Table 2.

Strategies for targeting EMP

Targeting EMP	Mouse model	How	Reference
Targeting extracellular inducers and receptors
TGFβ-TβRI inhibitors
Galunisertib/ LY2157299 (TβRI inhibitor)	Colon cancer	Maintained the cytotoxic T-cell response and rendered tumors susceptible to anti-PD-1/PD-L1 therapy.	[230]
	NSCLC and esophageal squamous-cell carcinoma (ESCC)	Promoted T-cell infiltration from the stroma into the tumor, enhanced the response to anti–PD-1 therapy.	[232]
	Melanoma	Enhanced the CTL response via ubiquitin-mediated degradation of Smad4.	[289]
	TNBC, 4T1 model	Increased T-cell numbers in treated tumors.	[231]
Vactosertib (TβRI inhibitor)	Orthotopic pancreatic cancer models	Inhibited ECM hyperplasia to allow paclitaxel to more easily access cancer cells.	[233]
AVID200 (selective inhibitor of TGF-β 1&3)	TNBC, 4T1 model	Enhanced anti-tumor T-cell activity.	[234]
FGFR inhibitors (tyrosine kinase inhibitors that non-specifically target FGFR)
Lenvatinib	Hepatocellular carcinoma	Reduced the tumor PD-L1 level and Treg differentiation to improve anti-PD-1 efficacy by blocking FGFR4.	[235]
	Renal cell carcinoma (RCC) cell lines	Decreased the population of TAMs and increased that of IFN-γ+ CD8+ T cells.	[236]
Pazopanib	Metastatic RCC	Inhibited the ERK/β-CATENIN pathway to prime DCs.	[290]
EGFR inhibitors
OSI774	EGFR-mutated NSCLC	Decreased the number of CD4+ effector regulatory T cells, and infiltration into the TME and enhanced the efficacy of anti-PD-1 mAb therapy.	[237]
ZD1839	Syngeneic mouse models	Destabilized PD-L1 and enhanced the therapeutic efficacy of PD-1 blockade.	[238]
RTK inhibitors (eg. Targeting AXL)
Cabozantinib	Advanced kidney cancer	Improved progression-free survival and the OS benefit when combined with nivolumab.	[291]
	metastatic castration-resistant prostate cancer (mCRPC)	Targeted mCRPC-infiltrating MDSCs and demonstrated a synergistic therapeutic response with ICB.	[292]
RXDX-106 (pan-TAM- TYRO3, AXL, MER small-molecule kinase inhibitor)	Multiple syngeneic mouse models	Increased intratumoral CD8+ T cells and potentiated the effects of α-PD-1 Ab treatment.	[247]
UNC4241	Melanoma	Increased CD8+ T-cell infiltration, and augmented anti–PD-1 checkpoint inhibitor immunotherapy.	[248]
BGB324 (Bemcentinib)	EGFR mutation-positive lung adenocarcinomas	Decreased the PD-L1 and CXCR6 mRNA levels.	[293]
	Mesenchymal-like glioblastoma tumors	Co-treatment with anti-BGB324 and anti-PD-1 antibodies improved survival in mouse GBM models.	[294]
	Lung cancers	Sensitized mesenchymal lung cancer cells to CTLs and NK cells via intracellular adhesion molecule-1 (ICAM-1)/leukocyte function-associated antigen-1 (ICAM1/LFA-1) and UL16 binding protein 1 (ULBP1)/ natural killer group 2, member D (NKG2D) interactions.	[246]
BMS-777607	Murine Model of Triple-Negative Breast Cancer	Blocks macrophage efferocytosis and Gas6-PS–opsonized apoptotic cell, and enhances anti-PD-1 mAb efficacy via up-regulating PD-L1 expression	[249]
SKI-G-801	B16F10 melanoma, CT26 colon and 4T1 breast model	Blocks metastasis through inducing CD8+ T cells, decreasing M2 macrophage and potentiates anti-PD-1 therapy	[250]
	TC1 and C3PQ mouse tumor models	Improves efficiency of anti-PD-1 therapy, exhibiting increased proportion of effector memory helper T cells, CD86+ macrophages.	[251]
Enapotamab vedotin (EnaV)	Melanoma and lung cancer models	Induced ICB benefit and promoted the induction of a memory-like phenotype in cytotoxic T cells.	[252]
R428	HER2+ breast cancer	Enhances anti-PD-1 responses via increased CD8+ T cells	[171]
PDGFR inhibitors
Imatinib	Gastrointestinal stromal tumors	Abrogated the IFN-γ induced upregulation of PD-L1 via STAT1 inhibition.	[295]
MET inhibitors
Crizotinib	NSCLC	In combination with cisplatin, induced immunogenic cell death by increasing PD-1 and PD-L1 levels in tumors and increased the response to anti-PD-1 treatment.	[296]
	ALK positive anaplastic lymphomas (ALCLs)	Decreased the PD-L1 level and promoted HLA class I antigen presentation.	[297]
Targeting intracellular transducers
AMPK activators
Metformin	Breast, melanoma and colorectal cancer (CRC) models (4T1-Luc2, B16-F10, CT26)	By reducing the stability and membrane localization of PD-L1, CTL activity was increased. Metformin boosted the efficacy of CTLA-4 immunotherapy.	[257]
	Hepatoma and TNBC models (H22 tumor-bearing mice, 4T1)	Repolarized M2-like TAMs to M1-like phenotype, resulting in the recruitment of CD8+ T cells and an improved therapeutic effect of anti-PD-1 antibody therapy.	[298]
PI3K/AKT/mTOR inhibitors
Ipatasertib	Multiple tumor xenograft models	Blocked AKT signaling in vivo and resulted in potent antitumor activity.	[299]
Targeting regulators
HDAC inhibitors
Vorinostat (SAHA)	Melanoma xenografts	Promoted SOX2 degradation and augmented the therapeutic effect of anti-PD-1 therapy.	[273]
Romidepsin	Lung adenocarcinoma mouse models	Increased chemokine expression, enhanced T-cell infiltration and enhanced the response to PD-1 blockade immunotherapy.	[274]
Panobinostat	Patients with Hodgkin lymphoma	Inhibited PD-1 expression in T cells.	[300]
MiRNA inducers or inhibitors
MRX34 (Snail inhibitor)	NSCLC	Promoted TILs and reduced CD8+ PD-1+ cells in vivo via the p53/miR-34/PD-L1 axis.	[270]
STAT3 inhibitors
Napabucasin (BBI608)	Microsatellite-stable colorectal cancer	Enhanced the response to anti-PD-1 therapy.	[267]
Targeting downstream effectors
Adhesion molecule inhibitors
Integrin-specific mAbs	Metastatic TNBC models	Integrin αvβ6/8 mAb induced a substantial survival benefit in combination with anti-PD-1 therapy.	[210]
	Metastatic pulmonary melanoma and osteosarcoma models	In vitro-generated CD103+ conventional DCs enhanced the response to CTLA-4 therapy.	[211]