Role of Non-Coding RNAs in Tumor Microenvironment

Version	Summary	Created by	Modification	Content Size	Created at	Operation
1		Paola Amero	--	4551	2023-09-08 21:15:58	\|
2	references update	Fanny Huang	Meta information modification	4551	2023-09-11 08:05:09	\|

This entry is adapted from the peer-reviewed paper 10.3390/ncrna9050052

Non-coding RNAs (ncRNAs) are a group of molecules critical for cell development and growth regulation. Cancer creates and expands the Tumor Microenvironment, which in turn supports cancer progression.

non-coding RNAs cancer tumor microenvironment

1. Introduction

Carcinogenesis is induced by changes in cellular, genetic, and epigenetic levels. Recent reports of the cancer genome have identified hundreds of thousands of mutations in coding sequences that promote cancer development. However, because coding sequences make up only 2% of the genome, scientists are also studying the functions of non-coding sequences in cancer transformation ^[1]. Non-coding RNAs (ncRNAs) are nucleic acids that do not code proteins. Based on cellular function, two types of non-coding RNAs can be distinguished: housekeeping non-coding RNAs (rRNA (ribosomal RNA), tRNA (transfer RNA), snRNA (small nuclear RNA), snoRNA (small nucleolar RNA), TERC (telomerase RNA), tRF (tRNA derived fragments)) and regulatory non-coding RNAs (miRNA (micro RNA), siRNA (small interfering RNA), piRNA (PIWI-interacting RNA), eRNA (enhancer RNA), lncRNA (long non-coding RNA), circRNA (circular RNA)) ^[2]^[3]. Regulatory non-coding RNAs are crucial for controlling cancer pathogenesis via regulating the processes of transcription, translation, and gene activity in cancer pathogenesis ^[4]. In addition, they also modulate immune cells’ response to tumors (e.g., circARSP91 activates the cytotoxic activity of natural killer (NK) cells in hepatocellular carcinoma) ^[5], epithelial-mesenchymal transformation (EMT) (e.g., lncRNA VIMAS1 promotes EMT in stomach cancer via Wnt/β-catenin signaling) ^[6], metastasis (piRNA-54265 promotes invasiveness of colorectal cancer) ^[7], and tumor angiogenesis (miRNA-126 inhibits the formation of new tumor blood vessels by blocking VEGF signaling in breast cancer) ^[8]. There are many methods for analyzing non-coding RNAs, including RT-qPCR, microarrays, bulk RNA-seq (bulk RNA sequencing), sc-RNA-seq (single-cell RNA sequencing), sp-RNA-seq (spatial RNA sequencing), metabolic labeling, chromatin immunoprecipitation (ChIP), and nuclear run-on (Table 1) ^[9]^[10]^[11]^[12]^[13]^[14]^[15]^[16].

Table 1. Methods of transcriptome analysis. Abbreviations: s4U, 4-thiouridine; EU, 5-Ethynyluridinee; Bru, 5′-bromouridine; RT-qPCR, reverse transcription–quantitative polymerase chain reaction.

Method	Brief Description	Advantages	Disadvantages	References
RT-qPCR	Technique based on PCR	High sensitivity	Time-consuming; requires primers; Allows for the evaluation of the expression of known transcripts	^[9]
Microarray	Technique based on the ability of complementary nucleic acid molecules to form double-stranded structures	Well-defined protocols for hybridization	Stringent criteria for sample collection requires a high quantity of RNA; expensive	^[10]
Bulk RNA-seq	Technique to evaluate mean gene expression of thousands of cells	Costs less than single-cell and spatial RNA-seq; requires less time compared to single-cell RNA-seq and spatial RNA-seq	Less detailed information on individual cells provide averaged gene expression in whole cells	^[11]
Single-cell RNA-seq	Sequencing technique to evaluate mRNA in a single cell	Enables analysis of the whole transcriptome including non-coding sequences; low background noise	Requires adequate preparation of tissue/cells; expensive; time-consuming; does not provide spatial information on transcriptome	^[12]
Spatial RNA-seq	Sequencing technique for evaluation of mRNA in the tissue area	Analyzes the whole transcriptome evaluates the interactions between cancer cells and tumor microenvironment	Requires adequate preparation of tissue/cells; cannot analyze a single cell; expensive; time-consuming	^[13]
Metabolic labeling	Technique in which RNA is labeled with uracil analogs (s4U, EU, Bru) in cell culture	Efficient; well-validated; high resolution	Uracil analogs are cytotoxic	^[14]
Nuclear run-on	Technique in which RNA in the isolated nucleus is labeled	Measurement of transcription in the primary state; allows distinct transcription and post-transcription changes in gene expression	Requires the ice-cold temperature to isolate nuclei; requires a large number of cells; results are dependent on the efficient induction of transcription outside the cell	^[15]
Chromatin immunoprecipitation (ChIP)	Technology based on antibodies to selectively isolate DNA-binding proteins and their DNA targets	Allows monitoring of changes in a single promoter in a time-dependent manner; may be used to follow transcription factors in the whole human genome	Low resolution; expensive; risk of protein rearrangement during analysis	^[16]

Among them, single-cell and spatial RNA sequencing techniques provide the most detailed information about tumor cells and the surrounding environment (referred to as the tumor microenvironment, TME). It is known that cancer cells affect adjacent cells to promote their proliferation, invasion, and migration ^[9]^[10]^[12]^[13]^[14]^[15]^[16]^[17]. TME is heterogeneous and consists of cancer cells, cancer-associated fibroblasts, fibroblasts, pericytes, endothelial cells, immune cells (B cells, neutrophils, dendritic cells, T cells, NK cells, macrophages), mesenchymal cells, stromal cells, myofibroblasts, and epithelial cells. Cancer cells can specifically reprogram healthy surrounding cells into cells that promote tumor growth ^[17]. Single-cell and spatial RNA sequencing analyses of cells in the TME may enable the design of therapies that can affect cancer cells, the TME, or both. In this context, non-coding RNA might be a promising tool to develop targeted cancer therapy and/or the TME to induce a cytotoxic immune response against cancer (e.g., miRNA-149-3p downregulates expression of inhibitor receptors and promotes T-cell proliferation) ^[18], induce apoptosis in cancer cells (e.g., LOC285194 siRNA leads to activation of an external apoptosis pathway) ^[19], or restore drug sensitivity (miRNA-21 increases the sensitivity of glioblastoma cells to paclitaxel) ^[20].

Exploring the role of non-coding RNA in cancer development may lead to the design of new anticancer therapies. Numerous clinical trials have been performed to deactivate gene expression using siRNA and thus inhibit the proliferation of cancer cells ^[21]^[22]. Despite the promising anticancer activity of non-coding RNA, the short half-life, low efficiency of encapsulation, and toxicity of these systems make it challenging to implement them in the clinical arena ^[23].

2. Role of Non-Coding RNAs in Tumor Microenvironment

Cancer creates and expands the TME, which in turn supports cancer progression. It is hypothesized that the development of cancer is driven by mutations and by changes in cell homeostasis. There are two types of genetic mutations: germinal (hereditary mutations) and somatic (non-hereditary mutations) ^[24]. It has been demonstrated that hereditary breast and ovarian cancer predisposition syndrome (HBOC) is mainly caused by germline mutation of BRCA1/2 genes. Testing BCRA1/2 mutations is expensive and time-consuming. Therefore, there is an ongoing search for novel techniques that can provide quick and affordable diagnoses. In 2020, Marques et al. attempted to analyze the expression of miRNAs as potential biomarkers to detect hereditary breast cancer. Researchers found out that in sporadic breast cancer, forty-nine miRNAs have increased expression compared to normal breast tissue, while in the case of hereditary breast cancer, seventy miRNAs had increased expression. Among these miRNAs, eight were differentially expressed in sporadic and hereditary breast cancer. These findings provide one of the first proofs of the usage of miRNAs as biomarkers to detect hereditary breast cancer ^[25].

Somatic mutations may also occur in miRNA genes in various cancers. In 2020, Kozłowski et al. performed the first thorough analysis of somatic mutations in these ncRNAs. The percentage of mutations in the miRNA genes varied according to the type of cancer. Cancer SKCM (skin cutaneous melanoma) exhibited the highest number of miRNA mutations and THCA (thyroid carcinoma) had the lowest. Moreover, over eighty miRNA coding genes were mutated in PAN-Cancer. This discovery may help to identify target miRNA genes for cancer treatment ^[26]. The miRNA analysis of the human genome revealed that there are more germline mutations in miRNA than somatic mutations. The specific role of each mutation in cancer development is still unknown. It has been discovered that mutations in miRNA-16-1-15α in 13q14,3 intron 4 of DLEU2 may be a predisposition for the development of CLL and breast cancer ^[27].

In 2012, Ziebarth et al. determined how somatic mutations of 3′UTR affect miRNAs in cancer. It has been demonstrated that somatic mutations of five genes (TAL1, BMPR1B, KDM5A, SCG3, BCAS3) disrupt the binding of miRNA and increase the expression of these genes which are prominent in cancer development ^[28].

Furthermore, both mutations, somatic and germline, of the 3′UTR KLK3 gene interfere with the binding of miRNA-675, miRNA-138, and miRNA-210, which promote the expression of the KLK3 gene in prostate cancer and regulate cancer proliferation. The identification of the disturbance caused by germline and/or somatic mutations may help identify prominent miRNA targets for cancer treatment ^[28].

Uncontrolled tumor growth accelerated cancer cell metabolism, and chaotic vascularization of cancer cells leads to hypoxia in the TME. The communication among the TME cell types is in part mediated by secreted proteins, cytokines, and non-coding RNAs transported by exosomes ^[29]. These factors in TME may induce epithelial-mesenchymal transition which increases the invasiveness of cancers ^[30].

2.1. Cytokines and Non-Coding RNA Intertwined in Tumor Microenvironment

Cytokines have a significant role in the communications of cancer cells and other TME cells ^[31]. Cytokines are proteins that regulate the proliferation, growth, and activation of immune cells ^[32]. Categorized according to their function, cytokines include chemokines (which induce chemotactic migration) ^[33], interleukins (involved in immune and inflammation processes) ^[34], interferons (which stimulate an immune response) ^[35], and tumor necrosis factors (TNFs) (pro-inflammatory proteins) ^[36].

Chemokines can be divided into four groups according to their structure: CC, CVC, CX3C, and XC ^[37]. One of the chemokines that induce cancer progression via the PI3K/AKT, JAK/STAT3, MAPK/ERK, and NF-κB pathways is CCL-5. CCL-5 produced by cancer cells induces cancer cell proliferation but also evokes infiltration of T cells and dendritic cells (DCs) into the TME. Overexpression of CCL-5 is observed in several solid cancers and leukemias ^[38]. Recently, Chen et al. showed that the expression of CCL5 in oral squamous cell carcinoma is modulated by lncRNA ZFAS1 which binds miRNA-6499-3p. The histological analysis revealed that lncRNA ZFAS1 is upregulated in tumor tissue. Moreover, in vitro studies showed that silencing lncRNA ZFAS1 using siRNA inhibits cancer progression, colony formation, invasion, and migration. The oncogenic character of lncRNA ZFAS1 is correlated with the downregulation of miRNA-6499-3p, which leads to increased expression of CCL-5. These findings identify lncRNA ZFAS1 as a potential target for anticancer treatment ^[39].

The second essential group of cytokines associated with TME is interleukins. More than 40 interleukins may be involved in tumorigenesis. They have a dual role in cancer progression: (1) recruiting anticancer cells to the TME (by IL-1β) and (2) suppressing anticancer immune response by promotion of T cell inhibitory receptors including PD-1, LAG3, TIM-3, and TIGIT (by IL-35) ^[34]. The diverse properties of interleukins make them a target of interest for anticancer therapies. The U.S. Food and Drug Administration (FDA) approved the first drug containing an interleukin (interleukin-2) for metastatic renal cell carcinoma treatment almost 30 years ago ^[34]. However, IL-2 causes serious adverse effects including cardiac and pulmonary toxicity ^[40]. Currently, there are 2072 clinical studies to use not only interleukin-2 in cancer treatment but also IL-12, -15, -18, -11, -6, -4, -7, and -21 ^[41]. Among them, it is worth noting that IL-6 is overexpressed in solid tumors and multiple myeloma ^[42]. IL-6 promotes tumor development by activation of the PI3K/Akt, NF-kB, and Mek/ERK pathways ^[43]. Thus, Kishimoto et al. showed that IL-6 increases the expression of lncRNA AU021063 which activates the Mek/ERK pathway in breast cancer. Researchers demonstrated that inhibition of any of these molecules may be important to develop novel strategies for breast cancer treatment ^[44].

Interferons may also play a key role in the TME, as they are secreted by immune and tumor cells. Interferons can modify immune activity against malignant diseases ^[35]. There are two types of interferons: –I and –II. These two groups play several functions in carcinogenesis including the promotion of production of IL-12 by DCs (IFN I), inducing cytotoxic activity of NK cells (IFN II), inducing transformation of macrophages from M1 to M2 (IFN I and II), and increasing the cytotoxic function of T cells (IFN I) ^[35]^[45]. Among these two groups, IFN-γ plays a key role in immune antitumor response ^[46]. In 2020, Chiocca et al. showed that IFN-γ signaling in glioblastoma is correlated with the expression of one of the non-coding RNAs: lncRNA INCR1. The bulk RNA sequencing analysis of patient-derived glioblastoma cell lines activated by IFN-γ revealed that lncRNA INCR1 was the most upregulated non-coding RNA. It has been shown that cell lines with high expression of this non-coding RNA also had a high expression of PD-L1. Knockdown of lncRNA INCR1 in the glioblastoma cell line led to inhibition of IFN-γ, and PD-L1 which allows the cytotoxic activity of T cells in vivo. In conclusion, lncRNA INCR1 may be a promising target for anticancer therapies because it plays a significant role in the regulation of IFN-γ signaling and immune antitumor response ^[47].

TNF-α is involved in a variety of regulatory processes in normal and cancer cells. There are two types of TNF-α receptors: TNFR1 (occurring in all cell types) and TNFR2 (mostly found in immune cells). It has been demonstrated that activation of TNFR2 leads to the progression of cancer. However, a series of preliminary studies have demonstrated that, depending on the cancer type, TNF-α can promote or inhibit apoptosis in tumor cells ^[48]. The anticancer activity of TNF-α is also associated with non-coding RNA, especially miRNA-145 ^[48]. Overexpression of miRNA-145 in combination with TNF-α leads to the induction of apoptosis in MDA-MB-231 cell lines via an external pathway ^[49]. Moreover, in cervical cancer, miRNA-130a downregulates TNF-α expression while TNF-α decreases the expression of miRNA-130a by activation of NF-κB ^[50].

2.2. Exosomes as External and Internal Carriers of Non-Coding RNAs in Tumor Microenvironment

Exosomes are messengers involved in the communication network in the TME ^[51]. Exosomes are small vesicles (30–150 nm) produced by various cells, including cancer and TME cells. Exosomes may contain a wide variety of cytoplasmic contents including non-coding RNA, integrins, lipids, and enzymes such as matrix metalloproteinase (MMP), among others.

Exosomes have unique properties such as high stability, low risk of induction of immune response, and the capability to cross biological barriers ^[52]. These natural extracellular molecules may be produced by various cell types of animals and plants and used as nanocarriers ^[52]. In 2020, Tao et al. loaded Bcl-2 siRNA in exosomes isolated from bovine milk. The in vitro results revealed that the designed system enabled the transfection of pancreatic and colon cancer cells with high efficiency. Moreover, this system decreased the survival of cancer cells by induction of apoptosis. The in vivo studies confirmed the anticancer activity of this approach system ^[53]. However, exosomes are isolated from fresh cells, and large-scale production may be cost-inefficient. The process of loading ncRNAs into exosomes is inefficient, and even loaded ncRNAs may form aggregates, which decreases the loading yield ^[52].

Exosomes are also produced in TME. Cancer-derived exosomes packed with ncRNAs may regulate angiogenesis, metastasis, cancer proliferation, and migration and modulate the immune system ^[54]^[55]^[56]^[57]. In 2019, He et al. showed that exosomal miRNA-499a-5p induces cancer proliferation and invasion by the promotion of EMT, activation of the mTOR pathway, and inhibition of apoptosis in non–small cell lung cancer (NSCLC) ^[55].

In addition, exosomes secreted by the TME may induce resistance to chemotherapy, e.g., exosomes packed with lncRNA-SNHG14 associated with the promotion of resistance to trastuzumab in breast cancer patients with HER2 (+), lncRNA-ARSR linked with resistance to sunitinib in renal cancer cells, lncRNA-SBF2-AS1 promotes resistance to temozolomide in glioblastoma cells, and lncRNA-CCAL promotes resistance to oxaliplatin in colorectal cancer cells. These suggest that exosomes might be crucial targets to overcome chemotherapy resistant ^[58]^[59].

Recent studies showed that exosomal lncRNAs also take part in the regulation of autophagy in the TME. lncRNA ANRIL promotes autophagy by preventing miRNA-99a and miRNA-449a binding to beclin 1 ^[59]^[60]. Overexpression of this lncRNA is observed in the urine of bone cancer patients. The results of this study may allow in the future to develop a new diagnostic method for bone cancer using lncRNA ANRIL ^[59]. The differences between the level of exosomes packed with ncRNAs in normal and cancerous cells make them potential biomarkers. It has been demonstrated that lncRNA H19 may be considered a predictive breast cancer biomarker. In prostate cancer, it has been shown that lncRNA-SAP30L-AS1 and SChLAP1 are important biomarkers. In NSCLC, lncRNA-GAS5 may be considered a diagnostic marker in the early stages of cancer development ^[58].

In 2016, Kanlikilicer et al. showed that exosomes derived from sensitive ovarian cancer cells (HeyA8, SKOV3-ip1, A2780) and resistant ovarian cancer cells (HeyA8-MDR, SKOV3-TR, A2780-CP20) have upregulated expression of miRNA-6126. Following this discovery, the most significant change in the expression of miRNA-6126 was visible in HeyA8 ovarian cancer cells. In the next step, the researchers analyzed the pathways that are regulated by miRNA-6126. It has been presented that overexpression of miRNA-6126 leads to reduced activation of the PI3K/AKT pathway in HeyA8-MDR, SKOV3-ip1, and SKOV3-TR cells, which leads to decreased invasion and migration of ovarian cancer cells. The in vivo studies confirmed the suppressor activity of miRNA-6126. These studies provide evidence of tumor suppressor activity of miRNA-6126 in ovarian cancer treatment ^[61]. In 2018, Lopez et al. demonstrated that miRNA-1246 is highly overexpressed in ovarian cancer cells (A2780, A2780-CP20, HeyA8m HeyA8-MDR, SKOV3ip1, and SKOV3-TR) compared to normal cell line HIO180. Researchers presented that miRNA-1246 plays an important role in the Cav1/PDGFRβ pathway. In the in vivo studies, combination therapy using an inhibitor of miRNA-1246 and paclitaxel led to the significant inhibition of tumor growth, which was associated with reduced proliferation of cancer cells, downregulation of PDGFRβ, and upregulation of Cav1 in cancer tissue. It has been presented that exosomal miRNA-1246 secreted by ovarian cancer cells SKOV3-ip1 leads to an increase in miRNA-1246 in M2-type macrophages. This shows that exosomal miRNA-1246 secreted by ovarian cancer cells my affect TME to promote the progression of cancer ^[62], thus, these two elegant manuscripts illustrate the role of exosomal miRNA in intercellular communications in the TME.

Exosomes containing ncRNAs may also affect immune cells. They can promote the M2 phenotype of macrophages (lnc-RPPH1 in colon cancer, lnc-BCRT1 in breast cancer), inhibit differentiation of T cells (miRNA-24-3p in nasopharyngeal carcinoma), impair T cell function (circRNA-002178 increase PD-1 expression in lung adenocarcinoma), and inhibit the immune response of dendritic cells (miRNA-203 in pancreatic cancer). Therefore, determining the molecular profile of exosomes found in the plasma of cancer patients may have the potential to assess the immune status of the patient and predict their response to immunotherapy ^[63].

The development of cancer tumors involves the supplementation of essential nutrients and oxygen to TME. CircRNAs including circRNA-SHKBP1, circRNA-100338, circR-NA-0007334, circRNA-KIF18A, circRNA-29, and circRNA-HIPK3 encapsulated in exosomes play an important role in this process ^[64]. The mechanism of regulation of angiogenesis by exosomal circRNAs is based on binding targeted miRNAs associated with tumor angiogenesis. These findings may be fundamental for the development of antiangiogenic cancer therapies in the future ^[65].

2.3. Role of Non-Coding RNA in Cancer-Associated Fibroblasts (CAFs) in Tumor Microenvironment

Another important component of the TME is cancer-associated fibroblasts (CAFs). There are five types of CAFs: the F1 group inhibits tumor growth, F2 stimulates tumor progression, F3 affects angiogenesis and tumor immunity, F4 regulates the transformation of the extracellular matrix, and the function of the F5 group is still unknown ^[66]. Contrary to normal fibroblasts, CAFs express α-SMA, FSP1, FAP, NG2, and PDGFRα/β ^[67], which promote cancer growth, enhance angiogenesis, and contribute to intercellular matrix remodeling. It was shown that increasing the expression of miRNA-31 in the co-culture of CAF and EC-1 reduces the invasion and migration of EC1 cells without effect on their proliferation ^[68]^[69]. Since then, around 16 non-coding RNAs in CAF have been described. It is worth noting that growth factors (FGF, PDGF) and hypoxia may activate fibroblasts to CAFs, which produce pro-cancer cytokines such as CXCL-1, -2, -3, -12, and -14; CCL-2, -5, and -17; and IL-18 ^[70]^[71]^[72]. In 2017, Zhao et al. reported that CXCL-14 secreted by CAFs in ovarian cancer can increase the level of lncRNA-LINC00092, which results in a higher risk of metastasis. These results show that the inhibition of CXCL-14 or lncRNA-LINC00092 may be a promising target for ovarian treatment ^[72].

2.4. Non-Coding RNA in the Regulation of Response of Macrophages in Tumor Microenvironment

Macrophages are crucial in cancer progression. Moreover, they constitute more than 50% of the TME. These cells regulate inflammation and early carcinogenesis. Cancer cells secrete chemokines (MCP-1, MIP-1α, VEGF, CSF1R) that favor the infiltration of monocytes, which are precursors of macrophages ^[73]. The monocytes in the TME differentiate under the influence of IL-6 and CSF-1 into macrophages, specifically tumor-associated macrophages (TAMs). In contrast to normal macrophages, TAMs do not have an immunostimulant function. TAMs that have an M2-like phenotype produce anti-inflammatory cytokines (IL-4, IL-10, IL-13), factors stimulating the formation of blood vessels (VEGF, IL-1β, TNF-α, IL-8, PDGF-β), growth factors (EGF, IL-6, bFGF), and cell migration factors (metalloproteinases 2, 7, 9). These unique qualities of TAMs promote tumor development by induction of angiogenesis, expression of oncogenes, and anti-apoptotic signaling in the TME ^[73]^[74]. The diverse functions of TAMs make them a promising target of anticancer therapy. There are two approaches to utilizing TAMs in cancer treatment: inhibition of the recruitment of TAM cells to the TME and restoration of antitumor activity of TAMs. Relationship between Macrophages and Non-Coding RNA in TMThe first anticancer strategy utilizes ncRNA to inhibit the recruitment of TAM to TME. The process of TAM survival and migration to the TME is controlled by CSF1, whose induced expression is linked with a poor prognosis of breast, prostate, endometrial, bladder, kidney, and esophageal cancer patients. Blockage of CSF1 expression by siRNA in the breast cancer in vivo model inhibited tumor growth and reduced the recruitment of macrophages to TME ^[75]^[76]. Olayioye et al. showed that the expression of CSF1 is linked with miRNA-149 expression in breast cancer. Upregulation of miRNA-149 in MDA-MB-231 cells leads to inhibition of recruitment of TAM to TME in vitro and in vivo. miRNA-149 also impedes M2 polarization ^[77]. The second approach utilizing TAMs to treat cancer is based on restoration of the antitumor activity of macrophages, which may be achieved through IgSF (immunoglobulin superfamily) inhibitors, immune checkpoint inhibitors, PI3Kγ inhibitors, agonists of Toll-like receptors (TLRs) or CD40, and non-coding RNA (siRNA and miRNA) ^[78]. In 2018, Yin et al. designed siRNA to target VEGF and PIGF. These two markers of angiogenesis are overexpressed in M2-type macrophages and breast cancer cells and the use of siRNAs against them led to the reversion of the M2 to M1 phenotype of TAM in TME which led to the inhibition of tumor growth in vitro and in vivo ^[79]. Moreover, because macrophages make up the majority of the TME, they are an interesting system for delivering non-coding RNA into cancer cells. In 2019, Wayne et al. developed an efficient method of loading siRNA lipoplex into macrophages. This modified macrophage system was efficient in transporting siRNA to cancer cells. When they tested the anticancer activity of the designed system, they found that macrophages loaded with CIB1 siRNA and co-cultured with breast cancer cells decreased the viability of the cancer cells ^[80].

2.5. Non-Coding RNAs in the Regulation of T-Cell Activity in the Tumor Microenvironment

In the TME, three subtypes of T cells can be distinguished: naive (mature T cells, precursors for other T cell subsets), memory (T cells that can recognize specific antigens), and effector (which have various functions in the immune response and includes cytotoxic, helper, and regulatory T cells) ^[81]^[82]^[83]. The functions of T cells in the TME are still largely unknown. On one hand, T cells have anticancer activity: CD8⁺ T cells decrease the viability of cancer cells, and Th1 cells secrete pro-inflammatory factors like TNF-α and IFN-γ, which stimulate the immune system against cancer cells. However, T cells also have pro-tumor activity; CD4⁺ T cells inhibit CD8⁺ T cells’ anticancer activity by producing IL-4 and -10, and Th17 cells produce IL-17, which promotes tumor growth. In addition, CD1⁺ TIM3⁺ T cells are exhausted and not able to mount an anticancer response ^[81]^[82]^[83].

In the TME, CD4⁺ and CD8⁺ T cells are inactivated by increased expression of immune checkpoints including PD-1, CTLA-4, LAG-3, TIM-3, BTLA, and TIGIT, which leads to anergy and exhaustion of T cells. Exhausted T cells have a high expression of CD69 and CD44 and a low expression of CD62L and are unable to secrete IL-2, TNF-α, IFN-γ, and granzyme B, which play crucial roles in anticancer activity. Therefore, reversion of T-cell exhaustion is an approach of interest for treating cancer ^[84]. Investigators have found that knocking down PD-1 in T cells using siRNA in combination with knocking down PD-L1 in the MCF-7 cell line can restore the effector function of lymphocytes and significantly decrease cancer cell survival. Moreover, the knockdown of PD-1 and PD-L1 increased IFN-γ and TNF-α production in vitro ^[85]. Deregulation of T-cell immune response in the TME may be associated with ZFP91, an oncogene protein that induces cancer progression and invasion and inhibits programmed cell death. Wang et al. knocked down ZFP91 in T cells in colon adenocarcinoma, which induced T-cell proliferation and anticancer activity. The knockdown of ZFP91 also increased the expression of genes linked with glucose metabolism, which are crucial for the anticancer activity of T cells. Furthermore, the knockdown of ZFP91 decreased the activation of the mTORC1 pathway, which is important in T-cell glycolysis ^[86].

2.6. Non-Coding RNAs in the Regulation of B Cells in Tumor Microenvironment

As mentioned, the TME is composed largely of immune cells, including B cells. The role of B cells in carcinogenesis has been underestimated for many years. Nonetheless, recent data suggest that B cells in the TME might be crucial in the anticancer response. In 2021, Lopez-Berestein et al. using Explainable Artificial Intelligence (XAI) showed that B cells are one of the most critical elements of TME for the prognosis of breast cancer. High expression of naïve B cells in TME was associated with better overall survival of breast cancer patients ^[87]. Also, Xia et al. showed that B cells play an important role in colon cancer. It has been demonstrated that one of the regulators of B cells in the TME is CXCL-13, which activates its receptor CXCR5. This receptor influences cancer cell differentiation (via miRNA-23a), migration (via MMP, N-cadherin, E-cadherin, Slug/Snail), invasion (via FAK/ERK, c-Myc/RANKL), and proliferation (via DOCK2/JNK) ^[88]^[89]^[90].

2.7. Non-Coding RNA in the Regulation of EMT in Tumor Microenvironment

EMT (epithelial-mesenchymal transition) is a crucial process in the development of metastasis and tumor progression. In EMT, a cell is deprived of connectivity with other cells and acquires the capacity to migrate. EMT is stimulated by increased expression of vimentin, SNAI1/2, TWIST, ZEB1/2, and non-coding RNAs including miRNA-200 and miRNA-205 ^[30]. In 2019, it was demonstrated that tamoxifen-resistant breast cancer cells express more EMT markers compared to non-resistant breast cancer cells. Moreover, tamoxifen resistance was associated with decreased expression of miRNA-200b and miRNA-200c. Transfection of resistant cells with pre-miRNA-200b and -200c notably reduced the expression of c-MYB. This finding prompted researchers to silence c-MYB, which restored the sensitivity of breast cancer cells to tamoxifen and reduced EMT ^[91]. The EMT process is controlled by various epigenetic mechanisms including DNA methylation and histone modifications ^[92]. In 2021, Zheng et al. used lovastatin (a cholesterol-lowering drug) against breast cancer. Lovastatin was shown to deregulate lysine succinylation of eight proteins, whereas elevated expression of these proteins in triple-negative breast cancer was linked with poorer overall survival. The mechanism of the anticancer activity of lovastatin was also associated with the inhibition of EMT in vitro and in vivo. Lovastatin also decreased metastasis to the liver ^[93].

Chemotherapeutics that act directly on cancer cells have limitations that include drug resistance as well as physiological and anatomical barriers to delivery to cancer cells. Cancer cells are genetically unstable, so some molecular targets that make cancer cells chemosensitive may be eliminated during treatment, leaving only cells resistant to treatment. These changes require a constant search for novel targets. As an alternative, drugs targeting the TME can affect growth factors, cytokines, and immune cells that are engaged in the interaction between normal and cancer cells. Despite the limitations of both types of drugs, the goal of current research is to find drug combinations that both act on cancer cells and modify the TME.

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