Targeting RNA N6-methyladenosine to synergize with immune checkpoint therapy

Zhou, Xianyong; Li, Chen; Chen, Tong; Li, Wenhao; Wang, Xiaolong; Yang, Qifeng

doi:10.1186/s12943-023-01746-6

Molecular Cancer

Table 3 Functions and mechanisms of m⁶A regulators in the regulation of immune checkpoints

From: Targeting RNA N6-methyladenosine to synergize with immune checkpoint therapy

m⁶A	Protein	Function	Tumor/cell	Mechanism	References
Writer	METTL3	Induces resistance to anti-PD-1 therapy	CRC	Decreases IFN‐γ‐STAT1‐Irf1 signaling	[98]
	METTL3	Promotes PD-L1 expression	NSCLC	m⁶A-modified circIGF2BP3 upregulates PKP3 expression, then PKP3 engages with FXR1 to stabilize OTUB1 mRNA, thus enhancing PD-L1 expression	[90]
	METTL3	Promotes PD-L1 expression	OSCC	NM	[86]
	METTL3	Promotes CD80 expression	DCs	TLR4/NF-κB signaling	[92]
	METTL3	Promote CD86 expression	Macrophage	Stabilizes and enhances STAT1 mRNA, then stimulates IFNγ-induced CD86 expression	[95]
	METTL14	Induces resistance to anti-PD-1 therapy	CRC	Decreases IFN‐γ‐STAT1‐Irf1 signaling	[98]
Eraser	FTO	Promotes PD-1 expression	Melanoma	Via the autophagy/NF-κB/FTO axis	[32]
	FTO	Promotes PD-L1 expression	Colon cancer	IFN-γ signaling-independent manner	[103]
	FTO	Promotes PD-L1, PD-L2, LILRB4 expression	AML	Directly upregulates LILRB4 expression via an m⁶A-dependent mechanism; NM	[101]
	ALKBH5	Induces resistance to anti-PD-1 therapy	Melanoma	Modulates Mct4/Slc16a3 gene and lactate content of the TME and the composition of tumor-infiltrating Treg and MDSCs	[105]
	ALKBH5	Induces resistance to anti-PD-1 therapy	CRC	Modulates Mct4/Slc16a3 gene and lactate content of the TME and the composition of tumor-infiltrating Treg and MDSCs	[105]
	ALKBH5	Promotes PD-L1 expression	ICC	Regulates PD-L1 mRNA stability, exerts overwhelming effects on nuclear/cytoplasmic PD-L1 mRNA pool	[106]
	ALKBH5	Promotes PD-L1 expression	Macrophage	NM	[106]
Reader	YTHDC1	Promotes PD-L1 expression	NSCLC	m⁶A-modified circIGF2BP3 upregulates PKP3 expression, then PKP3 engages with FXR1 to stabilize OTUB1 mRNA, thus enhancing PD-L1 expression	[90]
	YTHDF1	Promotes CD80 expression	DCs	TLR4/NF-κB signaling	[92]
	YTHDF1	Inhibits PD-L1 expression	NSCLC	NM	[108]
	YTDHF2	Induces resistance to anti-PD-1 therapy	CRC	Decreases IFN‐γ‐Stat1‐Irf1 signaling	[98]
	YTHDF2	Inhibits PD-1 expression	melanoma	Via the autophagy/NF-κB/FTO axis	[32]
	YTHDF2	Inhibits LILRB4 expression	AML	Deteriorates LILRB4 mRNA	[101]
	YTHDF2	Inhibits PD-L1 expression	ICC	Regulates PD-L1 mRNA stability, exerts overwhelming effects on nuclear/cytoplasmic PD-L1 mRNA pool	[106]
	YTHDF2	Inhibits PD-L1 expression	NSCLC	NM	[108]

CRC Colorectal cancer, NSCLC Non-small cell lung cancer, PKP3 Plakophilin 3, OSCC Oral squamous cell carcinoma, DCs Dendritic cells, HCC Hepatocellular carcinoma, STAT1 Signal transducer and activator of transcription 1, NK cell Natural killer cells, AML Acute myeloid leukemia, LILRB4 Leukocyte immunoglobulin-like receptor subfamily B4, TME Tumor microenvironment, Tregs Regulatory T cells, ICC Intrahepatic cholangiocarcinoma, TILs Tumor-infiltrating lymphocytes, and NM Not mentioned

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