CircRNAs regulate the crosstalk between inflammation and tumorigenesis: The bilateral association and molecular mechanisms

Abstract

Inflammation, a hallmark of cancer, has been associated with tumor progression, transition into malignant phenotype and efficacy of the chemotherapeutic agents in cancer. Chronic inflammation provides a favorable environment for tumorigenesis by inducing immunosuppression, whereas acute inflammation prompts tumor suppression by generating anti-tumor immune responses. Inflammatory factors derived from interstitial cells or tumor cells can stimulate cell proliferation and survival by modulating oncogenes and/or tumor suppressors. Recently, a new class of RNAs, i.e., circular RNAs (circRNAs), has been implicated in inflammatory diseases. Although there are reports on circRNAs imparting functions in inflammatory insults, whether these circularized transcripts hold the potential to regulate inflammation-induced cancer or tumor-related inflammation, and modulate the interactions between tumor microenvironment (TME) and the inflammatory stromal/immune cells, awaits further elucidation. Contextually, the current review describes the molecular association between inflammation and cancer, and spotlights the regulatory mechanisms by which circRNAs can moderate TME in response to inflammatory signals/triggers. We also present comprehensive information about the immune cell(s)-specific expression and functions of the circRNAs in TME, modulation of inflammatory signaling pathways to drive tumorigenesis, and their plausible roles in inflammasomes and tumor development. Moreover, the therapeutic potential of these circRNAs in harnessing inflammatory responses in cancer is also discussed.

Graphical abstract

In this review, we describe the molecular association between inflammation and cancer, and spotlight the regulatory mechanisms by which circular RNAs moderate tumor microenvironment in response to inflammatory signals. We present comprehensive information about the expression and functions of the circular RNAs in inflammation-associated tumor microenvironment and tumor development.

Inflammation and cancer

Inflammation, a hallmark of cancer, has been associated with tumor development, promotion, transition into malignant phenotype, and efficacy of chemotherapeutic agents in various forms of cancer.¹ Precisely, chronic inflammation provides a favorable environment for tumorigenesis and metastasis by inducing immunosuppression.² Cancer-inducing niches could be tracked back to chronic inflammation, which entails deep-rooted tissue damage and continuous repair in response to the release of various cytokines and growth factors.³ Concomitantly, tumor eliciting inflammation promotes cancer by stalling anti-tumor immunity, creating a tumor-permissive state by reforming the tumor microenvironment (TME), and carrying out tumor-promoting functions by applying direct signals onto cancer and epithelial cells.^4,5 Likewise, anti-cancer therapies may also elicit persistent inflammatory responses, thus sustaining cancer progression by incurring therapeutic resistance.⁶ On the contrary, acute inflammation prompts a tumor inhibitory environment by generating anti-tumor immune responses by promoting dendritic cell (DC) maturation as well as their function, and the initiation of effector T cells. Besides, acute inflammation can potentially encourage apoptosis/cell death in different types of cancer.⁷

First proposed by Rudolf Virchow in 1863, the inter-relationship between “cancer” and “inflammation” has been well established, whereby the sites of chronic inflammation can provide a preferred environment for tumor initiation, and tumor biopsies are found to be enriched with inflammatory cells.³ Moreover, persistently unresolved and dysregulated inflammation has been correlated with higher risk of developing malignant phenotypes in various cancer types.⁸ Both extrinsic and intrinsic inflammation provide a favored situation for tumor development by producing an immunosuppressive TME, through which inflammatory factors derived from the interstitial cells or tumor cells can stimulate cell proliferation and cell survival by either activating oncogenes or inactivating tumor suppressor genes,^9,10 as depicted in Figure 1.

Figure 1.

Molecular association between inflammation and cancer

(A) Mechanism of inflammation-induced cancer. Cancer development and progression may, pre-dominantly, be mediated by specific inflammatory cells, called “tumor infiltrating myeloid cells” that are capable of driving carcinogenesis through different schemes of action. Activation of NF-κB and STAT3 in response to the release of various pro-inflammatory cytokines promotes cell-cycle progression and inhibits apoptosis. STAT3 and NF-κB, once activated, can suppress the markers for epithelial differentiation, thereby prompting EMT. STAT3 induction can be hampered by binding of specific ILs to IL-BP. Moreover, secretion of inflammatory cytokines can induce genomic destabilization by activating AID and impair DNA repair by modulating HIF-1α expression, thus advancing tumorigenesis. TNF, tumor necrosis factor; TGF-β, transforming growth factor β; ROS, reactive oxygen species; MYD88, myeloid differentiation primary response 88; ILs, interleukins. (B) Mechanism of cancer-related inflammation. Tumor cells are proficient in engaging T cells, explicitly Tregs, thus exploiting their functional capabilities. These Tregs express specialized CC-chemokine receptors and are recruited to the site of tumor formation through binding of the respective CC-chemokine ligands with these receptors, whereby they encourage angiogenesis by stimulating the release of inflammatory mediators and repress T cell function. Tumor cells may also secrete various chemo-attractants and growth factors that mediate MDSC generation. These MDSCs secrete TGF-β and various other ILs (such as IL-3, IL-4, and IL-10), thus inhibiting the anti-tumor responses by T cells.

In the last two decades, non-coding RNAs have been extensively studied and shown to play important roles in various inflammatory conditions as well as in resolving inflammation.^11,12 Quite recently, a new class of such RNAs has been reported to have potential implications in inflammatory diseases, called circular RNAs (circRNAs).^13,14,15 circRNAs are largely pre-mRNA derivatives produced as a result of back splicing, unlike linear RNAs that follow the standard canonical splicing process for their formation. Owing to their covalently closed-loop structure and restricted degradation by exonucleases, circRNAs are rather more stable than their linear counterparts.¹⁶ circRNAs are generated via intronic complementary sequence-driven, RNA-binding protein (RBP)-driven, or lariat-mediated back splicing facilitated by splicing factors.¹⁷ The physiological and pathological functions of circRNAs occur through miRNA sponging, interaction with circRNA-binding proteins (cRBPs), protein translation, or transcriptional regulation.¹⁸

Although there are various reports on circRNAs imparting functions in inflammatory insults, whether these circularized transcripts hold the potential to regulate inflammation-induced cancer (extrinsic) or tumor-related inflammation (intrinsic), and modulate the interactions between TME and the inflammatory stromal/immune cells still requires elucidation. In this regard, this review describes the molecular association between inflammation and cancer, and spotlights the regulatory mechanisms by which circRNAs can moderate TME in response to inflammatory signals/triggers. We also present comprehensive information in regard to the immune cell(s)-specific expression and functions of circRNAs in TME, modulation of the inflammatory signaling pathways to drive tumorigenesis, and their plausible roles in inflammasomes and tumor development. Moreover, the therapeutic potential of these related circRNAs in harnessing inflammatory responses in cancer is also discussed.

Role of circRNAs in inflammation-induced carcinogenesis

circRNAs interfere with cancer/inflammation-related signaling pathways

Chronic infections are one of the causes of cancer. Globally, 15.6% and 17.7% of cancer cases reported in 1990 and 1995, respectively, were infection related.^19,20 Recently, there has been a surge in studies that link inflammatory diseases to cancer. Tumor initiation, progression, and poor cancer prognosis are associated with dysregulation in both inflammatory and oncogenic signaling pathways.^3,21 Upon pathogen sensing, NRLP (NOD-, LRR- and pyrin domain-containing proteins) inflammasomes are assembled to release cytokines, which amplify the inflammatory response by activating subsequent inflammatory signaling pathways, such as NF-κB (Nuclear Factor kappa-light-chain-enhancer of activated B cells) and MAPK (Mitogen-Activated Protein Kinase).²² Inflammation significantly impacts the composition of TME, which consists of fibroblasts, vascular cells, and inflammatory immune cells.⁶ Based on 8,500 published studies, 41 KEGG pathways were referred to as oncogenic in 49 human cancer types. Of these, the MAPK pathway was associated with up to 40 cancer types. Akt, mTOR, apoptosis, and NF-κB pathways were also involved in at least 34 cancer types, and closely connected to Wnt/β-catenin, STAT (Signal Transducer and Activator of Transcription), and p53 signaling pathways, whereby their synergistic dysregulation may contribute to tumorigenesis.²³ These pathways are frequently integrated to form a signaling network between inflammatory diseases and cancer.²⁴ In this regard, circRNAs have been reported to interfere with and regulate such signaling networks as one of their primary biological functions in disease progression.²⁵

Underlying mechanisms for circRNA-mediated regulation of the signaling pathways

circRNAs are implicated in both inflammation and cancers, where they either upregulate or downregulate certain cellular components, thus modulating cancer-related inflammatory signaling pathways through one of the three ways depicted in Figure 2. Many of these circRNAs have been reported to act as a miRNA sponge, thus activating or repressing the signaling pathways involved²⁶ (Table 1). Binding to cRBPs is another proposed mechanism for circRNA function⁷² (Table 2). In addition, translatable circRNAs encoding novel peptides are also involved in modulating disease-related signaling pathways^109,110 (Table 3). Involvement of competing endogenous RNAs in activation or repression of the downstream pathways by sponging miRNA is the primary mechanism of interaction between the circRNA and PI3K/AKT pathway.¹²⁹ Comprehensive proteogenomic analysis-based characterization of 95 prospectively collected endometrial carcinomas (83 endometrioid and 12 serous tumors) revealed a potential role of circRNAs in regulating epithelial-mesenchymal transition (EMT) through the Wnt/β-catenin pathway.¹³⁰ Likewise, the mechanistic interplay between circRNAs and the evolutionarily conserved Hippo pathway has also been well studied in the process of carcinogenesis.¹⁶

Figure 2.

Involvement of circRNAs in tumor- and inflammation-associated microenvironments

circRNAs are generated in the nucleus and released into the cytoplasm. circRNAs regulate tumor/inflammation signaling pathways mainly through miRNA sponging, cRBP binding, and protein translation. The signaling pathways, such as Akt, E-cadherin, EGFR, MAPK, NF-κB, STAT, TGF-β, VEGF, and Wnt/β-catenin, have been found to be involved in both IME and TME. NLRP3 and AIM2 inflammasomes have been identified in IME and TME, respectively. Upon activation of NLRP3/AIM2 inflammasomes by NF-κB/cytosolic DNA, pro-inflammatory cytokines are released into IME/TME to maintain these microenvironments that support the pathogenesis of inflammatory diseases. In IME, sponging of miR-421 by circHIPK3 inhibits the NF-κB pathway and prevents the activation of NLRP3 inflammasome in ischemic injury. circBBS9 promotes NLRP3 inflammasome activation in the PM2.5-induced lung inflammation mice. In TME, sponging miR-1184 by circNEIL3 induces DNA damage and triggers AIM2 inflammasome activation, resulting in pyroptosis upon lung adenocarcinoma radiotherapy. In chronic IME, upregulation of circCUL2 in fibroblasts mediates the conversion of NFs into iCAFs and contributes to CAF heterogeneity in pancreatic ductal adenocarcinoma by inducing the NF-κB signaling pathway. circ_0088300 derived from CAFs regulates STAT signaling by sponging miR-1305 to promote gastric carcinoma. circ_0001845 promotes the transition from colitis to colitis-associated cancer through the Wnt/β-catenin signaling pathway. Furthermore, the interaction between cancer cells and CAF promotes proliferation, migration, and metastasis of cancer cells by releasing cytokines and activating related signaling pathways in TME.

Table 1.

Representative circRNAs that regulate related signaling pathways by sponging miRNAs

Signaling pathways	circRNAs	miRNAs	Cancer [inflammation]	Ref.
Akt	circHIPK3	miR-29b	[IBD]	27
	circTLK1	miR-214	[IRI]	28
	circANAPC7	miR-373	PC	29
	circHMGCS1	miR-503-5p	HB	30
	circVAPA	miR-377-3p/miR-494-3p	SCLC	31
	circSPON2	miR-331-3p	PCa	32
	circSlc8a1	miR-130b/miR-494	BC	33
E-cadherin	circAKT3	miR-296-3p	[DN]	34
			ccRCC	35
	circHERC4	miR-556-5p	CRC	36
	circPRMT5	miR-30c	UCB	37
EGFR	circPRKCB	miR-339-5p	[I/R]	38
	circCDR1AS/ciRS-7	miR-7	CRC	39
MAPK	circZNF609	miR-145	[PU]	40
	circTLK1	miR-17-5p	[SCM]	41
	circASAP1	miR-326/miR-532	HCC	42
	circMAPK4	miR-125a-3p	Gliomas	43
	circRNA_C190	miR-142-5p	NSCLC	44
	circASAP1	miR-502-5p	GBM	45
	circFNDC3B	miR-1178-3p	BC	46
NLRP3/inflammasome activation	circHipk3	miR-421	[Ischemic injury]	47
	circBbs9	miR-30e-5p	[PM-induced airway inflammation]	48
AIM2/inflammasome activation	circNEIL3	miR-1184	LUAD	49
STAT	circ_0007059	miR-1278	[LN]	50
	circZNF652	miR-452-5p	[Asthma]	51
	circ_0003738	miR-490-5p	[PsO]	52
	circSnx5	miR-544	[DC-driven immunogenicity]	53
	circHipk3	miR124-3p	NSCLC	54
	circIGHG	miR-142-5p	OSCC	55
	circ_0088300	miR-1305	GC	56
	circCUL2	miR-142-3p		57
TGF-β	circTXNRD1	miR-892a	[PM-induced airway inflammation]	58
	circSlc8a1	miR-133a	[HF]	59
	circUCK2	miR-125b-5p	[IS]	60
	circCDK14	miR-125a-5p	[OA]	61
	circPVT1	miR-21-5p	[SIONFH]	62
	circANKS1B	miR-148a-3p/miR-152-3p	BC	63
	circEHBP1	miR-130a-3p		64
Wnt/β-catenin	circHIPK3	miR-30a-3p	[OA]	65
	circ_0025984	miR-143-3p	[IS]	66
	circEIF4G3	miR-4449	GC	67
	circSTX6	miR-449b-5p	PDAC	68
YAP/Hippo	circLARP4	miR-424-5p	GC	69
	circACTN4		ICC	70
	circPVT1	miR-497-5p	HNSCC	71

Table 2.

Representative circRNAs that regulate related signaling pathways by binding cRBPs

Signaling pathways	circRNAs	cRBPs	Cancer [inflammation]	Ref.
Akt	circCDYL2	GRB7	Breast cancer	73
	circKIF18A	FOXC2	GBMs	74
	circARHGAP29	IGF2BP2	PCa	75
	circFAM120A		SXT	76
	circRHOBTB3	HuR	CRC	77,78
Autophagy/ATG7	circTICRR	HuR	CC	79
Hh	circATG7	HuR	PC	80
MAPK	hsa_circ_0068631	EIF4A3	BC	81
	circPOLR2A	UBE3C/PEBP1	ccRCC	82
	circNFIB	MEK1	ICC	83
	circVPS13C	RRBP1	NFPAs	84
	circPDE5A	WTAP	PCa	85
STAT	circSCAR	ATP5B	[NASH]	86
	circSTX6	CUL2	PDAC	68
	circSCMH1	MeCP2	[AIS]	87,88
	mmu_circ_0001109	STAT3	[IBD]	89
	circLRIG3	EZH2/STAT3	HCC	90
	circANRI	PES1	[AS]	91
	circPOLR2A	PKR	[SLE]	92
	circMYBL2	PTBP1	AML	93
TGF-β	circCDR1as/CIRS-7	IGF2BP3	Melanoma	94,95
	circPTEN1	Smad4	CRC	96
	circTHBS1	HuR	GC	97
TNF-α	circDLC1	HuR	HCC	98
VEGF	circFndc3b	FUS	[CA]	99
Wnt/β-catenin	circStag1	HuR	[PO]	100
	circZNF292	SDOS	[Anti-inflammation]	101
	mmu_circ_0001845	β-catenin	CAC/[IBD]	89
	circGSK3β	GSK3β	ESCC	102
	circHuR	CNBP	GC	103
	circ-CTNNB1	DDX3		104
	circEIF4G3	δ-catenin		67
	circZKSCAN1	FMRP	HCC	105
	circACTN4	YBX1	ICC	70
	circMTCL1	C1QBP	LSCC	106
	circRNA_102171	CTNNBIP1	PTC	107
YAP/Hippo	circYap	eIF4G/PABP	Breast cancer	108

Table 3.

Representative circRNAs that regulate related signaling pathways by encoding proteins

Signaling pathways	circRNAs	Encoded protein/interacting molecules	Cancer [inflammation]	Ref.
Akt	circHER2	HER2-103/EGFR	TNBC	111
	circGSPT1	GSPT1-238aa/vimentin/Beclin1/14-3-3	GC	112
	circAKT3	AKT3-174aa/PDK1	GBM	113
EGFR	circEGFR	rtEGFR/EGFR	GBM	114
	circE-Cad	C-E-Cad/EGFR		115
Hh	circSMO	SMO-193a.a./SMO	GBM	116
MAPK	circNlgn	Nlgn173/H2AX	[HF]	117,118
	circMAPK1	MAPK1-109aa/MAP2K1	GC	119
	circMAPK14	circMAPK14-175aa/MAP2K6	CRC	120
	circASK1	ASK1-272a.a/Akt1	LA	121
NF-κB	circPLCE1	circPLCE1-411/RPS3	CRC	122
STAT	cGGNBP2	cGGNBP2- 184aa/STAT3	ICC	123
Wnt/β-catenin	circDIDO1	DIDO1-529aa/PARP1/PRDX2	GC	124
	circAXIN1	AXIN1-295aa/APC		125
	circβ-catenin	β-catenin-370aa/GSK3β	HCC	126
	circ-EIF6	EIF6-224aa/MYH9	TNBC	127
YAP/Hippo	circPPP1R12A	circPPP1R12A-73aa/MST1/LATS1	CC	128

circRNAs sponge miRNAs to regulate signaling pathways in cancer/inflammation

PubMed search revealed an explosive increase in recent publications on circRNAs regulating the signaling pathways through sponging miRNAs. Representative circRNAs that mediate inflammatory diseases or tumors by sponging miRNAs are listed in Table 1 and part B of Table 4. Involvement of circRNAs in STAT, TGF-β (Transforming Growth Factor β), and NF-κB signaling pathways is related more to inflammation, while Akt, E-cadherin, MAPK, and Hippo-YAP are rather associated with cancer.

Table 4.

NF-kB signaling associated representative circRNAs and circRNAs with multiple functions

Category	Signaling	circRNAs	Mechanism	Interacting molecules	Cancer [inflammation]	Ref.
A: signaling associated	NF-kB	circPLCE1	encoding protein	RPS3	CRC	122
		circPPM1F	cRBP binding	HuR/PPM1F	[T1DM]	131
		circDCUN1D4		HuR/TXNIP	LA	132
		circIKBKB		IKKβ	BC	133
		mmu_circ_0001109		p65	[IBD]	89
		circARF3	miRNA sponging	miR-103	[Ai]	134
		circ_003912		miR-123/miR-647/miR-31	[EOLP]	135
		circHIPK3		miR-124	LC	136
				miR-421	[Ischemic injury]	47
		circSirt1		miR-132/212	[VSMC]	137
		circNFATC3		miR-143-3p	BC	138
		circCUL2		miR-203a-5p	PDAC	139
		circTLK1		miR-17-5p	[SCM]	41
				miR-214	[IRI]	28
		circ_0005105		miR-26a	[OA]	140,141
		circ-UQCRC2		miR-326	[PP]	142
		circRNA104250		miR-3607-5p	[Airway inflammation]	143
		circRNA-000911		miR-449a	BC	144
		circANRIL		miR-622	[stroke]	145
		circGLIS2		miR-671	CRC	146
		circSHOC2		miR-7670-3p	[IBI]	147
		circLRP6		miR-205	[DN]	148
B: multiple functions	Akt	circHIPK3	miRNA sponging	miR-29b	[IBD]	27
	Wnt/β-catenin			miR-30a-3p	[OA]	65
	NF-kB			miR-421	[Ischemic injury]	47
	STAT			miR124-3p	NSCLC	54
	MAPK	circTLK1		miR-136-5p	RCC	149
	NF-kB			miR-17-5p	[SCM]	41
				miR-214	[IRI]	28
	E-cadherin	circAKT3		miR-296-3p	[DN]	34
					ccRCC	35
	TGF-β	circPVT1		miR-21-5p	[SIONFH]	62
	YAP/Hippo			miR-497-5p	HNSCC	71
	Akt	circSLC8A1		miR-130b/miR-494	BC	33
	TGF-β			miR-133a	[CH]	59
	MAPK	circPOLR2A	cRBP binding	PKR	[SLE]	92
	STAT			UBE3C	ccRCC	82
	YAP/Hippo	circACTN4	miRNA sponging/cRBP binding	YBX1	ICC	70
	Wnt/β-catenin			miR-424-5p
	EGFR	circCDR1AS/ciRS-7		IGF2BP3	melanoma	94,150
	TGF-β			miR-7	CRC	39
	VEGF	circFNDC3B		FUS	[CA]	99
	MAPK			miR-1178-3p	BC	46

circRNAs bind to cRBPs to regulate signaling pathways in cancer/inflammation

circRNAs can form circRNA-protein complexes to modulate signaling pathways.¹⁵¹ Dysregulation of RBPs has been experimentally verified in different cancer phenotypes, resulting in chronic inflammation and/or autoimmunity.^152,153 Among these extensively studied RBPs, human antigen R (HuR) (also named ELAVL1) is the most attractive RBP in the field. HuR is an established regulator of post-transcriptional gene regulation and is overexpressed in many human cancers. HuR drives the activation of a pro-inflammatory phenotype, and is linked to many chronic diseases, such as cardiac hypertrophy, pancreatitis, rheumatoid arthritis, asthma, and cachexia.¹⁵⁴ HuR plays essential pathophysiological roles in the development of different liver diseases, including hepatic inflammation, alcoholic liver disease, non-alcoholic fatty liver disease, viral hepatitis, liver fibrosis, and liver cancer.¹⁵⁵ LPS (lipopolysaccharide)-induced systemic inflammation causes intimal hyperplasia, and increased expression of Toll-like receptor 4 (TLR4) and HuR.¹⁵⁶ Increasing evidence is suggestive of altered signaling pathways as a consequence of interactive crosstalk between circRNAs and HuR in inflammation and cancer. Among the representative circRNAs in Table 3 and part A of Table 4, HuR is the hottest cRBP for circRNAs to interact with. It has been verified that PRKAR2A-derived mmu_circ_0001845 interacts with β-catenin to promote inflammation-to-carcinoma transformation of colitis-associated colorectal carcinoma through the Wnt/β-catenin signaling pathway in vivo and in vitro⁸⁹ (Figure 2).

circRNAs encode proteins to regulate signaling pathways in cancer/inflammation

circRNAs not only function by miRNA sponging or binding with cRBPs, but can also be translated in a cap-independent manner to encode novel proteins possessing novel physiological roles to either promote or suppress the disease. Some of these circRNA encoded proteins are also involved in signaling pathways to modulate cancer development and progression,¹⁰⁹ as listed in Table 4. Of these, only Nlgn173 peptide encoded by circNlgn mediates heart failure by interacting with H2A histone family member X (H2AX) in MAPK signaling,^117,118 while others act to regulate cancers by interacting with different proteins associated with Akt, EGFR, Hh, MAPK, NF-κB, STAT, Wnt/β-catenin, and Hippo-YAP pathways.

NF-κB signaling bridges the connection between inflammation and cancer

Inflammation, as a body’s protective response, is beneficial to the host in a timely manner. However, chronic inflammation poses high risk by altering the TME, which affects all stages of tumor development.^157,158 NF-κB is involved in recruiting inflammatory cells and mediating the release of inflammatory chemokines, thus creating an environment that facilitates cancer progression. Dysregulated NF-κB signaling contributes to the pathogenesis of various inflammatory diseases,¹⁵⁹ and is crucial to tumorigenesis as well. As an inducible transcription factor, NF-κB regulates multi-protein inflammasome complexes and mediates the pathogenesis of various inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, atherosclerosis, and so on.¹⁵⁸ Upon activation of the NLRP3 inflammasomes by NF-κB, pro-inflammatory cytokines are released into the TME or IME (inflammatory microenvironment) to maintain these microenvironments that support the pathogenesis of inflammatory diseases, and to subsequently trigger related signaling pathways in cancer.

Numerous human cancers have constitutive NF-κB activity due to the IME and various oncogenic mutations, which favors tumor growth by remodeling cancer cell metabolism, promoting proliferation, suppressing apoptosis, attracting angiogenesis, and facilitating distant metastasis, especially in solid tumors. Comparably, suppression of the NF-κB pathway leads to tumor regression, and may serve as an effective therapeutic strategy. Therefore, NF-κB is a master regulator in mediating a crosstalk between chronic inflammation and cancer at multiple levels.^158,160 In addition, activation of the NF-κB pathway and its downstream pro-inflammatory genes has also been verified in cancer-associated fibroblasts (CAFs) cultured on fibrous polymeric matrices. Moreover, CAFs with NF-κB pathway activation have been observed to increase tumor-promoting proinflammatory properties in breast cancer.¹⁶¹ In addition, mmu_circ_0001109 exacerbates colitis by upregulating STAT and NF-κB signaling pathways, and may play a promoting role during the inflammation or colitis-to-carcinoma transition.⁸⁹ Therefore, the NF-κB signaling pathway could serve as a bridge that connects the inflammatory cells and inflammation-triggered cancer cells within an immunosuppressive inflammatory TME, thus favoring tumor growth.

As shown in part A of the Table 4, 20 representative circRNAs modulating the NF-κB signaling pathway have been revealed to be associated with various inflammatory diseases (12 circRNAs) and cancers (8 circRNAs). Among these, 15 circRNAs modulate NF-κB signaling by sponging with miRNAs, four of them bind to cRBPs, and circPLCE1 encodes 411 amino acid (circPLCE1-411) peptides that interacts with RPS3 in colorectal cancer.

Multiple functions of circRNAs in signaling pathways related to cancer/inflammation

Among the representative circRNAs listed in the Tables 2, 3, and 4, some circRNAs exhibit multiple functions, which are summarized in part B of Table 4. As shown, most of these circRNAs may have modulatory roles in more than one disease. For instance, circHipk3 sponges four miRNAs to regulate inflammatory bowel disease, osteoarthritis, ischemic injury, and non-small cell lung cancer (NSCLC) through Akt, Wnt/β-catenin, NF-κB, and STAT pathways, respectively. Similarly, circTLK1 regulates two inflammatory diseases and one cancer by sponging three different miRNAs, as indicated.

circRNAs regulate immune cell(s) functions and responses

Both immune and tumor cells mutually impact various stages of cancer development and progression, thus adding to the TME intricacy by altering the immune cells to promote evasion, proliferation, and metastasis.^3,10 Of these, T lymphocytes, B lymphocytes, natural killer (NK) cells, and antigen-presenting DCs are predominantly involved in tumor suppression, while immunosuppressive functions are imparted by tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), CAFs, myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs). Thus far, there are only few studies to report the regulatory and immunomodulatory functions of circRNAs in different immune cells including neutrophils, tumor infiltrating lymphocytes (TILs), DCs, and TAMs in cancer. Nonetheless, certain studies which elucidated the expression and roles of these circRNAs in immune regulation driven by these immune/inflammatory cells are discussed in the subsequent sections and depicted in Figure 3 and Table 5.

Figure 3.

Regulatory functions of circRNAs in inflammatory cell responses during tumorigenesis

(A) In T lymphocytes, circRNA-002178 causes T cell exhaustion by regulating PD1 expression through miR-34 sponging. Similarly, overexpression of hsa_circ_0046523, circHMGB2, and circ-NT5C2 mediates immunosuppression by inducing CD8⁺ T cell apoptosis and exhaustion by sponging miR-148a-3p, miR-181a-5p/CARM1, and miR-448, respectively, thus promoting tumor growth, invasion, and metastasis. Besides, circ-LAMP1 is upregulated in T cell lymphoblastic lymphoma, whereby it stimulates cell proliferation and alleviates apoptosis through DDR2/RTK signaling dysregulation mediated by miR-615-5p. In nasopharyngeal carcinoma, circBART2.2 binding to RIG-I causes functional inhibition of these cells and immune escape. In CD4+ T cells, hsa_circ_0020397 modulates cell survival, invasion, and apoptosis by sponging miR-138, thus regulating PD-L1 and TERT expression in CRC. (B) In tumor-infiltrating lymphocytes (TILs), hsa_circ_0064428 is downregulated in HCC patients with high TILs and correlated with poor disease prognosis, therefore potentially regulating TIL formation. (C) In B lymphoma cells, upregulation of circEAF2 promotes cell apoptosis and lymphoma cell sensitivity toward epirubicin by targeting Epstein-Barr virus-encoded miR-BART19-3p/APC/β-catenin axis, thus retarding tumor growth by inactivating the Wnt signaling pathway. (D) Pertinent to NK cells, circARSP91 and circTRIM33-12 stimulate NK cell-mediated cytotoxicity, thus producing inhibitory effects on tumor growth and progression. Contrarily, circ_0000977 overexpression alleviates NK cell activity through miR-153 sponging, thus resulting in immune evasion in pancreatic cancer. Likewise, circHMGB2 and tumor-derived exosomal circUHRF1 drive cancer progression by turning off protective immune responses manifested by NK cell exhaustion and resistance to anti-PD1 therapy in NSCLC and HCC, respectively. In addition, hsa_circ_0007456 is revealed to modulate NK cell-mediated cytotoxicity through miR-6852-3p/ICAM-1 axis in HCC. (E) Both circSNX5 and circHMGB2 suppress dendritic cell activity, and promote their functional exhaustion, thus regulating immunogenicity in cancer. (F) circPACRGL has been discovered to bring about differentiation of neutrophils from N1 to N2, and promote cell proliferation, invasion, and migration through the miR-142-3p/miR-506-3p-TGF-β1 axis in CRC. (G) In MDSCs, circSLC8A1 interacts with miR-494, thus suppressing the release of immunosuppressive cytokines in a PTEN-dependent manner. Comparably, MDSC-derived exosomal S100A9 increased circMID1 expression, which functions through miR-506-3p sponging to promote tumorigenesis. Moreover, circDLG1 increases MDSC infiltration, thus promoting gastric cancer. (H) circHECTD1 is highly expressed in macrophages and modulates cell proliferation and migration by sponging miR-320-5p and regulating SLC2A1 activity in glioblastoma multiforme. Besides, exosomal circ_0001142 is overexpressed in breast cancer, whereby it regulates tumor growth, invasion-metastasis, autophagy, and macrophage polarization via miR-361-3p/PIK3CB pathway.

Table 5.

circRNAs associated with the inflammatory diseases that can potentially lead to cancer

circRNA	Inflammatory disease	Inflammatory/relative cell(s) response	Proposed mechanism	Potential-associated malignancy	Ref.
circZC3H4	silicosis	pulmonary macrophage activation	increasing ZC3H4 by miR-212 sponging	lung carcinoma	210
circHECTD1	silicosis	macrophage activation and fibroblast proliferation	balancing M1/M2 macrophages by ZC3H12A binding	lung carcinoma	189
circ-0003528	bronchitis	macrophage polarization	increasing CTLA4 by miR-224-5p, miR-324-5p and miR-488-5p sponging	lung carcinoma	211
circATRNL1	ovarian endometriosis	promoting proliferation, migration, and invasion of Ishikawa cells	increasing YAP1 by miR-141-3p and miR-200a-3p sponging	ovarian carcinoma	212
circ_0088194	rheumatoid arthritis	promoting the invasion and migration of rheumatoid arthritis fibroblast-like synoviocytes	increasing MMP2 by miR-766-3p sponging	osteosarcoma	213
circRNA.33186	osteoarthritis	promoting proliferation and inhibit apoptosis of IL-1β-treated chondrocytes	increasing MMP-13 by miR-127-5p sponging	osteosarcoma	214
circFBXW4	hepatic fibrosis	inhibiting activation, proliferation and induced apoptosis of hepatic stellate cells	increasing FBXW7 by miR-18b-3p sponging	liver cancer	215
circ_103765	Crohn’s disease	promoting proliferation and apoptosis of human intestinal epithelial cell	increasing DLL4 by miR-30 family sponging	colorectal carcinoma	216
circHECTD1	ulcerative colitis	promoting enterocyte autophagy	increasing HuR by miR-182-5p sponging	colorectal carcinoma	217
circ_0089172	Hashimoto’s thyroiditis	N/A	increasing IL-23R by miR-125a-3p sponging	lymphoid tissue lymphoma	218

circRNAs regulate T-, B-, TIL-, and NK-cell-mediated immune responses

T lymphocytes play a significant role in generating responses as part of the adaptive immune system. Tumor-associated antigen can stimulate CD8+ T cell-mediated cytotoxicity, targeting the tumor cells in particular. Nonetheless, the molecular mechanisms involved in tumor promotion may halt their activity due to T cell exhaustion, stemness, senescence, and anergy in humans.¹⁶² circRNAs have been reported to incur immunosuppression by activating tumor escape mechanisms and altering T cell-mediated immune response. For instance, high hsa_circ_0046523 expression has been shown to induce apoptosis and CD8⁺ T cell exhaustion, thus suppressing their function and stimulating the release of immunoinhibitory cytokines, such as TGF-β and IL-10 (interleukin-10). In peripheral blood mononuclear cells, hsa_circ_0046523 inhibited IFN-γ (interferon gamma) and IL-2 secretion, via sponging miR-148a-3p and modulating PD-L1 (programmed death-ligand 1) expression in pancreatic cancer.¹⁶³ Similarly, circHMGB2 is also reported to repress immune system through miR-181a-5p/CARM1 axis manifested by the exhaustion of CD8⁺ T cells and resistance to anti-PD-1 in both squamous cell carcinoma and lung adenocarcinoma.¹⁶⁴ circRNA-002178 may result in T cell exhaustion by regulating PD1 (programmed death-1) expression through miR-34 sponging.¹⁶⁵ circNT5C2 mitigates the immune response by sponging miR-448, thus increasing tumor growth, invasion, and metastasis.¹⁶⁶ Besides, circLAMP1 is upregulated in T cell lymphoblastic lymphoma, whereby it stimulates cell proliferation and alleviates apoptosis through sponging miR-615-5p and mediating DDR2/RTK signaling dysregulation.¹⁶⁷ Moreover, circ_0020397 has been shown to sponge miR-138, thus activating the immune escape mechanism by altering CD4+ T cells function in tumorigenesis.¹⁶⁸ Yet another circRNA encoded by Epstein-Barr virus (EBV) named circBART2.2 has been revealed to mediate immune evasion by inhibiting T cell function in RIG-1 (retinoic acid-inducible gene I)-dependent manner and modulating PD-L1 in nasopharyngeal carcinoma.¹⁶⁹ Hence, circRNAs hold functional capabilities to modulate the immune response mediated by lymphocytes in various forms of cancers.

Besides T lymphocytes, B cells are an important module in the TME, whereby they alleviate tumor progression by secreting immunoglobulins (anti-bodies) and modulate other immune cells to produce anti-tumor responses. Pertinently, circRNAs have been reported to modulate B cell-mediated immune responses in various pathological conditions, including cancer. circEAF2 overexpression has been observed to promote apoptosis in EBV-positive B cell lymphoma, thus counteracting cancer progression by regulating the miR-BART19-3p/APC/β-catenin axis in diffuse large B cell lymphoma.¹⁷⁰ Pertinent to TILs, downregulation of circ_0064428 has been reported in high TIL patients, and correlated with poor disease prognosis in hepatocellular carcinoma (HCC), therefore potentially regulating TIL formation.¹⁷¹

NK cells have been known to play a critical role as first line defenders against tumor cells by mediating cytotoxic activity in response to chemokine/cytokine secretion. In this regard, specific circRNAs associated with the tumor cells have been shown to impart functions in regulating cytotoxic activity of the NK cells. In HCC, circARSP91 improves the innate immune response by inducing NK cell mediated cytotoxicity.¹⁷² Moreover, circTRIM33-12 is observed to have tumor inhibitory effects by increasing NK cell activity through NKG2D expression regulation.¹⁷³ Contrarily, circ_0000977 overexpression has been reported to alleviate NK cell activity, thus resulting in immune evasion by stimulating HI1FA accumulation through miR-153 sponging in pancreatic cancer.¹⁷⁴ Likewise, circHMGB2 and tumor-derived exosomal circUHRF1 drive cancer progression by turning off protective immune responses manifested by NK cell exhaustion and resistance to anti-PD1 therapy in NSCLC and HCC, respectively.^164,175 In addition, hsa_circ_0007456 has been shown to modulate NK cell-mediated cytotoxicity through the miR-6852-3p/ICAM-1 axis in HCC.¹⁷⁶ Therefore, circRNAs can alter the dynamics of tumor progression by regulating NK cell-mediated cytotoxicity depending on the type of cancer, precisely hinting toward the tissue/organ-specific expression and functions of these circRNAs.

circRNAs regulate immune responses mediated by antigen-presenting DCs

DCs are an important component of the innate immune system that are capable of presenting tumor-associated antigens to naive T cells, thus generating anti-tumor T cell responses.¹⁷⁷ Overexpression of circHMGB2 has been associated with exhaustion of DCs in NSCLC, whereby it inhibits the immune response mediated by type 1 IFN. Mechanistically, circHMGB2 increases the expression levels of CARM1 (the downstream effector molecule) by acting as a miR-181a-5p sponge.¹⁶⁴ In addition, circSNX5 acts to regulate the activity and function of DCs by sponging miR-544, thus altering the signaling dynamics through suppression of cytokine signaling 1 and impeding PU.1 translocation into the nucleus.⁵³ Comprehensively, both circSNX5 and circHMGB2 suppress DC cell activity, and promote their functional exhaustion, thus regulating DC immunogenicity in cancer. Furthermore, mature DCs have been studied to exhibit high expression of exonic circFSCN1, whereby circFSCN1 knockdown prompts tolerogenic DCs to prevent alloimmune rejection, increase allograft survival, lessen fibrosis, and induce in vivo generation of Tregs.¹⁷⁸

circRNAs regulate TANs and circulating neutrophils

Neutrophils (granulocytes) are the most abundant and indispensable component of TME, thus producing significant roles in cancer progression. Both TANs and circulating neutrophils can produce dual roles, i.e., tumor promoting or tumor inhibiting depending on the organ of tumor origin or cancer type. Where circulating neutrophils can enhance the metastatic spread (tumor promoting), TANs are capable to respond either as tumor promoting or inhibiting entities depending on what the TME prompts.¹⁷⁹ A specific circRNA population has been implicated in neutrophil function. A circularized exosomal RNA circPACRGL derived from cancer cells has been observed to produce pro-tumorigenic functions and mediate differentiation of neutrophils from N1 to N2 form by modulating the miR-142-3p/miR-506-3p-TGF-β1 axis.¹⁸⁰ Therefore, circRNAs can potentially affect the elaborative roles of neutrophils in the TME, and alter the dynamics of cancer progression.

circRNAs regulate MDSC activity

MDSCs compose a big proportion of the cells that are predominantly known to modulate immune response negatively. In tumorigenic conditions, MDSCs are aberrantly activated in the TME, whereby they release immunosuppressive cytokines (iNOS, ROS, and ARG1) that function to repress T cell-mediated cytotoxicity.¹⁸¹ As reported, circSLC8A1 interacts with miR-494 in MDCSs, thus suppressing the release of immunosuppressive cytokines in a PTEN-dependent manner.³³ Comparably, MDSC-derived exosomal S100A9 increased circMID1 expression, which functions through miR-506-3p sponging to promote tumorigenesis.¹⁸² Moreover, circDLG1 increases MDSC infiltration, thus promoting gastric cancer.¹⁸³ Therefore, circRNAs hold the potential to control MDSC function and regulate subsequent immune reaction during tumorigenesis.

circRNAs regulate tumor-associated macrophages

Macrophages are the effector cells that are crucial in abridging innate and acquired immune responses through specialized pattern-recognition receptors, i.e., TLRs. These TLRs are capable of recognizing antigens associated with the tumor cells through increased chemokine and cytokine secretion, thus advancing subsequent immune reaction and antigen presentation.¹⁸⁴ circRNAs have been reported to perform explicit regulatory functions in modulating such immune responses mediated by macrophages. Relevantly, circHECTD1 is widely expressed in macrophages, and has been described to enhance cell proliferation and migration by modulating miR-320-5p/SLC2A1, miR-1256/USP5, and miR-485-5p/mucin-1 in glioblastoma multiform,¹⁸⁵ gastric cancer,¹⁸⁶ and HCC, respectively.¹⁸⁷

In addition, macrophages are capable of differentiating and polarizing to distinct phenotypes, i.e., M1 and M2, whereby the M1 phenotype is activated primarily by IFN-γ and LPS, and the M2 phenotype is either triggered by the immune complex or some specialized ILs. Intriguingly, both these types of macrophages have been shown to exhibit distinct circRNA expression profiles.¹⁸⁸ Henceforth, circRNAs may play critical roles in macrophage polarization and conversion into either of these two forms. In this regard, circHECTD1 has been revealed to have an important role in regulating macrophage polarization.¹⁸⁹ Likewise, exosomal circ_0001142, released under endoplasmic reticulum stress has been observed to promote macrophage polarization into M2 type, resulting in breast cancer progression.¹⁹⁰

circRNAs regulate the activity of CAFs and inflammatory CAFs

CAFs are one of the components of stromal remodeling and play crucial roles in initiation, progression, metastasis, and therapeutic resistance in most solid tumors.¹⁹¹ CAFs are derived from normal fibroblasts (NFs). As depicted in Figure 2, CAFs exhibit two phenotypes; CAFs and inflammatory CAFs (iCAFs). Evidence suggests that CAFs are driven by TGF-β, while iCAFs are induced by NF-κB signaling in pancreatic cancer.¹⁹² CAFs exhibit a matrix-producing contractile phenotype, i.e., myoCAFs relating to myofibroblasts, and iCAFs with immunomodulating secretome-regulating inflammation.¹⁹³ In HCC, CAFs secrete higher levels of CCL2 and CCL5 than peri-tumor fibroblasts that increase migration through activation of the hedgehog pathway, and higher levels of CCL7 and CXCL16, thus promoting both migration and invasion of HCC cells through the TGF-β pathway.¹⁵⁹ Based on the correlation analysis using public datasets containing over 3,000 BC samples, Chen et al. identified a role for iCAFs in tumor progression, which is significantly related to poor prognosis. Single-cell RNA sequencing from 19 different cell types in the bladder carcinoma (BC) microenvironment also indicated iCAFs to be the key factors in BC progression.¹⁹⁴ Multiple mechanisms targeting NFs, such as contact signals, extracellular matrix, DNA damage, TGF-β, physiological stress, inflammatory signals, and RTK ligands, activate CAFs in TME.¹⁹³ CAFs promoted aggressive phenotypes in breast cancer cells through EMT induced by TGF-β1 activation.¹⁹⁵ Various inflammatory modulators promote CAF activation through different signaling pathways in a context-dependent manner.¹⁹³ Interactions between cancer cells and fibroblasts can promote the CAF phenotype in ductal breast carcinoma in situ through the Jagged1/Notch2 signaling pathway.¹⁹⁶ Silencing or downregulation of Notch effector CSL in dermal fibroblasts is sufficient for CAF activation and induces senescence of primary fibroblasts from the dermis, oral mucosa, breast, and lung, but not in squamous cell carcinomas.¹⁹⁷ IL-1α-induced ELF3/YAP pathway activation also regulates iCAFs differentiation.¹⁹⁸ iCAFs represent a major prognosis determining cell type in rectal cancer. Targeted repolarization of CAFs can improve therapeutic response and long-term survival for rectal cancer patients.²¹ The conversion from NFs to CAFs is mainly mediated by TGF-β and STAT signaling pathways. The crosstalk of CAFs with cancer cells is associated with multiple signaling pathways. CAF-mediated signaling pathways, such as STAT, Wnt/β-catenin, Hippo/YAP, MAPK, EGFR, and NF-κB, are activated by cytokines, chemokines, and growth factors, and are widely involved in cancer cell proliferation, stemness, invasion, migration, metastasis, angiogenesis, EMT process, and therapeutic resistance.²⁴ circRNAs from CAF-derived exosomes contribute to cancer progression.¹⁹⁹ Accumulating evidence suggests that abundant miRNAs in CAFs have regulatory roles in tumor progression.²⁴ For example, circHIF1A from CAF exosomes plays an important role in breast cancer by modulating the miR-580-5p/CD44 axis.²⁰⁰ Akt, β-catenin, and MAPK signaling pathways are mediated by CD44.²⁰¹ As Figure 2 summarizes, CAFs deliver exosomal circ_0088300 to GC tumor cells, and promote proliferation, migration, and invasion of these cells through the STAT signaling pathway by sponging miR-1305.⁵⁶ Similarly, circCUL2 is specifically expressed in CAFs but not in cancer cells, whereby its upregulation in fibroblasts mediated the conversion of NFs into iCAFs and contributed to CAF heterogeneity in pancreatic ductal adenocarcinoma by inducing the NF-κB signaling pathway. Hence, circCUL2 is critical for inducing and maintaining CAF pro-tumor properties.¹³⁹ Furthermore, the interaction between cancer cells and CAFs in TME promotes proliferation, migration, and metastasis of cancer cells by releasing cytokines and activating related signaling pathways.

Role of circRNAs in cancer-induced inflammation: Inflammasomes and cancer development

Extensive literature on TME informs that tumor progression is largely driven by the interactive networking between the tumor and the stromal cells. Similarly, the capacity of cancer cells to secrete soluble mediators and the immune response is of utmost importance in mediating tumor progression, whereby cancer cells have the ability to modulate both innate and adaptive immune responses. Pertinently, tumor cells can turn on T cell-mediated responses by modulating Tregs, and can induce macrophage, neutrophil, and MDSC activities as well. Importantly, cancer cells are capable of reprogramming the immune cells into an immuno-inhibitory phenotype through soluble mediators, thus facilitating an anti-tumor immune response.²⁰²

Cancer-elicited inflammation is triggered by a variety of immune cells, including macrophages, neutrophils, DCs, NK cells, T lymphocytes, and B lymphocytes.⁸ Inflammasome formation (a multimeric protein complex) is the pivotal mechanism that drives inflammation in immune cells by activating cysteine protease caspase-1, which subsequently triggers pyroptosis (inflammatory cell death) through the release of inflammatory cytokines.²⁰³ In recent years, circRNAs have been thought to play roles in tumor-mediated regulation of the immune system. NLRP3-inflammasome activation by circRNAs, such as circHIPK3 and circBBS9, is related to inflammatory diseases in IME. Pertinently, circBBS9 promotes activation of NLRP3 inflammasome to release pro-inflammatory cytokines into the IME. In contrast, circHIPK3 inhibits activation of NLRP3 inflammasomes (Figure 2). AIM2 (absent in melanoma 2)-inflammasome activation by circRNAs is also associated with cancer development. For example, circNEIL3 activates AIM2 inflammasomes and promotes pyroptosis of lung adenocarcinoma (Figure 2). circRNAs modulate the inflammasome activation in dual ways. circBBS9 promotes NLRP3 inflammasome activation in PM2.5-induced lung inflammation mice.⁴⁸ circNEIL3 triggers AIM2 inflammasome activation through sponging miR-1184 to induce pyroptosis in lung adenocarcinoma.⁴⁹ It is known that circHIPK3 can improve blood perfusion in ischemic injury of the skeletal muscles by preventing activation of the NLRP3 inflammasome.⁴⁷ This is achieved by targeting FOXO3a expression through sponging miR-421, resulting in NF-κB pathway inhibition, and the subsequent release of IL-1β and IL-18 in ischemic injury.

Therapeutic implications of the circRNAs associated with inflammation-related cancers

Attributable to the association between inflammation and tumor progression, exploiting inflammation may plausibly serve as an effective and useful avenue for therapeutic management of different types of cancers. Comparably, IME is also a major attribute that governs the efficacy of various conventional anti-cancer therapies, including chemotherapy, immunotherapy, and radiotherapy. Contextual to this, altered expression profiles of different circRNAs have been related with clinico-pathological parameters that are detectable in various biological specimens, such as biopsies and/or body fluids, and can be exploited to modulate immune response in different cancer types. In this regard, tertiary lymphoid structures have been reported to enhance the efficacy of immunotherapeutic agents in melanoma,²⁰⁴ bladder cancer,²⁰⁵ and gastric cancer.²⁰⁶ However, the exact mechanism might not be fully elucidated thus far; the B cell-driven signaling pathways may sustain better outcomes, explicitly when harnessed in conjunction with the use of circRNAs modulating immune responses in various forms of cancers. For instance, circ0000190 may serve as a potential marker in regard to immunotherapy in lung cancer patients.²⁰⁷ Also, circ_0064428 has been reported to be correlated with poor disease prognosis in high TIL patients diagnosed with HCC.¹⁷¹ Thus, inhibition of the circRNAs that suppress immune system may help in strengthening immune response against different cancers, such as circ-NT5C2, circ_0000977, circLAMP-1, and various others, as depicted in Figure 3.

Besides, circRNAs may be used as potent vaccine adjuvants, thus helping to boost both innate and adaptive immune systems. Transfecting circRNAs in distinct cancer cell lines has been reported to drive the overexpression of specific cytokine-related genes and NF-kB signaling, thus activating an innate immune response.²⁰⁸ Moreover, exogenous circRNAs lacking m⁶A modification can enhance the expression of genes related with the immune system by stimulating RIG-1.²⁰⁹ Furthermore, DCs may be a promising therapeutic target owing to their ability to serve as a foundation for propagating T cell-mediated anti-tumor responses. In this regard, DCs isolated from mice showed that circFOREIGN could directly stimulate DCs and indirectly mediate CD4+ and CD8+ T cell activities by allowing cross-presentation of the antigen.²⁰⁹ Moreover, melanoma mice vaccinated with circFOREIGN manifested significant increase in overall survival compared with those who received no circFOREIGN injection.²⁰⁹ Tumor-specific DC subsets may exhibit distinct circRNA profiles. Accordingly, exploiting and targeting these DCs through the use of associated circRNAs in an attempt to instigate and promote anti-tumor immune responses can serve as a novel approach for therapeutic management of various types of cancers driven by an inflammatory insult. Therefore, circRNAs can potentially activate immune cells to combat tumors either by functioning as a tumor antigen or being regulated to prompt favorable immune reaction. Nevertheless, if circRNAs can be used in combating anti-cancer therapy-induced inflammation is a niche that still requires rigorous investigation.

Conclusion and perspective

Having considered a firmly established relationship between inflammation and cancer, the functional mechanisms as to how circRNAs can regulate the interactive networking between the inflammatory processes and tumor progression remain to be comprehensively elucidated. As presented in this review, more than 90% of the studies recruited have spotlighted miRNA sponging as a mechanism of circRNA function in inflammation and cancer, but much fewer discuss circRNA binding with cRBPs and their translatability into respective peptides as a potential mechanism of circRNA function in either inflammation-induced cancers (extrinsic inflammation) or cancer-related inflammation (intrinsic inflammation). Molecular mechanisms pertinent to the immune cells and the IME that abridge the crosstalk with the tumor cells have been well studied, with STAT3 and NF-κB pathways bridging the two pathological states, i.e., inflammation and cancer. Depending on the tissue-specific distinct expression profiles, as well as tumor-promoting and anti-tumor facets of circRNAs modulating the inflammatory cells functions and the integrated signaling pathways, circRNAs can be exploited to develop novel therapeutic strategies for treating inflammation-induced cancers or cancer-induced inflammation. Knowing that not every organ’s inflammation culminates into tumorigenesis, it would be highly intriguing to investigate if circRNAs have any role in enduring inflammation into tumorigenesis, owing to their tissue-specific expression. Harnessing inflammation through the use of circRNAs can potentially alter the dynamics of tumor development and may prove valuable in devising novel therapeutic options for treating different cancers, together with improving the efficacy of conventional anti-cancerous therapeutic approaches. Nonetheless, it is pivotal to understand the molecular events and signaling cascades behind these bilateral disease mechanisms, i.e., inflammation and tumorigenesis, as well as the functional intricacies of circRNAs, to pave a way for acquiring adequate translational and therapeutic outcomes through the use of circRNA-based anti-cancer therapy for clinical management.