuminoids and flavonoids on tumour-associated cells.

Agents	Model	Effects	Lit.
Phytosomal curcumin	Immune-competent syngeneic C57BL6 mice with orthotopically implanted mouse GL261 (GBM) cells	TAM phenotype (↓STAT3 ↓IL10, ↑IL12, ↑STAT1, ↓ARG1 and ↑MCP-1), ↑NK recruitment and ↑TAM repolarization from M2 to M1	[149]
TriCurin	Mice implanted with UMSCC47 (HNSCC) cells	TAM phenotype (↓ARG1, ↓IL10, ↑iNOS, ↑IL12, ↓STAT3, ↑STAT1 and ↑NF-KB), ↑NK recruitment and ↑TAM repolarization from M2 to M1	[150]
Curcumin	Mice implanted with GL261 (GBM) cells	Microglia phenotype (↑iNOS, ↓ARG2 and ↑NF-kB)	[205]
Pro-EGCG	Mice implanted with AN3CA and RL95-2 (EC) cells	↓VEGFA ↓HIF1α, ↓SDF1 and ↓TAM infiltration	[206]
EGCG exosomes	Mice implanted with 4T1 (BC) cells	TAM phenotype (↓IL-6, ↓TGF-β, and ↑TNF-α), ↓CSF-1, ↓CCL-2, ↓tumour growth and ↑TAM repolarization from M2 to M1	[207]
Curcumin	Mice implanted with HepG2 (HC) cells	(MDSC inducers (↓GM-CSF and ↓G-CSF), ↓MSDC phenotype (↓TLR4/NF-κB), ↓IL-6, ↓IL-1β, ↓PGE2, ↓COX-2, ↓VEGF and CAF marker (↓CD31 and ↓αSMC)	[208]
Curcumin	Mice implanted with Lewis lung carcinoma cells	↓IL-6 and ↓MDSCs	[158]
Curcumin	Mice implanted with 4T1 (BC) cells	↓G-MDSC and ↑M-MDSC polarization to M1 TAMs, ↑CD4+ T cells and ↑CD8+ T cells	[209]
Curcumin−PEG conjugate	Mice implanted with B16F10 (melanoma) cells	↓Treg cells ↓MDSC and CAF markers (↓α-SMA and ↓CD31)	[210]
Lipid-based Trp2 peptide combination vaccine		↑CD4+ T cells and ↑CD8+ T cells
Curcumin	Mice implanted with OSCC (induced by 4NQO) cells	↑CD8+ T cells, ↓Treg cells and ↓MDSCs	[159]
Bisdemethoxycurcumin	Immunocompetent mice implanted with subcutaneous or lung metastasised MB79 (bladder cancer) cells	↑CD8+ T cells, ↓Treg cells and ↑IFN-γ	[162]
α-PD-L1 antibody combination		↓MDSCs and CD8+ T cells (↑IFN-γ, ↑granzyme B, ↑perforin and ↓exhaustion)
Quercetin	Human and mouse G-MDSCs	↑ESR/STAT3, ↑NOS2 and prolonged MDSC survival in mice	[211]
EGCG	M-MDSCs	↓Arg-1/iNOS/Nox2/NF-κB/STAT3, ↓IL-6, ↓IL-10, ↓TGF-β, ↓GM-CSF, and ↑apoptosis	[212]
	Mice implanted with 4T1 (BC) cells	↓MDSCs ↑CD4+ T cells ↑CD8+ T cells
Polyphenon E	Transgenic TH-MYCN mice	↓MDDCs	[213]
	NOD/SCID mice implanted with SHSY5Y (neuroblastoma) cells	0MDSCs
	A/J mice implanted with syngeneic Neuro 2A (neuroblastoma) cells	↓MDSCs
	MDSCs	↑G-CSF, ↑IL-6, ↓Treg cell induction
Curcumin	Coculture of a primary BC line + T cells	↓TGF-β, ↓Treg cell phenotype induction (IL-2Rα, IL-6, and FoxP3) in CD4+ T cells	[214]
	Mice implanted with 4T1 cells	↓Treg cell phenotype (CD4+, CD25+, and FoxP3+)
Curcumin	HNSCC tissue	↓CCL22 (Treg cell mobility)	[215]
Curcumin	Patients with colon cancer	↑Conversion of Treg cells into Th1 cells and ↑induction of a Th1 cell phenotype (↓FoxP3 and ↑IFN-γ)	[216]
Curcumin	Patients with lung cancer	↑Conversion of Treg cell into Th1 cells and ↑induction of a Th1 cell phenotype (↓FoxP3 and ↑IFN-γ)	[154]
Curcumin	Primary TSCC CAFs	↓α-SMA, ↓TGF-β1, ↓SDF-1, ↓MMP-2, ↓SMAD2/3, ↓Cal27, and ↓proliferation	[173]
Curcumin	Mice implanted with Cal 27 (TSCC) cells	↓α-SMA and ↓Ki67
Curcumin	CAFs cocultured with Capan-1 and Panc-1 (pancreatic carcinoma) cells	↓CAF phenotype (↓α-SMA and ↓vimentin), ↑E-cadherin, ↓EMT and ↓cancer cell migration	[174]
	nu/nu nude mice implanted with Panc-1 tumour cells	↓Lung metastasis
Curcumin	CAFs cultured with prostate cancer pC-3 cells	↓ROS, ↓IL-6, ↓CXCR4 and ↓MAOA/mTOR/HIF-1α	[217]
Curcumin	Primary breast CAFs	↓α-SMA, ↓JAK2/STAT3, ↓SDF-1, ↓IL-6, ↓MMP-2 and ↓MMP-9, ↓TGF-β and ↓migration ability	[218]
Curcumin	TNF-α-activated ECs	↓NF-κB, ↓adhesion molecules (↓ICAM-1 and ↓VCAM-1) and ↓monocyte adhesion	[189]
Curcumin and EGCG or both agents combined	Coculture of ECs with SW620, HCT116, and HT-29 (CC) cells	↓TEC transition, ↓TEC phenotype (↓JAK, ↓STAT3, ↓IL-8, ↓TEM1, ↓TEM8 and ↓VEGFR2) and ↓TEC migration	[185]
	Mice implanted with patient-derived CCs	↓JAK, ↓STAT3 and ↓IL-8

α-SMA, alpha-smooth muscle actin; ARG1, arginase 1; ARG2, arginase 2; CD31, a platelet endothelial cell adhesion molecule; COX-2, cyclooxygenase-2; G-CSF, granulocyte colony-stimulating factor; ESR, oestrogen signalling receptor; GM-CSF, granulocyte−macrophage colony-stimulating factor; iNOS, inducible nitric oxide synthase; IL-1β, interleukin 1β; IL-2Ra, interleukin 2 receptor alpha; IL-6, interleukin 6; IL-8, interleukin 8; Il-L-10, interleukin 10; IL-12, interleukin 12; ICAM-1, intercellular adhesion molecule 1; JAK, Janus tyrosine kinase; HIF-1α, hypoxia-inducible factor 1α; NOS2, NADPH oxidase 2; nitric oxide synthase 2; PGE2, prostaglandin E2; ROS, reactive oxygen species; TGF-β, transforming growth factor beta; TEM1, tumour endothelial marker 1; TEM8, tumour endothelial marker 1; TLR4, Toll-like receptor 4; STAT3, signal transducer and activator of transcription 3; SDF-1, stromal-cell-derived factor 1; VCAM-1, vascular cell adhesion molecule 1; VEGF, vascular endothelial growth factor; VEGFR2, vascular endothelial growth factor receptor 2; 4NQO 4-nitroquinoline-1-oxide; G-MDSCs, granulocytic MDSCs; M-MDSCs, monocytic MDSCs; BC, breast carcinoma; CC, colorectal carcinoma; EC, endometrial carcinoma; GBM, glioblastoma; HC, hepatocellular carcinoma; HNSCC, head and neck squamous cell carcinoma; OSCC, oral cavity squamous cell carcinoma; TSCC, the squamous cell carcinoma. ↑ curcuminoids/flavonoids activation/induction; ↓ = curcuminoids/flavonoid repression/inhibition; 0 = without change.