Table 2.

Cellular mediators and therapeutic approaches for modulating immunosuppression in the TME

Cellular mediator	Mechanism of intervention	Target	Strategy	Reference
TAMs	Inhibition of macrophage recruitment	CCL2/CCR2, CCL5/CCR5, CSF-1	CCL2 neutralizing antibody, Maraviroc, CCL5 neutralizing antibody, CCR5 blocking antibody, CSF-1 neutralizing antibody	[190–192]
	Suppressing TAM survival	FRβ, legumain	Bisphosphonate, clodronate, anti-FRβ-Pseudomonas exotoxin A, legumain-based DNA vaccine	[193–195, 201]
	Enhancing M1 macrophage activity	NFκB pathway, MAPK/ERK pathway, VEGF	TLR agonists, CuNG, GM-CSF	[196–198]
	Blocking M2 tumor-promoting activity	STAT3, PI3Kγ	Sunitinib, IPI-549	[199, 200]
MDSCs	Blocking development of MDSCs	JAK2/STAT3 signaling	cucurbitacin B, sunitinib	[209, 272]
	Differentiation of MDSCs into mature cells	Flt3	Retinoic acid, vitamins D3.	[273, 274]
	Inhibiting the function of MDSCs	PDE5, COX-2/PGE2, JAK1/STAT3	Sildenafil, SC58236, acetylsalicylic acid, celecoxib, CDDO-Me	[212, 214, 275, 276]
	Depletion of MDSCs	Hsp90	Gemcitabine, 17-DMAG	[277, 278]
Tregs	Blocking Tregs recruitment	CCR4/CCL22	Anti-CCR4 mAb (KW-0761)	[226]
	Intratumoral Treg depletion	IL-2Rα/CD25	Daclizumab	[227]
	Modulation of Tregs	STAT3, STAT5	Cyclophosphamide, imatinib mesylate, sunitinib, sorafenib	[228–231]
	Inhibiting the function of Treg	CTLA4	Anti-CTLA4 mAb	[232]
TAFs	Inhibiton of TAF activation	FAP, PDGF-R, TGF-β, SDF-1, Hh signaling	Anti-FAP vaccination, imatinib, AMD3100, Hh antagonist, anti-Hhligand-blocking antibody	[253, 255, 256, 263]
	Blocking interactions between TAFs and tumor cells	CXCL12/CXCR 4, TGF-β, HGF, COX-2/PGE2	AMD3100, LY550410, celecoxib, dexamethasone	[257–261]
	Blocking interactions between TAFs and endothelial cells	VEGF, PDGFs, FGFs, MMPs	Avastin, sorafenib yosylate, imatinib mesylate, ponatinib, batimastat	[254, 262, 264, 265]
	Targeting TAF-induced inflammation	NFκB, CXCL12, CXCL13	QNZ, AMD3100, tadalafil, sildenafil	[266–268]