Immunosuppressive cells including myeloid-derived suppressive cells (MDSCs) and tumor-associated macrophages (TAMs) are crucial factors associated with immune resistance (46). Cytokines and signals released by immunosuppressive cells can foster cancer progression and immune evasion. Targeting immunosuppressive cells is a promising therapy to overcome immune resistance. miRNAs may affect the therapeutic effects of immunotherapy by regulating the activity of immunosuppressive cells ( Figure 2 ). The expression level of miR-449c was increased in myeloid progenitor cells of melanoma-bearing mice in response to activation of C-X-C motif chemokine receptor 2 (CXCR2) (47). Overexpressed miR-449c promoted the expansion of monocytic MDSCs (mo-MDSCs) by downregulating signal transducer and activator of transcription 6 (STAT6) ( Table 1 ). Conversely, deficiency of miR-449c repressed differentiation of myeloid progenitor cells into mo-MDSCs. MDSCs are found to play a role in blunting antitumor immunity and enhancing cancer resistance to immunotherapy (58). Thus, it is necessary to verify whether miR-449c can regulate melanoma cell response to immunotherapy.

Exosomes are small membrane-enclosed vesicles released by diverse cell types and function as key regulators in cell-to-cell communication via transmitting diverse constituents (e.g., DNAs, lipids, ncRNAs and proteins) (59). Gastric cancer-released exosomes transported miR-107 to MDSCs (48). Exosomal miR-107 promoted the expansion and activation of MDSCs by downregulating tumor suppressors double-stranded RNA-specific endoribonuclease 1 (DICER1) and phosphatase and tensin homolog (PTEN) while upregulating arginase 1 (ARG1). Tumor-derived miR-107 mediated the communication between cancer cells and MDSCs, leading to tumor development and enhancement of immunotherapy resistance. EC cells facilitated monocyte transformation to M2-like TAMs under hypoxic condition (49). Mechanistically, hypoxic EC cells secreted miR-21-containing exosomes, which were taken up by monocytes. Exosome-derived miR-21 increased the expression of interleukin-10 (IL-10) and CD206, hence promoting M2-like macrophage polarization. Exosomal miR-21 reshaped the tumor immune microenvironment, which potentially facilitated EC development. Collectively, miRNAs act as mediators in tumor immune evasion. However, the exact effect of these miRNAs on the anticancer activity of immunotherapy should be further determined.

Cytotoxic CD8⁺ T cells function to induce apoptosis and efficiently eradicate cancer cells via direct cellular contacts (60, 61). CD8⁺ T cells have been recognized as the most powerful effectors in antitumor immunity and are the mainstay of successful cancer immunotherapy. Exposure to epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment increased miR-1 expression in patients with lung adenocarcinoma (LUAD) (50). The cytokines C-C motif chemokine ligand 5 (CCL5) and C-X-C motif chemokine ligand 10 (CXCL10) can induce migration of intratumoral CD8⁺ T cells in cancer (62). Upregulated miR-1 inhibited the therapeutic effect of EGFR-TKI and restricted the migration of CD8⁺ T cells by downregulating CCL5 and CXCL10. miR-1 could be useful in identifying EGFR-TKI-resistant patients who may benefit from immunotherapy. Forced expression of miR-1 may be a mechanism underlying resistance to immunotherapy (e.g., ICI) in LUAD patients. miR-93-5p functioned as a critical initiating oncogene during hepatocarcinogenesis (51). Galectin-9 (Gal-9) causes the inactivation of various immune cells, such as natural killer (NK) cells and T cells, enabling cancer cells to evade from immunosurveillance (63, 64). miR-93-5p induced infiltrated CD8⁺ T cell dysfunction by favoring Gal-9 augmentation. Anti-Gal-9 antibodies reversed anti-PD-1 therapy resistance in a miR-93-5p-induced hepatocellular carcinoma (HCC) mouse model. The clinical benefit of targeting miR-93-5p and its target Gal-9 in HCC awaits further verification.

Hypoxia caused the enrichment of miR-424 in CRC-derived exosomes, which were subsequently transferred to tumor-infiltrating dendritic cells (DCs) and T cells (52). Exosome-delivered miR-424 impeded the CD28-CD80/86 costimulatory signaling in these immune cells, contributing to the formation of an immunosuppressive tumor microenvironment. Deficiency of tumor-derived miR-424 suppressed CRC development in a murine tumor model. In contrast, intratumoral inoculation of miR-424-containing exosomes accelerated tumor growth by blunting CD28-CD80/86-dependent antitumor immunity. The CD28-CD80/86 costimulatory pathways could repress PD-1-mediated T cell dysfunction and positively correlated with patient response to anti-PD-1 treatment (65–67). It was thus inferred that miR-424 was able to affect immunotherapy response in CRC. Consistently, specifically blocking tumor-derived functional miR-424 restored adaptive antitumor immunity and re-sensitized CRC cells to anti-PD-1/CLTA-4 treatment. Modification of immunosuppressive miRNA-containing exosomes could be developed as an adjuvant treatment for ICI-resistant CRC. Substantial research efforts should be made to comprehensively explore immune-related miRNAs in cancer cells and their derived exosomes.

Gap junctional shuttling of ncRNAs represents a vital mechanism of immunosuppression. miR-192-5p was strikingly enriched in hypoxic melanoma cells (53). The connexin-43 (Cx43)-constituted gap junctions mediated the transfer of miR-192-5p to DCs and melanoma-specific cytotoxic T lymphocytes (CTLs). Moreover, the delivery of miR-192-5p inhibited the cytotoxic activity of CTLs and contributed to cancer immune escape by downregulating zinc finger E-box binding homeobox 2 (ZEB2), a transcription factor that modulated the expression of terminal effector genes in CD8⁺ T cells. Altogether, these findings may provide new opportunities for the development of anticancer immunotherapies aimed to improve clinical outcomes of cancer patients.

The PD-1/PD-L1-based pathway has become a pivotal immune checkpoint in recent years and is a key target for cancer immunotherapy. However, emerging evidence indicates that the PD-1/PD-L1 pathway has opposite effects on immunotherapy efficacy. On the one hand, reduction of PD-L1 expression via genetic or pharmacological inhibition reinforces the efficacy of anti-PD-1/PD-L1 therapy. The expression level of miR-15b-5p gradually reduced with the development of microsatellite stable (MSS) CRC (54). The protein level of PD-L1 showed an opposite trend. Further study demonstrated that overexpressed miR-15b-5p prevented CRC tumorigenesis and sensitized cancer cells to PD-1 blockade by downregulating PD-L1 at the posttranscriptional level in vivo. Conversely, depletion of miR-15b-5p supported CRC tumorigenesis by upregulating PD-L1 and repressing the recruitment of CD8⁺ T cells. Increasing miR-15b-5p expression enhanced the efficacy of ICI therapy. The therapeutic effects of combined miR-15b-5p and PD-1 blockade should be verified in further clinical studies. Likewise, miR-105-5p promoted the activation of CD8⁺ T cells in gastric cancer by directly targeting PD-L1 (55). The expression of miR-105-5p was induced by the hypomethylation of a cancer- and germline-specific promoter of its host gene, GABRA3. miR-105-5p may be a target for gastric cancer immunotherapy, which warrants follow-up studies.

On the other hand, downregulation of PD-L1 mediates the resistant response to ICI (68). miR-513a-5p promoted proliferation, invasion and migration of HCC cells by reducing PD-L1 expression, leading to increased resistance to anti-PD-1 therapy in HCC (56). Specifically, β-glucuronidase-mediated inhibition of miR-513a-5p inhibited HCC progression and improved the efficacy of anti-PD-1 treatment in murine tumor model. Antagonism of miR-513a-5p may be an effective approach for improving the therapeutic potential of anti-PD-1 treatment. The addition of ncRNA-based therapies targeting a large variety of immune checkpoints would pave the way for surmounting the resistance to immunotherapy and enable better clinical outcomes in cancer patients.

Ferroptosis, an iron-dependent form of regulated necrosis, is mainly initiated by the lethal accumulation of lipid peroxidation catalyzed by cellular labile free iron (69). Cancer cell ferroptosis induced by interferon-γ (IFN-γ) released by tumor-infiltrating CD8⁺ T cells potentiates the efficacy of immunotherapy (70). The involvement of miRNAs in ferroptosis suggests their regulatory effects on the therapeutic effect of immunotherapy. Thioredoxin reductase 1 (TXNRD1) acts as a negative regulator of ferroptosis (71). miR-21-3p promoted IFN-γ-mediated ferroptosis by downregulating TXNRD1 to impel lipid peroxidation (57) ( Figure 3 ). Importantly, miR-21-3p overexpression sensitized melanoma cells to anti-PD-1 therapy through promotion of ferroptosis. Nanoparticle delivery of miR-21-3p was proven to synergize with anti-PD-1 antibody without obvious adverse effects in a preclinical mouse model. Nanoparticle delivery of ferroptosis-related ncRNAs may have translational potential in cancer immunotherapy, which deserves more detailed investigations.

LncRNAs play important roles in cancer immunotherapy resistance. Disruption of the antigen presentation pathway forms a significant mechanism of cancer resistance to immunotherapy. LncRNAs are vital regulators of the antigen presentation process ( Figure 4 ). The lncRNA LINK-A exhibited a tissue-specific expression pattern in mammary glands (72). This lncRNA promoted the interaction between phosphatidylinositol- (3,4,5)-triphosphate (PIP3) and inhibitory G-protein-coupled receptor (GPCR) pathways, resulting in the inactivation of the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling pathway ( Table 2 ). This led to the inhibition of PKA-mediated phosphorylation of an E3 ubiquitin ligase tripartite motif-containing 71 (TRIM71). Hypophosphorylated TRIM71 facilitated K48-linked polyubiquitination and proteasome-mediated degradation of the antigen peptide-loading complex (PLC) components (e.g., tapasin, transporter associated with antigen processing 1 (TAP1), TAP2, and calreticulin (CALR)) and inherent tumor suppressors Rb and p53. Thus, LINK-A acted to attenuate intrinsic tumor suppressor barriers via the GPCR/PKA/TRIM71 signaling cascade, forming a resistance strategy for immunological cancer escape. Knockdown of LINK-A markedly improved the protein stability of the PLC components and MHC class I (MHC-I) complex and enhanced the infiltration of CD8⁺ T cells into the tumor tissue, hence sensitizing breast cancer cells to ICI.

The long intergenic ncRNA (linRNA) EPIC1 could interact with the histone methyltransferase enhancer of zeste homolog 2 (EZH2), resulting in the epigenetic silencing of antigen presentation genes (e.g., human leukocyte antigen A (HLA-A), HLA-B, HLA-C), antigen processing genes (e.g., endoplasmic reticulum aminopeptidase 1/2 (ERAP1/2), TAP1/2 and tapasin) as well as the IFN-γ receptor IFNGR1 (73). Consequently, EPIC1 induced breast cancer resistance to ICI therapy through inhibition of antigen presentation and the IFN-γ/Janus kinase (JAK)/STAT1 pathways. Oppositely, knockdown of EZH2 counteracted the tumor-promoting effect of EPIC1. The linRNA EPIC1 may serve as a potential target for cancer immunotherapy. The mechanisms by which EPIC1 regulates the interaction between EZH2 and its target genes warrant further study.

Cancer immunotherapy predominantly relies on either activating or restoring the function of CD8⁺ T cells (80). LncRNAs can coordinate the activation of T cells and thus affect the immunotherapy response ( Figure 5 ). LncRNA small nucleolar RNA host gene 14 (SNHG14) served as a tumor promoter in diffuse large B cell lymphoma (DLBCL) (74). SNHG14 increased ZEB1 expression to activate PD-1 by sponging miR-5590-3p. Consequently, SNHG14/miR-5590-3p repressed CD8⁺ T cell activity and promoted DLBCL progression through ZEB1-mediated activation of PD-1/PD-L1 immune checkpoint. Particularly, the supplementation of anti-PD-1 or anti-PD-L1 reversed the effect of SNHG14 overexpression on CD8⁺ T cell activity. Depletion of SNHG14 potentially blocks immune evasion and enhances the effectiveness of immunotherapy in DLBCL through regulating the PD-1/PD-L1 axis.

Cyclin-dependent kinase 1 (CDK1)-related lncRNA, LINC00261, was significantly downregulated in LUAD compared with normal tissues and was correlated with poor prognosis in LUAD (75). The level of IL-8, mainly derived from macrophages, dramatically elevated in ICI-resistant patients, which could be ascribed to the downregulation of LINC00261 in LUAD. These results suggested the interrelation between the LINC00261 level and immunotherapy resistance in LUAD. In addition, reduced expression of LINC00261 was likely to correlate with increased infiltration of regulatory T cells (Tregs) and decreased infiltration of cytotoxic T cells, eventually leading to immunosuppression. Enforced expression of LINC00261 may improve the effectiveness of immunotherapy, which is worthy of further study. Concerted research efforts are required to reveal the mechanisms through which LINC00261 affects the responsiveness to immunotherapy in LUAD.

The expression level of LINC01132 was remarkably higher in HCC tissues than normal tissues and correlated with poor prognosis of HCC patients (76). LINC01132 increased the expression of dipeptidyl peptidase 4 (DPP4) by competitively binding to nuclear factor erythroid 2-related factor 1 (NRF1). Depletion of LINC01132 promoted the intratumoral infiltration of CD8⁺ T cells and potentiated the efficacy of anti-PD-L1 therapy in HCC-bearing mice via DPP4 inhibition.

Pancreatic ductal adenocarcinoma (PDAC)-produced IL-6 induced the expression of the lncRNA plasmacytoma variant translocation 1 (PVT1) in tumor-associated nonmyelinating Schwann cells (TASc) (77). Tryptophan 2,3-dioxygenase (TDO2), an important enzyme in the kynurenine pathway, fostered cancer progression by inducing CD8⁺ T cell dysfunction (81). PVT1 fostered TDO2 phosphorylation and enhanced its enzymatic activities in the conversion of tryptophan to kynurenine. As a result, PVT1 reduced CD8⁺ T cell infiltration and promoted PDAC carcinogenesis (77). TASc inhibition significantly suppressed PDAC growth and enhanced the intratumoral infiltration and cytotoxicity of CD8⁺ T cells. Reportedly, high levels of kynurenine contribute to immunotherapy resistance in cancer patients (82). As expected, TASc inhibition synergized with anti-PD-1 antibody in PDAC-bearing mice, which could be partially attributable to reduced kynurenine production. It will be important to validate the direct effect of PVT1 on the status of the TME and the efficacy of anti-PD-1 antibody in further studies.

LncRNAs have been implicated in the regulation of multiple pathways through diverse genetic or epigenetic mechanisms (83). LncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) increased the expression of myo-inositol oxygenase (MIOX) in HCC by sponging miR-362-3p (78) ( Figure 3 ). MIOX facilitated the production of reactive oxygen species (ROS) and reduced the intracellular levels of nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione (GSH), thus promoting ferroptosis. In vitro and in vivo experiments manifested that upregulation of NEAT1 strengthened the anticancer potency of ferroptosis activators erastin and RAS-selective lethal 3 (RSL3) through promotion of ferroptosis. Inducing ferroptosis via NEAT1 overexpression could serve as a prospective therapeutic method for HCC immunotherapy.

LINC01085 was deleted in docetaxel-resistant castration resistant prostate cancer (CRPC) and predicted favorable outcomes of CRPC patients (79). It could competitively interact with TANK-binding kinase 1 (TBK1) and glycogen synthase kinase 3β (GSK3β), hence abating the affinity of TBK1 and GSK3β and reducing TBK1 phosphorylation at the Ser-172 site. These events inhibited the activation of the stimulator of interferon genes (STING)/mitochondrial antiviral signaling protein (MAVS)/IFN regulatory factor 3 (IRF3) signaling pathway, contributing to downregulation of nuclear factor-κB (NF-κB) and PD-L1 as well as reduced production of type I/III IFNs. In vivo experiments indicated that overexpression of LINC01085 in combination with anti-PD-L1 treatment produced a significant tumor-antagonizing effect than anti-PD-L1 treatment alone. Overall, this study provided a scientific rationale to combine LINC01085 agonists with ICI therapy to enhance the therapeutic effect for CRPC in the future.

CircRNAs have emerged as key factors that act in an entangled network of interactions with diverse miRNAs or proteins to remodel the tumor immune microenvironment ( Figure 6 ). CircUHRF1 was upregulated in HCC tissues compared with matched adjacent normal tissues, and its high expression indicated NK cell exhaustion and poor prognosis in HCC patients (84). CircUHRF1 was also highly expressed in HCC cell-derived exosomes. T cell immunoglobulin and mucin domain-containing protein-3 (TIM-3) is a major inhibitory receptor on NK cells (85), and NK cells with elevated TIM-3 expression displayed a decreased capacity to initiate antitumor immune responses (86). HCC-secreted exosomal circUHRF1 could be delivered into NK cells, where it restricted NK cell ability to secrete IFN-γ and tumor necrosis factor-α (TNF-α) by targeting miR-449c-5p to enhance TIM-3 expression (84) ( Table 3 ). CircUHRF1 supported HCC development in a NK cell- and exosome-dependent manner. CircUHRF1 deficiency increased HCC cell sensitivity to anti-PD-1 treatment and improved the overall survival rate in a xenograft mouse model. Altogether, circUHRF1 mediates the crosstalk between HCC cells and NK cells, leading to the impairment of NK cell function through upregulation of TIM-3 expression. CircUHRF1 functions as a critical factor affecting resistance to anti-PD-1 treatment. Reduction of circUHRF1 expression in HCC may improve patient outcomes by rescuing NK cell function. Tumor-infiltrating CD8⁺ T cells also had high expression levels of TIM-3. It is intriguing whether exosomal circUHRF1 could induce T cell dysfunction by regulating the miR-449c-5p/TIM-3 pathway. The involvement of circUHRF1 in the communication between cancer cells and tumor microenvironment is worthy of continued study.

CircFAT1 was strikingly upregulated in head and neck squamous cell carcinoma (HNSCC) relative to matched normal tissues and its high expression indicated HNSCC metastasis and poor prognosis (87). CircFAT1 combined with STAT3 and facilitated its activation by reducing Src homology 2 domain-containing phosphatase 1 (SHP1)-mediated dephosphorylation of phosphorylated STAT3 (pSTAT3). pSTAT3 bound to STAT1 to block type I IFN (IFN-I) response (98). As expected, circFAT1 depletion enhanced the production of IFN-I-induced chemokines (e.g., CXCL9 and CXCL10) that were intertwined with recruitment of CD8⁺ T cells to the tumor site (99). Consistently, circFAT1 knockdown potentiated the efficacy of anti-PD-1 treatment in vivo by promoting CD8⁺ T cell infiltration into tumor tissues (87). Upregulation of circFAT1 represents a vital molecular mechanism, which contributes to the molding of an immunosuppressive microenvironment in HNSCC.

CircZNF451 was highly expressed in the exosomes of LUAD patients refractory to anti-PD-1 treatment (88). LUAD-derived exosomal circZNF451 could induce the ubiquitination of fragile X-related protein 1 (FXR1) via the E3 ligase TRIM56 in macrophages. CircZNF451-mediated FXR1 degradation abolished the inhibition on the downstream E74-like factor 4 (ELF4)/IRF4 signaling pathway. ELF4 plays an important role in both innate and adaptive immunity by affecting the development and activity of NK and CD8⁺ T cells (100). Accordingly, exosomal circZNF451 reshaped the immunosuppressive tumor microenvironment by fostering macrophage polarization toward an anti-inflammatory M2-like phenotype as well as dysfunction of cytotoxic CD8⁺ T cells. Overexpression of circZNF451 attenuated the sensitivity of anti-PD-1 therapy in a xenograft model, while conditional silencing of ELF4 in macrophages reversed this effect. Collectively, exosomal circZNF451 may act as a new indicator for immunotherapy resistance and a target to enhance the efficacy of PD-1 blockade in LUAD. Another LUAD-enriched circ_0004140 could support cancer cell proliferation and migration (89). Circ_0004140 elevated the expression of CCL22 by directly interacting with miR-1184. CCL22 can recruit Tregs in the tumor microenvironment (101). Tregs are able to suppress CTL proliferation and induce immune suppression. Thus, overexpression of circ_0004140 was associated with impairment of CTL function. Combining CCL22/C-C motif chemokine receptor 4 (CCR4) axis inhibitor and anti-PD-1 treatment reversed immune resistance and reduced LUAD progression.

The plasma levels of exosomal circUSP7 were higher in NSCLC patients than healthy controls and correlated with poor clinical prognosis and CD8⁺ T cell dysfunction in NSCLC (90). CircUSP7 in patient plasma was mainly secreted by NSCLC cells via exosomes. Exosomal circUSP7 suppressed the ability of CD8⁺ T cells to secrete granzyme B (GzmB), IFN-γ, perforin and TNF-α. SHP2 is a ubiquitous tyrosine phosphatase that affects diverse immune cell signaling cascades (102). Importantly, SHP2 negatively regulated CD8⁺ T cell proliferation and function. Exosomal circUSP7 restrained CD8⁺ T cell function by serving as a miR-934 sponge to increase SHP2 expression (90). The in vivo experiment showed that exosomal circUSP7 overexpression enhanced the resistance to anti-PD-1 treatment and promoted tumor progression in NSCLC-bearing humanized NSG mice through induction of CD8⁺ T cell exhaustion. Furthermore, NSCLC patients with high levels of exosomal circUSP7 showed an apparent phenotype of resistance to anti-PD-1 therapy. Altogether, exosomal circUSP7 played a critical role in promoting tumor immune escape and immunotherapy resistance via the miR-934/SHP2 axis in NSCLC. Peripheral blood exosomal circUSP7 could be used as a novel marker of anti-PD-1 treatment in NSCLC. Reduction of circUSP7 expression may be effective in restoring CD8⁺ T cell functionality and augmenting immunotherapy efficacy in NSCLC patients.

The increased expression of PD-L1 on cancer cells restricts the function of tumor-infiltrating T cells through interaction with PD-1 loaded on T cells and contributes to an immunosuppressive microenvironment (36). Circ_0000052 directly interacted with miR-382-3p to relieve its inhibition of PD-L1 (91). The resultant upregulation of PD-L1 led to HNSCC cell aggressiveness. Hsa_circ_0000190 could enhance the expression of soluble PD-L1 (sPD-L1) in NSCLC (92). The expression level of sPD-L1 showed a positive linkage with disease progression in NSCLC patients following immunotherapy, hinting the crucial role of sPD-L1 in regulating immunotherapy response. Hsa_circ_0000190 might mediate NSCLC immune resistance through upregulation of sPD-L1. The mechanism by which hsa_circ_0000190 coordinates sPD-L1 expression remains to be deciphered.

NSCLC-enriched circIGF2BP3 showed a negative interrelation with the infiltration level of intratumoral CD8⁺ T cells (93). CircIGF2BP3 acted as a molecular sponge for miR-328-3p and miR-3173-5p to elevate plakophilin 3 (PKP3) expression. PKP3 enhanced the mRNA stability of the deubiquitinase ovarian tumor domain-containing ubiquitin aldehyde-binding protein 1 (OTUB1) by binding to FXR1, further protecting PD-L1 from proteasomal degradation. The circIGF2BP3/PKP3 regulatory axis accounted for cancer cell escape from immune surveillance by increasing PD-L1 expression. Accordingly, circIGF2BP3 dampened T cell-mediated antitumor immunity and accelerated NSCLC growth. PKP3 knockdown reinforced the therapeutic effect of PD-1 blockade in tumor-bearing mice.

High expression levels of hsa_circ_0020714 was correlated with resistance to anti-PD-1 immunotherapy and predicted a poor prognosis in NSCLC patients (94). Reportedly, the oncogene Sry-related high-mobility group box 4 (SOX4) favored immune escape and improved resistance to PD-1 blockade in cancer (103). Hsa_circ_0020714 induced NSCLC immune evasion and attenuated sensitivity to anti-PD-1 treatment by sponging miR-30a-5p to upregulate SOX4 (94). Blockade of the hsa_circ_0020714/miR-30a-5p/SOX4-related pathway may result in better immunotherapeutic effects in NSCLC.

CircCCAR1 was enriched in serum exosomes of HCC patients compared with those of healthy controls (95). CircCCAR1 acted as an oncogenic driver in HCC by sponging miR-127-5p to upregulate its target Wilms tumor 1-associated protein (WTAP). Moreover, exosomal circCCAR1 released by HCC cells was ingested by CD8⁺ T cells and resulted in CD8⁺ T cell dysfunction by stabilizing PD-1. Exosomal circCCAR1 released by HCC cells enhanced resistance to anti-PD-1 immunotherapy and reduced the survival time of HCC-bearing mice by retarding CD8⁺ T cell expansion and infiltration into tumor tissues. Modulation of PD-L1/PD-1-regulating circRNAs may represent an effective strategy to reverse T cell exhaustion and maximize immunotherapeutic effect in cancer patients. Nevertheless, clear evidence is needed to better understand the role of these circRNAs in modifying immunotherapy responsiveness.

Oncogenes have been implicated in immune system dysfunction and thus affect the benefits of immune-based cancer treatments (104). CircRNAs counteract the anticancer efficacy of immunotherapy through modulation of oncogenes. The expression level of circ_CELF1 was higher in NSCLC tissues than their adjacent nontumor tissues (96). Circ_CELF1 increased the expression of the oncogene epidermal growth factor receptor (EGFR) by acting as a competitive endogenous RNA (ceRNA) for miR-491-5p. Thus, circ_CELF1 could foster NSCLC development. Moreover, enforced expression of circ_CELF1 diminished the anticancer effects of anti-PD-1 therapy and shortened the survival time of NSCLC-bearing mice. Circ_CELF1 may represent a potential manageable target to overcome therapy resistance in NSCLC. Intensive research efforts should be encouraged to validate and expand this assumption.

The expression level of circHMGB2 was remarkably higher in NSCLC tissues than matched normal tissues (97). High expression of circHMGB2 was associated with poor prognosis of patients with LUAD and lung squamous cell carcinoma (LUSC). CircHMGB2 could upregulate coactivator-associated arginine methyltransferase 1 (CARM1) by sponging miR-181a-5p, thereby blocking the IFN-I response in LUAD and LUSC. These events contributed to formation of an immunosuppressive microenvironment and promotion of tumor growth in NSCLC-bearing mice. As expected, circHMGB2 overexpression profoundly reduced the therapeutic effect of PD-1 blockade in vivo. Pharmacological or genetic inhibition of CARM1 increased the sensitivity of circHMGB2-overexpressing NSCLC cells to anti-PD-1 treatment in murine cancer models. The interaction network between cancer cells and tumor microenvironment is complicated, and elucidating the underlying mechanisms is critically essential to preventing cancer immune evasion. Solid experimental data are still required to establish the role of circHMGB2 in the communication between cancer cells and tumor microenvironment.