Mechanism research of non‐coding RNA in immune checkpoint inhibitors therapy

Abstract

Immune checkpoint inhibitor (ICI) therapies for tumors of different systems have attained significant achievements and have changed the current situation of tumor treatment due to their therapeutic characteristics of high specificity and low side effects. The immune checkpoint Programmed death 1/Programmed cell death‐Ligand 1 (PD‐1/PD‐L1) axis exerts a vital role in the immune escape of tumor cells. As a result, it has become a key target for tumor immunotherapy. Therefore, to perfect research into potential regulatory factors for the PD‐1/PD‐L1 axis, in order to understand and illustrate tumor ICI therapy mechanisms, is a significant goal. Moreover, ncRNA has been verified to regulate the PD‐1/PD‐L1 axis in the tumor immune microenvironment to regulate tumor genesis and development. ncRNAs can improve or decrease the efficacy of ICI therapy by modulating PD‐L1 expression. This review aimed to investigate the mechanisms of action of ncRNA in regulating the PD‐1/PD‐L1 axis in ICI therapy, to provide more efficient immunotherapy for tumors of different systems.

Abbreviations

• circRNAs
• circular RNAs
• CTLA-4
• cytotoxic T lymphocyte-associated antigen-4
• ICIs
• immune checkpoint inhibitors
• lncRNAs
• long non-coding RNAs
• miRNAs
• microRNA
• mRNA
• messenger RNA
• ncRNA
• non-coding RNA
• PD-1
• Programmed death 1
• PD-L1
• Programmed cell death-Ligand 1

INTRODUCTION

Immunotherapy is a novel treatment based on immune escape mechanisms in which tumor cells develop distant metastasis by escaping the recognition and attack of the immune system. Immunotherapy has the potential to treat multiple types of tumors and is associated with features of low toxic effect and high persistent reactivity.¹ Of the recent antitumor immunotherapies, ICI therapy is an active immunotherapy, and has become one of the major ways to reverse immunosuppression and enhance the antitumor activity of the immune system.²

ICIs are a type of immune checkpoint molecule drugs targeting PD-1, PD-L1 or CTLA-4 that can block the immunosuppressive signals between tumor cells and T cells to activate the immune system of the patient to attack their cancer cells. As the most common immune checkpoint target, the PD-1/PD-L1 axis has been demonstrated to have significant therapeutic efficacy in multiple cancers. When the PD-L1 expressed by tumor cells binds to the PD-1 produced by T cells, it will trigger a series of suppressive signals, resulting in a decline in function and apoptosis of T cells.³ Noteworthily, during the expression process, the PD-L1 molecule will be regulated by post-protein translational modifications including glycosylation, phosphorylation and ubiquitination.⁴ At present, ICI therapy that realizes immune checkpoint blockage through targeting the PD-1/PD-L1 axis has exhibited prominent clinical benefits and is a great development prospect in the treatment of advanced malignant tumors.⁵

Recently, several studies have reported that ncRNAs participate in the regulatory processes of immune checkpoint molecules during tumor carcinogenesis.⁶ ncRNAs are RNA molecules produced during the gene transcription process but cannot encode proteins. According to their shape, length, size and cellular functions, ncRNAs can be classified as miRNAs, lncRNAs, circRNAs, short interfering RNAs (siRNAs), or piRNAs.^7,8 miRNAs, lncRNAs and circRNAs are critical ncRNA types that exert significant regulatory effects on the physiological and pathological processes of the body.⁹ Mature miRNAs are a type of single-stranded ncRNA of approximately 22 nucleotides in length, and can result in mRNA degradation and induce translational suppression.¹⁰ lncRNAs are ncRNAs more than 200 nt long that emerge as vital regulatory factors for encoding genes in different diseases, and exert key functions including antigen presentation, immune activation and immune cell infiltration.¹¹ circRNAs lack the special covalent closed-loop structure of the 3′poly(A) tail and the 5′-cap, which promotes the proliferation, migration, invasion and immune escape of tumor cells, and can be used as a potential biomarker in the diagnosis of various diseases.¹²

ncRNAs have critical effects on regulating the expression of immune checkpoint molecules like PD-1, PD-L1 and CTLA-4, indicating that ncRNAs have the potential to become the ICI treatment targets and biomarkers.¹³ The mechanisms by which ncRNAs exert an influence on PD-1 expression in the body can be roughly divided into the following four aspects: transcriptional regulation of PD-1/PD-L1 expression, miRNA sponge, RNA-binding protein, and encoding peptide or protein (Figure 1).

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In terms of similarity, lncRNAs, circRNAs and miRNAs can all reduce the expression of PD-L1 or inhibit translation by binding to the 3′UTR of mRNA, thus participating in the post-transcriptional regulation of genes. Moreover, lncRNAs and circRNAs can simultaneously regulate multiple target genes through sponging miRNAs, which reduces miRNA target mRNA and blocks the inhibitory effect of miRNA on target genes.¹⁴ RNA-binding protein (RBP) is a general term for a class of proteins that bind to RNA during regulation by ncRNAs. The combination of RBP and ncRNAs can realize the regulation of target mRNA and regulate the expression of post-transcriptional genes, thus leading to the occurrence and development of various tumors.¹⁵ Unlike other ncRNAs, circRNAs and lncRNAs have the potential to be translated into proteins and peptides. The coding sequences of lncRNAs and circRNAs have open reading frame (ORF) sequences, which can be translated into proteins by internal ribosome entry into internal ribosome entry sites (IRES) sites or M6A-mediated initiation.¹⁶ (Figure 2).

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In this review, we summarize the mechanisms of abnormally expressed ncRNAs from tumors of different systems in antitumor immunotherapy.

TRANSCRIPTIONAL REGULATION OF PD-1/PD-L1 EXPRESSION

Intracranial tumor

miR-138 is downregulated in neuroglioma; transfection of miR-138 into human CD4⁺ T cells suppresses the expression of PD-1 and CTLA-4, reduces T-cell death and enhances the immune capacity of the body.¹⁷

Thymoma

The high levels of expression of LncRNA XLOC_003810 can increase the production of CD4⁺ T cells and inflammatory cytokines and decrease the proportions of PD-1 in thymoma cells.¹⁸ Consequently, suppressing the PD-1/L1 axis may be one of the mechanisms for LncRNA XLOC_003810 in improving the immune function of thymoma cells. CircZNF451 is highly expressed in the exosomes of non–small-cell lung cancer (NSCLC) patients. It can bind to TRIM56 to promote the ubiquitination of FXR1 and activate the FXR1/ELF4/IRF4 axis in macrophages to remodel the tumor immune microenvironment.¹⁹ miR-33a is downregulated in NSCLC, which can regulate the PD-1/PD-L1 axis to improve the prognosis of NSCLC.²⁰ Overexpression of miR-4458 can target STAT3 to block the PD-1/L1 axis to enhance the antitumor immunity.²¹ miR-125a-5p is lowly expressed in non–small-cell lung cancer, and it can regulate the IGSF11/VSIG3 expression to increase the expression level of PD-1.²²

Digestive system tumor

lncRNA AC099850.3 is significantly positively correlated with PD-1, PD-L1 and CTLA-4, making it a potential target for ICI therapy for liver cancer.²³ CircPRDM4 is upregulated in liver cancer, and serves as the support to recruit HIF-1α into the CD274 promoter, which promotes HIF-1α-mediated PD-L1 trans-activation and induces the immune escape of liver cancer cells.²⁴

miR-152 and miR-200b are downregulated in gastric cancer tissue, and can suppress the expression of B7-H1 in gastric cancer cells to decrease binding to PD-1.²⁵ The expression of miR-374b is downregulated in liver cancer tissues, and its synergistic effect with PD-1 can regulate cytokine-induced killing cells and enhance the ICI therapy efficacy.²⁶ miR-233 expression decreases in liver cancer tissue, and can suppress the activation of the hypoxia-mediated PD-1/L1 axis via adenovirus to block the progression of liver cancer. Therefore, miR-233 has an important effect in regulating hypoxia-induced tumor immunosuppression.²⁷ miR-105-5p can bind to the cis-acting regulatory domain in the 3′UTR of PD-L1 in gastric cancer cells, suppress the expression of PD-L1 at the total protein and surface levels, and induce the activation of CD8⁺ T cells; Further, it has been verified that miR-105-5p can be the predicting factor for PD-1/PD-L1 axis-based ICI therapy.²⁸

Urologic neoplasm

In kidney cancer, the high expression of Linc01270 can regulate the PD-1/PD-L1 axis to stimulate the proliferation, invasion and migration of kidney cancer cells. Therefore, Linc01270 may become a new target for immunotherapy for kidney cancer.²⁹ The expression levels of miR-195 and miR-16 are negatively related to PD-L1, PD-1 and CTLA-4.³⁰ In addition, miR-195 and miR-16 can block PD-L1 expression and activate T cells in the tumor microenvironment. Therefore, high levels of miR-195 and miR-16 in prostate cancer are indicative of good prognosis in patients. miR-138 is expressed at low levels in bladder cancer tissue, and can improve the effect of immunotherapy on bladder cancer by activating the miR-138/PD-L1 axis via targeting PD-L1.³¹

Gynecological tumor

lncRNA TCL6 can regulate tumor-associated CD8⁺ T cells and CD4⁺ T cells. It is positively related to immune checkpoint molecules PD-1, PD-L1 and CTLA-4.³² Consequently, lncRNA TCL6 can serve as the potential molecular marker for ICI therapy for breast cancer. miR-424 and miR-322 are expressed at low levels in ovarian cancer cells, and their expression negatively regulates PD-L1, PD-1 and CTLA-4.³³ Binding of miR-424 and miR-322 to the 3′UTR of PD-L1 can decrease the PD-L1 expression, therefore activating T lymphocytes and improving the sensitivity of patients to immunotherapy. miR34a and miR-200 show low expression in ovarian cancer tissue, but they can bind to the 3′UTR of PD-L1 to downregulate PD-L1, making them potential targets for the development of ICI therapy.³⁴ miR-4759 shows low expression in breast cancer tissue, and can reduce PD-L1 expression to recover the killing sensitivity of immune cells to breast cancer cells.³⁵

Head and neck squamous cell carcinoma

The expression of miR-138 is downregulated in oral squamous cell carcinoma, and its binding to γδTDE can increase the expression of CD8⁺ T cells, PD-1 and CTLA-4, and improve a cancer prognosis.³⁶

Melanoma

In melanoma, miR-28 can bind to multiple inhibitory receptors to reduce PD-1 expression.³⁷ The miR-28 inhibitor can increase the expression of exhausted T cells and PD-1, providing a potential new therapeutic target of anticancer immunotherapy. miR-21-3p is expressed at low levels in melanoma tissue, and its synergy with anti-PD-1 antibody can enhance the therapeutic effect of immunotherapy in melanoma patients³⁸ (Table 1).

TABLE 1 ncRNAs regulate the transcriptional expression of PD-1/PD-L1 in different system tumors.

Tumor	ncRNAs	Mechanism	Function	Expression	Refs
Intracranial tumor	miR-138	Inhibits the expression of CTLA-4 and PD-1 after transfecting CD4+ T cells	Inhibits the proliferation and invasion ability of glioma cells	Down	17
Thymoma	LncRNA XLOC_003810	Activates CD4+ T cells and inhibits the expression of PD-1/PD-L1	Reduces the possibility of proliferation, invasion and metastasis of tumor cells	Up	18
LncRNA C5orf64	Develops expression of PD-1 and PD-L1 in lung adenocarcinoma tissues	As a biomarker improves tumor prognosis significantly	Up	61
CircZNF451	Activates the ELF4-IRF4 pathway in macrophages and reduces the expression of PD-1	Remodels tumor immune microenvironment and delays tumor progression	Up	19
miR-33a	Reduces the post-transcriptional expression of PD-1	Improves the prognosis of lung adenocarcinoma	Down	20
miR-4458	Reduces PD-L1 expression by targeting STAT3	Inhibits immune escape and malignant progression of tumor cells	Down	21
miR-20b-5p	Targets PD-L1 and inactivates the PD-1/PD-L1 pathway	Enhances sensitivity to radiation therapy	Down	62
miR-125a-5p	Regulates the expression of IGSF11/VSIG3 in lung cancer cells and decreases the expression of PD-1	Improves the efficacy of immunotherapy to lung cancer	Down	22
Digestive system tumor	LncRNA AC099850.3	Increases the expression of PD-1 and activates PRR11/PI3K/AKT pathway	The proliferation and invasion ability of hepatocellular carcinoma (HCC) cells are enhanced	Up	23
CircUHRF1	Improves the expression of TIM-3 and controls function of natural killer (NK) cells	Promotes immune evasion and anti-PD-1 immunotherapy resistance	Up	63
CircPRDM4	Accelerates HIF-1α-mediated trans-activation of PD-L1	Leads to the incidence of immune escape in tumor	Up	24
miR-142-5p	Binds to the 3′UTR of PD-L1 and inhibits the expression of PD-L1 in pancreatic cancer	Improves the expression of immune cells and enhances the antitumor immune effect	Down	64
miR-152\miR-200b	Inhibits the expression of B7-H1 and PD-1 in gastric cancer cells	Improves the prognosis of patients with gastric cancer	Down	25
miR-374b	Interacts with PD-1 and affects the tumor targeting ability of CIK cells	Restrains the progression of liver cancer	Down	26
miR-21	Improves Th17/Treg cell imbalance and regulates the expression of PD-1	Improves the survival level of prognosis in gastric cancer	Down	65
miR-105-5p	Inhibits the expression levels of PD-L1 in total protein	As a predictive marker for ICI therapy	Down	28
miR-233	Inhibits the activation of PD-1/PD-L1 pathway by adenovirus	Decreases the progression of hepatocellular carcinoma	Down	27
Urologic neoplasm	Linc 01270	Regulates the PD-1/L1 axis	Becomes a new target of immunotherapy for kidney cancer	Up	29
Linc 00941	Correlates with Th1 cells and Tregs cells and regulates the PD-1/L1 axis	Affects the malignant phenotype of kidney cancer	Up	66
miR-195/miR-16	Reduces transcription of PD-L1 and activates T-cell responses	Enhances sensitivity to radiation therapy for prostate cancer	Down	30
miR-138	The miR-138/telomerase reverse transcriptase (TERT), PD-L1 and Mir-138-5P axes are formed by targeting TERT and PD-L1	Improves the effect of immunotherapy and provides a new treatment strategy for bladder cancer	Down	31
Gynecological tumor	LncRNA TCL6	Regulates tumor-associated immune checkpoint molecules PD-1, PD-L1	Serves as the potential molecular marker of ICI therapy for breast cancer	Up	32
miR-424/miR-322	Binds to the 3′UTR region of PD-L1, thus reducing the transcription	Improves ovarian cancer resistance to drug therapy	Down	33
miR-34a/miR-200	Controls the expression of PD-L1 by binding to the PD-L1 3′UTR region	As a potential target to prevent immune escape from ovarian epithelial cancer	Down	34
miR-149-3p	Decreases the expression of PD-L1 and increases T-cell activation	Promotes CD8+ T-cell immune response and reverses T-cell depletion	Down	67
miR-424-5p	Regulates PD-L1 and constitutes the delivery system of triple negative breast cancer immunotherapy	Slows down tumor proliferation, invasion and metastasis	Down	68
miR-4759	Binds to the 3′UTR of PD-L1 and inhibits the transcriptional expression	Restores the sensitivity of immune cells to breast cancer cells	Down	35
Head and neck squamous cell carcinoma	miR-138	Enhances the expression of PD-1 by combining with γδTDE	Improves the occurrence, development and prognosis of tumor	Down	36
Melanoma	miR-28	Silences PD-1 and restores the depleted state of T cells	Improves the tumor immune function of patients	Down	37
miR-21-3p	Targets TXNRD1 and reduces the expression of PD-1 in melanoma	Improves the late prognosis of melanoma patients	Down	38

miRNA SPONGE

Thymoma

CircFGFR1 sponges miR-381-3p and increases the expression of CXCR4, thus promoting the progression of NSCLC and reduces resistance to PD-1 therapy.³⁹ The expression of circRNA-002178 is upregulated in NSCLC, and can competitively suppress miR-34 expression to increase PD-L1 expression, thereby triggering T-cell exhaustion.⁴⁰ circRNA-002178 can be transported into CD8⁺ T cells via the exosomes to induce a high expression of PD-1. In addition, circUSP7 can activate the circUSP7/miR-934/SHP2 axis to suppress the function of CD8⁺ T cells and the sensitivity of cancer patients to PD-1 ICI therapy.⁴¹

Digestive system tumor

Linc00460 is upregulated in pancreatic cancer tissue. It can form a positive feedback loop with miR-503-5p and Anillin to regulate T-cell-mediated cytotoxicity and PD-1 expression, thus promoting the immune escape of pancreatic cancer cells.⁴² CircDLG1 can activate the CircDLG1/miR-141-3p/CXCL12 axis and suppress CD8⁺ T-cell function, thus promoting the immune escape of gastric cancer cells.⁴³ CircTMEM181 is highly expressed in liver cancer; it can upregulate CD39 through the absorption of miR-488-3p. In addition, it can activate the eATP adenosine pathway together with CD73 in liver cancer, and increase PD-1 expression.⁴⁴ As a result, CircTMEM181 has become a potential therapeutic target for liver cancer. CircRERE is expressed at low levels in colorectal cancer, and serves as the sponge for miR-6837-3p to upregulate mitochondrial antiviral signaling protein (MAVS) expression and form the EP300/CircRERE/miR-6837-3p/MAVS axis, thus activating the type I IFN signaling pathway and suppressing the immune escape phenomenon in colorectal cancer.⁴⁵

Urologic neoplasm

The high expression of LncRNA KCNQ1OT1 can sponge miR-15a, hinder the cytotoxicity of CD8⁺ T cells and upregulate the expression of PD-L1, thus promoting the progression of prostate cancer.¹⁴

Gynecological tumor

High expression of LncRNA FOXP4-AS1 can activate the PD-1 and CTLA-4 signaling pathways.⁴⁶ Circ-0001068 is highly expressed in ovarian cancer tissue, and can induce PD-1 expression by activating the Circ-0001068/miR-28-5p axis, thereby promoting the invasion and metastasis of ovarian cancer.⁴⁷

Lymphoma

LncRNA SNHG14 is highly expressed in diffuse large B-cell lymphoma tissue. It can bind to miR-5590-3p to regulate the PD-1/PD-L1 axis, thus promoting the progression and immune escape of tumor cells⁴⁸ (Table 2).

TABLE 2 ncRNAs regulate the expression of PD-1 by sponging miRNA.

Tumor	ncRNAs	Mechanism	Function	Expression	Refs
Thymoma	CircFGFR1	Sponges miR-381-3p and increases the expression of CXCR4	Promotes the progression of NSCLC and reduces resistance to PD-1 therapy	Up	39
CircRNA-002178	Sponges miR-34 and enhances the expression of PD-1 and PD-L1	Facilitates cancer cell proliferation, invasion and metastasis	Up	40
CircUSP7	Sponges miR-934 and upregulates the expression of SHP2	Inhibits CD8+ T-cell functionality and promotes resistance of PD-1 immunotherapy in NSCLC	Up	41
CircCELF1	Sponges miR-491-5p and increases the expression of EGFR	Improves the sensitivity of cancer cells to PD-1 thereby promoting the progression of NSCLC	Up	69
CircASCC3	Sponges miR-432-5p and improves the drug resistance of PD-1	Reshapes the tumor microenvironment and promotes the proliferation and differentiation of cancer cells	Up	70
Digestive system tumor	LncRNA PCED1B-AS1	Sponges has-miR-194-5p and targets PD-L1	Induces immunosuppression of hepatocellular carcinoma and promotes cell proliferation, colony formation	Up	71
LncRNA MIR155HG	Sponges miR-223 and activates the miR-223/STAT1 axis, thereby increasing the expression of PD-L1	Promotes the malignant progression of hepatocellular carcinoma	Up	72
LINC00460	Sponges miR-503-5p and forms a positive feedback loop with ANLN, thus regulating expression of PD-1	Promotes the proliferation, migration and invasion of pancreatic cancer cells	Up	42
CircUBAP2	Sponges miR-494 and targets CXCR4, thereby upregulating the expression levels of PD-1	Promotes the invasion and metastasis of pancreatic cancer cells	Up	73
CircMET	Sponges miR-30-5p and activates the Snail/DPP4/CXCL10 axis	Improves ICI therapy resistance and promotes occurrence of liver cancer	Up	74
CircDLG1	Sponges miR-141-3p and increases CXCL12 expression	Accelerates proliferation, migration, invasion and adds resistance to PD-1 therapy in gastric cancer	Up	43
CricTMEM 181	Sponges miR-488-3p and adds CD39 expression in macrophages	Impairs CD8+ T-cell function and drives anti-PD-1 resistance	Up	44
CircHMGCS1-016	Sponges miR-12363p and activates the PD-1/PD-L1 axis	Promotes the development and immune tolerance of tumors	Up	75
CircRERE	Sponges miR-6837-3p and induces MAVS expression	Activates type I IFN signaling and promotes antitumor immunity	Down	45
CircSCUBE3	Sponges miR-744-5p and increases the expression of PD-L1	Boosts the immune escape of gastric cancer	Up	76
CircSOD2	Sponges miR-497-5p and increases the expression of ANXA11	Inhibits the progression of hepatocellular carcinoma and promotes drug resistance to PD-1 therapy	Up	77
Urologic neoplasm	LncRNA KCNQ1OT1	Sponges miR-382-3p and enhances the expression of PD-L1	Leads to immune escape in prostate cancer	Up	14
Gynecological tumor	LncRNA FOXP4-AS1	Sponges miR-136-5p and activates the PD-1 signaling pathway	Promotes the proliferation, migration and invasion of cervical cancer cells	Up	46
Circ-0001068	Sponges miR-28-5p and induces PD-1 overexpression	Facilitates the development, invasion and metastasis of ovarian cancer	Up	47
Lymphoma	LncRNA SNHG14	Sponges miR-5590-3p and activates the SNHG-14/miR-5590-3p/ZEB1 axis to regulate PD-1/L1	Promotes proliferation, invasion, metastasis and immune evasion of diffuse large B-cell lymphomas	Up	48

RNA-BINDING PROTEIN

Intracranial tumor

LncRNA NEAT 1 is upregulated in glioblastoma. Its interaction with polymerase I and transcript release factor (PTRF) mRNA can activate the expression of the LncRNA NEAT 1/NF-kB/PD-L1 axis, increase PD-L1 transcription and T-cell cytotoxicity, and promote the immune escape of glioblastoma cells, revealing that LncRNA NEAT 1 can be the potential target for ICI therapy.¹⁵

Digestive system tumor

Expression of Linc02096 in esophageal squamous cell carcinoma is upregulated. Its binding to MLL-1 can block MLL-1 ubiquitination mediated by the ankyrin repetitive sequence and SOCS-containing box 2, increase the PD-L1 expression in tumor cells, and eventually achieve the goal of suppressing CD8⁺ T-cell infiltration and activation.⁴⁹ CircCCAR1 is highly expressed in liver cancer and can be absorbed by activated CD8⁺ T cells and enhance PD-1 molecule stability. CircCCAR1 can activate the CircCCAR1/miR-127-5p/Wilms tumor 1 associated protein (WTAP) axis to promote the growth and metastasis of liver cancer.⁵⁰

Urologic neoplasm

High expression of LncRNA PMSB8-AS1 can activate the lncRNA PMSB8-AS1/miR-382-3p/PD-L1 axis, increase the PD-L1 expression and result in the occurrence of immune escape.⁵¹

Gynecological tumor

LncRNA HITT binds together with RGS2 to the PD-L1 5′-UTR and decreases the expression of PD-L1, which inhibits the proliferation, invasion and migration of breast cancer cells⁵² (Table 3).

TABLE 3 ncRNAs regulate the expression of PD-1 by RNA-binding protein.

Tumor	ncRNAs	Mechanism	Function	Expression	Refs
Intracranial tumor	LncRNA NEAT1	Stabilizes the mRNA of PTRF and promotes the expression of NF-kB/PD-L1 axis by interacting with PTR	Promotes immune escape and induces tumor proliferation, metastasis and invasion	Up	15
Digestive system tumor	LINC02096	Binds to MLL1 and prevents ASB2-mediated MLL-1 ubiquitination, thereby increasing the expression of PD-1	Promotes the occurrence of immune escape of esophageal cancer cells	Up	49
CircCCAR1	Combines M6a-modified WTAP with IGF2BP3 and increases the expression of PD-1	Promotes the growth and metastasis of hepatocellular carcinoma	Up	50
Urologic neoplasm	CircFAM13B	Binds to IGF2BP1 and inhibits PKM2 mRNA stability in bladder cancer	Inhibits immune escape and improves the sensitivity of immunotherapy of bladder cancer	Down	51
Gynecological tumor	LncRNA HITT	Binds with RGS2 to PD-L1 5′UTR and decreases the expression of PD-L1	Inhibits proliferation, invasion and migration of breast cancer cells	Up	52

ENCODING PEPTIDE OR PROTEIN

Intracranial tumor

CircSHPRH can encode SHPRH-146aa and prevent CircSHPRH from degrading, which reduces the proliferation, invasion ability and tumorigenicity of cancer cells in glioma cells.⁵³

Thymoma

CircFBXW7 reduces the interaction between m6A and β-catenin by encoding the protein FBXW7-185a, thereby promoting the proliferation and invasion of lung adenocarcinoma cells, inhibiting the sensitivity to chemotherapy drugs.⁵⁴

Digestive system tumor

LncRNA HOXB-AS3 encodes HOXB-AS3-53aa and inhibits the proliferation, migration, invasion and tumorigenesis of colon cancer cells by regulating the tumor energy metabolism, and revealing the level of prognosis in advanced patients.⁵⁵ The isotype of the protein encoded by Circβ-catenin can evade the apoptotic effect of PD-1 by activating the Wnt/β-catenin pathway in hepatocellular carcinoma, thereby inhibiting the body's immune system and promoting tumor growth and metastasis.⁵⁶

Gynecological tumor

CircTRIM1 promotes the occurrence of CAM-dependent myristoylated alanine-rich C-kinase substrate (MARCKS) translocations and the activation of the PI3K/AKT/mTOR axis by encoding TRIM1–269aa. Thereby promoting the immune escape of breast cancer cells and enhancing chemotherapy drug resistance, revealing its potential as a potential therapeutic target.⁵⁷ (Table 4).

TABLE 4 ncRNAs regulate the expression of PD-1 by encoding peptide or protein.

Tumor	ncRNAs	Mechanism	Function	Expression	Refs
Intracranial tumor	CircSHPRH	Encodes SHPRH-146aa and prevents CircSHPRH from degrading	Reduces the proliferation, invasion ability and tumorigenicity of cancer cells	Up	53
Thymoma	CircFBXW7	Reduces the interaction between m6A and β-catenin by encoding the protein FBXW7-185a	Promotes the proliferation and invasion of lung adenocarcinoma cells, inhibits the sensitivity to chemotherapy drugs	Up	54
Digestive system tumor	LncRNA HOXB-AS3	Encodes HOXB-AS3-53aa and regulates tumor energy metabolism	Inhibits the proliferation, migration, invasion of colon cancer cells	Up	55
Circβ-catenin	Encodes the isotype of protein and evades the apoptotic effects of PD-1 by activating Wnt/ β-catenin pathway	Boosts the growth, invasion and metastasis in hepatocellular carcinoma	Up	56
Gynecological tumor	CircTRIM1	Encodes TRIM1-269aa and activates the PI3K/AKT/mTOR axis	Increases drug resistance of chemotherapy drugs	Up	57

CONCLUSIONS

To sum up, with the increasing knowledge and research of the immune markers in tumor immune microenvironment and the immune regulatory pathways, ICI therapy has gradually become a brand new and effective treatment strategy following traditional treatments such as secondary, radiotherapy, chemotherapy and targeted therapy. Tumors can regulate the expression of immune checkpoint molecules, including PD-1, PD-L1 and CTLA-4, to escape monitoring by and the attack of the host immune system, thus achieving the goal of advanced metastasis and invasion.⁵⁸ It has been reported that the abnormally expressed ncRNAs in tumor cells have crucial effects on the efficacy of ICI therapy and prognosis of patients. The mechanisms of ncRNAs that regulate the expression of PD-1 and affect the therapeutic effect of ICIs mainly include transcriptional regulation of PD-1/PD-L1 expression, miRNA sponge, RNA-binding protein and encoding peptide or protein, all of which have a significant effect on the expression of PD-1 and participate in the biological functions of different systems tumors. The translation function of ncRNAs is still in the initial stage, and has great research potential.

However, although ncRNAs can target the PD-1/PD-L1 axis to improve antitumor immunotherapy, some problems remain to be solved to perfect the PD-1/PD-L1 axis regulatory mechanism between ncRNAs and ICIs. For instance, a minor portion of cancer patients with abnormal expression of ncRNAs develop clinical resistance to ICI therapy and are susceptible to severe side effects of ICI therapy.⁵⁹ Changing the transport mode of ncRNAs could improve the therapeutic effect. For example, exosomes can act as messengers between CircCCAR1 and PD-1 to regulate the function of target cells and the stability of the body's immune system.⁵⁰ The delivery of miR-138-5P through aerosol inhalation can increase the proportion of CD4⁺ T cells and provide a new preventive regimen for lung cancer.⁶⁰ In addition, recent studies on the regulation of PD-1 expression have mainly focused on gene transcription, which is still unknown at the translation level.⁵² Therefore, additional investigations into the detailed molecular mechanisms of ncRNAs in regulating the PD-1/L1 axis in tumors of different systems can help to better utilize ICIs to improve the prognosis of tumor patients.

AUTHOR CONTRIBUTIONS

Na Fang: Conceptualization. Jie Bian: Writing – original draft; writing – review and editing. Rui Shao: Data curation; formal analysis. Juan Li: Validation. Jing-Feng Zhu: Validation. Ai-Zhong Shao: Resources; validation. Chao Liu: Formal analysis; resources. L. V. Lu: Formal analysis; resources. Hui-Wen Pan: Formal analysis; resources. Yi-Jun Shi: Conceptualization; funding acquisition.

ACKNOWLEDGMENTS

Not applicable.

FUNDING INFORMATION

The sixth “169” engineering academic and technical backbone research project in Zhenjiang City, project number: 2021-169GG-27. Key R&D Plan-Social Development Project in Zhenjiang City, project number: SH2022041. The second phase of the “Jinshan Doctor” medical field leading talent project in Zhenjiang City, project number: 2022-JSYZ-6.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflict of interest.

ETHICS STATEMENT

Approval of the research protocol by an Institutional Reviewer Board: N/A.

Informed Consent: N/A.

Registry and the Registration No. of the study/trial: N/A.

Animal Studies: N/A.

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