The regulatory role of long non- coding RNAs as a novel controller of immune response against cancer cells

Immunotherapy has been established as a promising therapy for different cancer types. However, many patients experience primary or secondary resistance to treatment. Immune cells and anti-inflammatory factors are regulated by long noncoding RNAs (lncRNAs). In addition, lncRNAs have a role in immune resistance through antigen presentation loss or attenuation, PD-L1 upregulation, loss of T-cell activities, and activation of G-MDSCs and Tregs in the tumor environment. LncRNAs can also influence the interaction between cancer stem cells and immune cells in the tumor microenvironment, potentially resulting in cancer stem cell resistance to immunotherapy. Immunological-related lncRNAs can influence immune responses either directly by affecting neighboring protein-coding genes or indirectly by sponging miRNAs through various mechanisms. We have emphasized the role and levels of expression of lncRNAs that have been linked to immune cell formation, differentiation, and activation, which may have an influence on immunotherapy efficacy.


Introduction
Cancer and the immune system are bonded strongly together. Immune cells switch from a passive sentinel to an active responder when they detect foreign threats or endogenous alterations in the microenvironment [1]. Cancer immunotherapy (CI) is one of the developing therapy forms which can supplement conventional cancer treatments like chemotherapy, radiation and surgery [2]. Conventional cancer treatments can be destructive to all dividing cells leading to severe side effects like anemia, exhaustion, and emotional stress [3]. However, CI aims to activate the immune system directly to identify and destroy tumor cells and is therefore potentially more specific. The primary characteristics of CI are the broadness of response, specificity and memory against tumor antigens, which can result in better clinical outcomes and consequently improve quality of life, especially in patients with metastatic disease [4]. CI encompasses many different approaches like the use of monoclonal antibodies (mAbs), checkpoint inhibitors (CPIs), cytokines, vaccines, and a chimeric antigen receptor-T cell (CAR-T cell) therapy ( Fig. 1) [5]. These approaches can be either active or passive immunotherapies. In passive immunotherapies, immune checkpoint inhibitors (ICIs) are different monoclonal antibodies which deactivate checkpoint receptors and activate T cells to kill cancerous cells. Anti-PDL1 and anti-CTLA-4 ICIs are passive immunotherapy drugs which have recently been used [6]. Active immunotherapies mainly aim to produce longlasting memory responses, via the exploitation of immune cells such as dendritic cells which are potent immunomodulatory cytokines and antigen-presenting cells (APC) [7]. However, there are various obstacles to CI which make active and passive immunotherapies highly challenging. The most common challenge is that many individuals fail to respond to CI due to high mutation rates. This suggests that CI must be individualized by carefully comprehending and identifying the rate-limiting step operating on a specific patient [8]. Several cellular mechanisms can affect the functions of the immune system, which could influence the patient's response to immunotherapy. LncRNAs are one of these strategies. LncRNAs are transcripts that are longer than 200 nucleotides and lack the ability of protein-encoding [9], due to the presence of 7-methyl guanosine (m7G) at their 5′ ends. LncRNAs are not appropriately spliced at the 3' ends compared to mRNA, which has full splicing at the 3' end [10]. Although more than 90% of lncRNAs have no protein-coding potential, certain transcripts have been shown to produce short open reading frames (ORFs) of 300 nt or less, which could be translated into small peptides [11].
LncRNAs have a critical role in determining immune responses, therefore they form a logical class of target in cancer immunotherapy studies. Because of their conditionspecific expression pattern, lncRNAs are an appealing target for prospective biomarkers and treatments [12]. LncRNAs play a role in immune cells` regulation system; for example; in many particular types of immune cells, the expression of lncRNAs is stimulated by the activation of Toll-like receptor (TLR) when bind with intracellular signalling pathways (such as NF-κB). Also, it can be suppressed by activation of cytokines receptors such as IL-6 or TGF-β, consequently, mediating immune responses [13]. In addition, lncRNAs control cytokines and immune checkpoints and enhance the development of the immunosuppressive environment, which either promotes the progression or suppression of tumor and drug resistance [14]. In this review, we try to summarize the critical roles and functions of these lncRNA-mediated approaches, which have considerable potential in immunotherapies to facilitate cancer treatment and diagnosis.

The role of lncRNAs in gene expression
LncRNAs have a crucial role in different biological processes, including transcriptional activation and interference, chromatin remodeling, mRNA translation and RNA processing [15] (Fig. 2). Most lncRNAs' biological activities and molecular mechanisms are still substantially unknown, with only a few being partially understood. Existing evidence suggests that these metabolites serve key roles in the epigenetic, transcriptional, and post-transcriptional control of various cellular activities, including protein-coding gene expression [16].
As previously noted, most lncRNAs preferentially localize in the nucleus and chromatin, and growing evidence suggests that some nuclear lncRNAs epigenetically control gene expression by modifying chromatin structure [17]. LncRNAs mediate changes in chromatin and gene expression in two ways. First, they interact directly with chromatin-modifying enzymes. They act as guides in cis or trans, attracting chromatin modifiers to specific genomic loci to promote DNA methylation or histone modification. These modifications regulate chromatin states and effects on gene expression [18]. In the second mechanism; lncRNAs act as adaptors, connecting specific chromatin loci to ATPdependent chromatin-remodelling complexes and serving as guides for the regulation of nucleosome remodelling and gene expression [18].
Furthermore, lncRNAs have been discovered to be important regulators of epigenetic processes, including X-chromosome inactivation, genomic imprinting, cellular differentiation, and maintenance of cell identity [19]. LncRNAs regulate gene expression at the transcriptional level by different mechanisms as (A) Gene transcription regulation; they facilitate mobilization of the transcription and ceRNAs are important for regulating many basic biological functions [22].
Decoy lncRNAs act as modulators of transcription by trapping or decreasing the availability of different regulatory factors, including catalytic proteins, miRNAs, transcription factors and sub-units of larger chromatinmodifying complexes [23]. Scaffold lncRNAs have a vital structural role, they serve as platforms for the assembly of multiple-component complexes, and other regulatory cofactors such as ribonucleoprotein (RNP) complexes. RNP complexes can regulate gene expression by targeting certain genomic regions [24]. Guide lncRNAs can regulate transcription by binding with different factors like regulatory or enzymatically active proteins and organize their localization on specific sites on the genome either cis (adjacent) or trans (distant) from their transcriptional locus [25]. Signal lncRNAs function as molecular signals to control transcription in response to different stimuli. As a result, the presence and production of these components act as an indicator factors to the promoter region of target genes, interacting with RNA polymerase II, affecting protein localization, and acting as transcriptional activators or repressors. (B) Repression of target gene transcription; they form lncRNA-DNA hybrids with the target gene and promote DNA methylation or acetylation [20]. LncRNAs mediate mRNA stability, translation, degradation, and pre-mRNA alternative splicing genes. Thus they affect gene expression and regulate biological processes at the post-transcriptional level.
LncRNAs function as competing for endogenous RNAs (ceRNAs) or sponges, decoys, signals, guides and scaffolds according to their mode of action [21]. LncRNAs act as ceRNAs or endogenous microRNAs (miRNAs) sponges through two pathways; (A) they can sequester miRNAs, preventing them from attaching to target mRNAs. (B) In the case in which lncRNAs and miRNAs have common binding sites in the target mRNA, lncRNAs can interact directly with target mRNA transcripts, blocking miRNA binding sites in mRNA molecules. Interactions between miRNAs concentration. Furthermore, increased HOTAIR suppressed Ig synthesis, natural killer (NK) cell activity, and the ratio of CD4/CD8 T cell subsets in B-lymphocytes, and lowered the levels of transforming growth factor, interferon, interleukin-10, and tumor necrosis factor in PB and T-lymphocyte proliferation. Additionally, over-expressed HOTAIR boosted the expression of cyclinD1, GSK-3, and c-Myc in the bone marrow of mice, resulting in better survival and proliferation [31].
LncRNA p21 plays an important role as a regulator of tumor-associated macrophages (TAMs) in breast cancer. TAMs show different phenotypes in cancer development, where they have a pro-inflammatory phenotype, generate an anti-tumor type-1 inflammatory response, and suppress tumor cell proliferation by generating TNF, reactive oxygen species (ROS), or phagocytosis during the primary stage of tumor development. In contrast, tumor microenvironmenteducated macrophages release IL-10 and TGF and inhibit the activation of CTLs and NK cells at advanced stages of tumor development. Downregulation of lncRNA p21 facilitates interaction between p53 and Mouse double minute 2 homolog (MDM2), resulting in activation of NF-κB and STAT3 signaling pathways, reversed TAMs phenotype and generating TNF-α to destroy cancer cells [33].
LncRNA Cyclooxygenase-2 (Cox-2) is located about 50 kb downstream of the mouse Cox-2 gene. LncRNA Cox-2 is a broad-acting regulatory component of the inflammatory response regulation circuit, where the repression or activation of various immune genes can mediate by it. In hepatocellular carcinoma (HCC), lncRNA Cox-2 has an important role in the suppression of the tumor immune evasion and development by enhancing the polarization of M1 macrophages and suppressing the polarization of M2 macrophages [34]. In contrast, the lnc-epidermal growth factor receptor (EGFR) enhances HCC progression and development. LncRNA EGFR enhances differentiation of Treg and suppresses CTLs by binding with EGFR and blocking its interaction with c-Casitas B-lineage Lymphoma (c-CBL). The latter is an E3 ubiquitin-protein ligase that helps in cell signaling and protein ubiquitination. Additionally, for transcription activity and also under specific conditions, they can modulate specific signaling pathways [26].
In summary, lncRNAs are widely expressed and play important roles in gene regulation. They can modulate chromatin function, regulate the assembly and function of membraneless nuclear bodies, modify the stability and translation of cytoplasmic mRNAs, and interfere with signaling pathways depending on their localization and specific interactions with DNA, RNA, and proteins.

The effect of lncRNAs on the efficacy of cancer immunotherapy
Rapid advances in transcriptomic profiling have led to the identification of immune-related lncRNAs as regulators of immune cell-specific gene expression that mediates both immune stimulation and suppression, implying that lncRNAs could improve the efficacy of immunotherapy against tumors. Tables 1 and 2 summarize the regulatory role of lncRNAs in cancer progression or cancer suppression via different immune responses. Some lncRNAs act as immunomodulators, influencing inflammatory cytokine production, altering innate immune cells, or creating resistance to immunotherapy [27]. Others can affect antigen presentation, control the production of PD-L1, and regulate the actions of immunosuppressive cells to modify the T-cell-mediated immune response that leads to immunosuppression [28]. In this review, we focus on lncRNAs associated with the immune response as a target for improving immunotherapy resistance in different cancer types (Fig. 3). For Example, in acute lymphoblastic leukemia (ALL), lnc-Insulin receptor (INSR) has a role in tumor growth and progression via overexpression of T regulatory cells (Treg) and decreases the percentage of cytotoxic T lymphocytes (CTLs) [29]. In addition, lnc INSR directly attaches and blocks INSR ubiquitination, leading to activation of INSR and PI3K/AKTsignaling pathway, which results in induction of suppressive immune microenvironment (IME).
PI3K is an abundant protein in white blood cells and abnormality in its signaling pathway inhibits T cell activation. Also, the PI3K/AKT pathway enables T cell receptor signaling to control the expression of forkhead box P3 (Foxp3), which binds to certain areas of DNA and helps to regulate the activity of genes involved in immune system regulation [30]. LncRNA HOTAIR increases the immunologic rejection in mice leukaemia cells via the activation of the Wnt/-catenin pathway, in which mice given HOTAIR mimics as well as small interfering RNA HOTAIR. The results revealed the up regulation of lncRNA HOTAIR, which resulted in an increase in the percentage of leukocytes and decreasing the percentage of PLTs and haemoglobin   formula using Cox regression and the least absolute shrinkage and selection operator (LASSO) analysis to investigate the differences in overall survivals (OSs) between high-and low-risk groups. The risk score (RS) method contained eleven immune-related lncRNAs that were linked with survival. There is a marked relation between high-risk score cases that had poor survival in both the TCGA and CGGA and Foxp3 expression, which induce immunosuppression in HCC patients [35].
In a recent in silico study, Xia P. and colleagues used a similar strategy with The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) patients. A total number of 812 immune-related lncRNAs founded to be linked directly to glioma. The authors developed a risk score  [39].
In summary, lncRNAs are expressed in a variety of immune cells and have a role in both innate and adaptive immunity. The discovery of lncRNAs has provided a unique perspective for investigating the regulation of TME. LncRNAs promote the formation of an immunosuppressive microenvironment through related different pathways, like the PI3K/AKT pathway, Wnt/-catenin pathway, JAK/STAT pathway and TNF-α/ NF-κB pathway, thereby controlling the escape of tumors from immune surveillance and promoting the development of metastasis and drug resistance in different cancer types. groups related to Glioma patients. The RS formula exhibited a good prediction accuracy in the CGGA dataset equals (5-year Area under Curve (AUC) = 0.730) and could accurately forecast the prognosis of glioma patients that equals (5-year AUC = 0.749). These results from the model's robust prediction function, give specific guiding values for glioblastoma etiology and clinical treatment analysis, allowing users to find prospective therapeutic targets for glioma treatment [36].
In another study, the immune-related lncRNA signature (IRLS) in bladder cancer was determined using the LASSO Cox regression model. Using LASSO Cox regression analysis, the authors chose five prognostic lncRNAs to create IRLS. They discovered that IRLS positively linked with immune cell infiltration and expression of important immunological checkpoints in the tumor microenvironment (TME), implying that immunosuppressive TME may play a role in poor prognosis [37]. LncRNA NKX2-1-AS1 was originally detected in lung carcinoma cells. Overexpression of lncRNA NKX2-1-AS1 can reduce cell migration and immune system evasion by decreasing the expression of CD274, the gene encoding PD-L1 [38]. In contrast, lncRNA . Tregs are CD4 + T cells that promote tumor growth and are usually identified by the Foxp3 + CD25 + CD4 + T cell subset. They suppress effector T cells and other immune cells by secreting immunosuppressive cytokines such as IL-35, IL-10, and TGF-β. The interplay between CSCs and Treg in TME, suggests their roles in maintaining immunosuppression and promoting tumor infiltration of different types of cancers. Mainly, Treg infiltration is induced by CSCs in the TME via co-stimulatory molecules and STAT3 signaling, whereas Tregs regulate CSCs proliferation and expansion either directly through IL-17 and PGE2 production or indirectly through TGF-mediated angiogenesis and epithelial-mesenchymal transition (EMT) [44].
NK cells represent a subpopulation of cytotoxic lymphocytes, known as large granular lymphocytes (LGL) which account for 5-20% of all circulating lymphocytes in humans. NKs are critical for innate immune response and are considered one of the cell types which has the most potential for targeting and killing the tumor cells. CSCs can evade NK by increasing the expression of MHC-I on their surface, where most immune responses are triggered by NK in tumor cells through down-regulation of MHC-I. Also, EMT-derived NK cell is one of the cellular pathways which NK cells promote in CSCs according to the type of cancer. For example; in melanoma, NK cells secret IFN-γ and TNF-α and enhance CSCs to undergo EMT, inducing them to invasive phenotypes and increasing the expression of stemness markers [46].
In contrast, in colorectal cancer, EMT promotes antitumor immune response by increasing the expression of NK group 2, member D (NKG2D) receptor which has an important role in cancer immunosurveillance [47]. LncRNAs have a potential impact on immune modulation and regulation of CSCs. Several studies showed that TME and CSCs niches have a crucial role in the maintenance of lncRNA-regulated therapy resistance in CSCs. For example, in HCC and breast cancer, Hypoxia-associated lncRNA (HAL) and lncRNAs runt-related transcription factor 1 Intronic Transcript 1 (RUNX1-IT1) enhance cancer stemness and increase resistance to apoptosis, under the regulation of Hypoxia which represents one of the key features of TME [48,49]. As mentioned above, crosslinking between CSCs and two pathways-TNF-α/ NF-κB signaling and IL-6/STAT3-regulates

The role of lncRNAs in cancer stem cell resistance to immunotherapy
The cancer immune-editing theory and the hierarchy model of cancer initially explained the ability of cancer stem cells (CSCs) to resist immunological destruction. Pluripotent and long-living cancer cells are subpopulations of CSCs which are responsible for drug resistance, recurrence, and metastasis and tumor initiation [40]. CSCs can hide from the immune-mediated destruction and interact with different immune cells by releasing several intracellular, soluble and membrane-bound factors that allow them to survive and inhibit innate and adaptive anti-tumor immune responses in their niche [41]. The CSCs can dysregulate the expression of various anti-apoptotic proteins, including survivin, Bcl-xL, and Bcl-2 in different tumor types. Also, CSCs can evade immune-mediated apoptosis promoted by NK and effector T cells, or immunotherapeutic antibodies by secreting many cytokines and other molecules, such as IL-10, IL-6, IL-4, FasL, and prostaglandin E 2 (PGE2). In addition, CSCs maintain the immunosuppressive TME and enhance tumor infiltration by releasing diverse immunosuppressive cytokines and chemotactic factors such as TGF-β, IL-10 and IL-2. These factors otherwise suppress the activities of effector immune cells such as NK cells, CTLs and T cells or/and enhance immunosuppressive immune cell subpopulations, including MDSCs, Tregs and TAMs [42]. Also, other studies on multifaceted interactions between CSCs and the immune system showed that CSCs can recruit and enhance the properties of macrophages into TAMs. TAMs usually express M2 phenotypes which have pro-tumor and immunosuppressive properties and are related to cancer progression and recurrence [43]. TAMs are required for CSCs self-renewal and maintenance in different cancer types via activation of the STAT3/NF-κB pathway (Sainz et al., 2016). DCs are APCs that generate innate or adaptive immune responses. CSCs can recruit immunosuppressive properties of DCs by producing immunosuppressive cytokines, including IL-13, IL-10, IL-4, and co-inhibitory molecules like B7-H3, IDO1 and PD-L1 which induce tumor properties of DCs [44].
The MDSCs play a crucial role in enhancing an immunosuppressive environment in TME and are employed as a prognostic biomarker for patients` response to immunotherapy and their rate of survival. The MSDCs can be categorized into two subtypes based on their different nuclear morphologies: granulocytic-MDSC (gMDSC) and monocytic-MDSC (mMDSC). They have two different immunosuppressive mechanisms. Cross linking between CSCs and MDSCs at the tumor site can enhance tumorigenesis and metastasis in different cancer types. For example; CSCs activate IL-6/STAT3 signaling, which enhances the and reducing the expression of tumor suppressors or vice versa [54].
The relationship between lncRNAs and miRNAs was shown to alter cancer immunotherapy resistance in several earlier investigations (Tables 3 and 4). For Example, in breast cancer, overexpression of lncRNA small nucleolar RNA host gene 1 (SNHG1) could decrease immune escape and tumor progression by enhancing the expression of miRNA-448 and repression of Indoleamine 2,3-dioxygenase (IDO) level, resulting in inhibition of Treg differentiation. The IDO is a vital component of the immune system that aids in natural defense against a variety of infections. Also, it has a role in the suppression of T cell immunity and promoting the maturation and differentiation of Treg cells [55]. In contrast, another study by Liang and his colleagues showed that knockdown of lncRNA breast cancerrelated transcript 1 (BCRT1) could decrease breast cancer progression in vitro and in vivo. LncRNA BCRT1 acts as a ceRNA for miRNA-1303 which targets Poly pyrimidine tract-binding protein 3 (PTBP3), thus protecting PTBP3 from degradation and promoting breast cancer progression. PTBP3 is an essential RNA-binding protein that regulates gene expression and influences the biological behaviour of many malignancies. It also plays a key role in RNA alternative splicing. In addition, lncRNA BCRT1 can transfer to macrophages by exosomes, accelerating M2 polarization and promoting its impact on tumor progression [56].
Diffuse large B cell lymphoma (DLBCL) is the most common disorder derived from the B-lymphocytes. LncRNA small nucleolar RNA host gene 14 (SNHG14) induced immune evasion and DLBCL progression by sponging miRNA-5590-3p, increasing the expression of Zinc finger E-box binding homeobox 1 (ZEB1). ZEB1 is a transcriptional factor that functions as an oncogene regulating migration, invasion, EMT, and development of various types of cancer [59].
LncRNA down-regulated in liver cancer stem cells (lnc-DILC) has an inhibitory role in liver cancer stem cells' selfrenewal and suppresses its expansion by down-regulation of IL-6 transcription and STAT3 activation. In addition, lnc-DILC modulates the crosstalk between TNF-α/ NF-κB signalling and IL-6/STAT3, resulting in a decreased hepatic inflammation and liver cancer stem cell proliferation [50]. Another study showed that crosslinking between lncRNA H19 and TAMs in EMT induced stemness and accelerated HCC invasion of HCC cells in vitro through modulation and activation of the miR-193b/MAPK1 axis, suggesting that lncRNA H19 could be a promising anti-cancer therapy strategy for reducing HCC aggression and improving clinical outcomes [51].
In glioblastoma, stem-like subpopulation cells which are exited in multiform and have a role in tumor progression, resistance to apoptosis and recurrence are called glioma stem cells (GSCs). Crosstalk of the miR-146b-5p/HuR/lincRNA-p21 axis inhibits expression and activity of β-catenin, resulting in increased apoptosis and radio sensitivity, decreased cell viability, neurosphere formation capacity and stem cell marker expression, and induced differentiation in GSCs [52]. LncRNA HOTAIR regulates proliferation, invasion, colony formation, and self-renewal capacity through the modulation of the miR-34a/ Sox2/ p53 /p21 axis in breast cancer CSCs [53].
In summary, CSCs release a variety of immunosuppressive cytokines and chemotactic factors such as; PGE2, IL-10, TGF-β, IL-4, IL-13 and IL-35 that affect different immune cells in the TME and promote tumor invasion and progression. Also, the interaction between lncRNAs, CSCs and immune cells in TME, has a key role in immune escape and resistance to immunotherapies through different cellular pathways including; EMT, IL-6/STAT3 signaling pathway, STAT3/NF-κB pathway and TNF-α/ NF-κB pathway.

The effect of lncRNAs on the miRNAs involved in immunotherapy responses
The miRNAs are a subset of noncoding RNA with a length of ~ 22 nucleotides that have a functional role in the posttranscriptional regulation of protein-coding genes by mRNA cleavage, direct translational suppression, and/or mRNA instability. LncRNAs affect miRNAs through a variety of pathways, as mentioned above, which control a variety of biological processes. The interaction between miRNAs and lncRNAs can influence tumor growth, invasion, and metastasis by enhancing the activation of oncogenic pathways

Studying the clinical trials of lncRNAs to find a potential prognostic factor for efficient immunotherapy
The relevance of lncRNA as a predictive factor for cancer cell immunotherapy responsiveness was previously demonstrated in a clinical trial. The data for this study came from TCGA of immunotherapy patients, which included 419 cancer patients. Patients were divided into two groups: (a) 348 patients with bladder cancer from the IMvigor 210 trial phase 2 who were treated with the PD-L1 inhibitor "Atezolizumab," and (b) 71 patients with melanoma who were treated with anti-PD-1, anti-cytotoxic T-lymphocyteassociated protein 4 (CTLA4), and cytokine tumor vaccine. Other cancer patients who participated in this study were 493 patients with lung squamous cell carcinoma, 1082 patients with breast cancer, 406 patients with bladder cancer, and 457 patients with melanoma. LASSO was included in the study since since the patients were naive to immunotherapy medications. To expect an appropriate Interestingly, lncRNA HOTAIR enhances immune escape and tumor progression of both gastric cancer and cervical cancer by promoting the expression of human leukocyte antigen (HLA)-G. HLA-G is a member of the non-classical MHC family and plays a key role in tumor cell escape from host immune surveillance by inhibiting immune cell activities. In gastric cancer, HOTAIR acts as a ceRNA by sponging miRNA-152, resulting in promoting HLA-G expression [61]. Meanwhile, in cervical cancer, HOTAIR triggers the expression of HLA-G by directly sponging and inhibiting miRNA-148a [62].
In summary, both miRNAs and lncRNAs can influence tumor growth, invasion, and metastasis by enhancing the activation of oncogenic pathways and reducing the expression of tumor suppressors, hence regulating tumor growth, invasion, and metastasis. Some examples of lncRNAs-miRNAs interactions which contributed to enhancement of immune escape and tumor progression of different cancer types, include lncRNA SNHG1/ miRNA-448, lncRNA BCRT1/ miRNA-1303, lncRNA FENDRR/ miRNA-423-5p, lncRNA SNHG14/ miRNA-5590-3p, lncRNA SMAD5-AS1/ miRNA-135b-5p and lncRNA HOTAIR. Also, lncRNA HOTAIR promotes the expression of HLA-G  have functional immune predictions, according to the findings. Patients with lower levels of these lncRNAs had a higher OS, overall response, and full response length [63].

Current challenges and future perspectives
This review mainly focuses on the crosslinking between lncRNAs and TME which affects the response of cancer patients to immunotherapy. Immunotherapy has become one of the most well-established treatment options for a wide range of cancers. The most recent forms of immunotherapies with excellent outcomes, notably in hematologic malignancies, are CPIs and CAR-T-cells [66]. Many changes and mutations in cancer cells as well as other stromal cells in the tumor microenvironment can lead to immune escape and resistance. Immune-related lncRNAs play a key role in the regulation of immunological cell-specific gene expression, which modifies immune processes by controlling the environment and activities of immune cells as well as anti-inflammatory substances [1]. LncRNAs have the features of tissue-specific expression. They are characterized by relative stability in circulating body fluids, which make lncRNAs useful as cancer biomarkers and facilitate non-invasive detection. Immunotherapy based on lncRNAs has numerous advantages. LncRNAs can regulate a number of downstream target genes by participating in a variety of cell signalling pathways, which can help to control cancer treatment. Furthermore, many regulatory sites of lncRNAs can interact and interfere with other molecules, facilitating the development of new structure-based anticancer medicines [67]. More importantly, lncRNAs can also influence the interaction between CSCs and immune cells in the tumor microenvironment, potentially resulting in CSC resistance to immunotherapy and increased tumor growth and progression. Immunological-related lncRNAs might influence immune responses either directly by influencing adjacent protein-coding genes or indirectly by sponging miRNAs through several pathways [68]. Finally, we sought to outline and emphasize the role and levels of expression that have been linked to immune cell formation, differentiation, and activation, which may influence immunotherapeutic responses for a variety of malignancies and other disorders. Future research may be required to elucidate the many processes and pathways of immune-related lncRNAs in the tumor microenvironment, which might influence cancer development and progression.

Conclusion
LncRNAs play a key function in modifying the TME and controlling tumor cell immune escape. As a result, lncRNAbased targeted cancer immunotherapy has a bright future ahead of it. Despite the ongoing issues with lncRNA-based therapy, as research advances and becomes more refined, Another clinical investigation found that lncRNAs have a function in the organization of immunity and the TME in non-small cell lung cancer (NSCLC), which might be useful for prognosis. To differentiate a lncRNA Signature (TILSig) as an indication of immune cell infiltration in patients with NSCLC, researchers developed a unique computational technique . This method was developed using information gathered from an integrated investigation of immune and clinical lncRNA profiles in 115 immune cell lines, 187 NSCLC cell lines, and 1533 NSCLC patients. TILSig divided the patients into two categories: (A) Patients in the high-risk group are immune-cold and have less immune cell infiltration; (B) patients in the low-risk group are immunologically hot and have more immune cell infiltration. Seven TILncRNAs (HCG26, PSMB8-AS1, TNRC6C-AS1, CARD8-AS1, HCP5, LOC286437, and LINC02256) were shown to be associated with immune infiltration in NSCLS patients. Furthermore, patients in the immunological-hot group had a considerably higher survival rate and immune cell infiltration than those in the immune-cold group [64].
Another clinical trial intended to create a lncRNA-based risk signature and nomogram that might predict OS in gastric cancer (GC) patients. The primary cohort consisted of 341 patients with clinical and lncRNA expression data in The Cancer Genome Atlas stomach adenocarcinoma (TCGA STAD), the internal validation cohort consisted of 172 randomly assigned patients, and the external validation cohort consisted of 300 patients from the GSE62254 dataset. Gene set enrichment analysis (GSEA) was also used to investigate the pathway enrichment for the risk signature [65]. The expression patterns of various lncRNAs were also investigated in clinical samples from ten GC patients. The findings indicated a 14-lncRNA signature that was strongly associated with GC patients' OS and performed well on C-index, the area under the curve, and calibration curve assessments. In univariate and multivariate Cox regression analysis, the lncRNA signature was demonstrated to be an independent predictor of GC patients. Therefore, a nomogram combining the lncRNA signature and clinical factors was developed to predict OS in patients with GC in the original cohort, and it demonstrated high predictive values for survival in the TCGA cohort and the other two validation cohorts. GSEA also observed that the newly identified lncRNAs may affect carcinogenesis and prognosis in GC patients via influencing the autophagy pathway. According to experimental validation, the expression of lncRNAs in clinical samples and the STAD dataset followed the same pattern. Both the risk signature and the nomogram are excellent prognostic markers for GC patients, according to these studies [65].