Association of interleukin-17A and chemokine/vascular endothelial growth factor-induced angiogenesis in newly diagnosed patients with bladder cancer.

BACKGROUND: The human interleukin-17 (IL-17) family comprises IL-17A to IL-17 F; their receptors are IL-17RA to IL-17RE. Evidence revealed that these cytokines can have a tumor-supportive or anti-tumor impact on human malignancies. The purpose of this study was to assess the expression of CXCR2, IL-17RA, and IL-17RC genes at the mRNA level as well as tissue and serum levels of IL-17A, vascular endothelial growth factor (VEGF), and transforming growth factor ß (TGF-ß) in patients with bladder cancer (BC) compared to control. RESULTS: This study showed that gene expression of IL-17RA, IL-17RC, and CXCR2 in the tumoral tissue of BC patients was significantly upregulated compared with normal tissue. The findings disclosed a significant difference in the serum and tissue concentrations of IL-17A, VEGF, and TGF-ß between the patient and the control groups, as well as tumor and normal tissues. CONCLUSION: This study reveals notable dysregulation of CXCR2, IL-17RA, and IL-17RC genes, alongside changes in IL-17A, VEGF, and TGF-ß levels in patients with BC than in controls. These findings indicate their possible involvement in BC development and their potential as diagnostic and therapeutic targets.

Evaluation of the CCL17/CCL22-CCR4 axis in pediatrics with B-cell acute lymphoblastic leukemia before and after a chemotherapy course.

AIMS: Acute lymphoblastic leukemia (ALL) is the most common type of pediatrics cancer. Chemokines exert different roles in leukemia process through leukocyte recruitment and regulation of disease severity. Due to the prominent roles of chemokine/receptor axes, this study aimed to measure the blood expression levels of CCR4 and their ligands in pediatrics with B-cell ALL (B-ALL). We also evaluated the impact of cytotoxic chemotherapy on this axis. MATERIAL AND METHOD: Thirty children suffering from B-ALL were included in the study and followed up for 30 days after completion of a chemotherapy course. The blood sampling was performed before and after chemotherapy. 30 healthy donors have also entered the study as control subjects. The mRNA expression of CCL17, CCL22 and CCR4 genes was determined by quantitative real-time PCR. The frequency of the peripheral blood mononuclear cells expressing CCR4 (CCR4 + PBMCs) was also evaluated by the flow cytometry method. Moreover, we evaluated the association of the CCL17/CCL22-CCR4 axis with some diagnostic, prognostic and predictive biomarkers in ALL patients. RESULTS: There was overexpression of the CCL17/CCL22-CCR4 axis along with lactate dehydrogenase (LDH) in pediatrics with B-ALL compared to healthy controls. After induction of chemotherapy, the blood expression levels of the CCL17/CCL22-CCR4 axis have reached the levels of healthy controls. The findings for the blood expression levels of CCR4 were also confirmed using flow cytometry. CONCLUSION: The CCL17/CCL22-CCR4 axis can be used as a novel predictive and prognostic biomarker in B-ALL.

Reciprocal Interactions Between Apelin and Noncoding RNAs in Cancer Progression.

Apelin, a bioactive peptide that serves as an endogenous ligand for the apelin receptor (APJ), is overexpressed in various types of cancers and contributes to cancer cell proliferation, viability, migration, angiogenesis, and metastasis, as well as immune deviation. Noncoding RNAs (ncRNAs) regulate gene expression, and there is growing evidence suggesting a bidirectional crosstalk between ncRNAs (including long noncoding RNAs [lncRNAs], circular RNAs [circRNAs], and microRNAs [miRNAs]) and apelin in cancers. Certain miRNAs can directly target the apelin and inhibit its expression, thereby suppressing tumor growth. It has been indicated that miR-224, miR-195/miR-195-5p, miR-204-5p, miR-631, miR-4286, miR-637, miR-4493, and miR-214-3p target apelin mRNA and influence its expression in prostate cancer, lung cancer, esophageal cancer, chondrosarcoma, melanoma, gastric cancer, glioma, and hepatocellular carcinoma (HCC), respectively. Moreover, circ-NOTCH1, circ-ZNF264, and lncRNA BACE1-AS upregulate apelin expression in gastric cancer, glioma, and HCC, respectively. On the other hand, apelin has been shown to regulate the expression of certain ncRNAs to affect tumorigenesis. It was revealed that apelin affects the expression of circ_0000004/miR-1303, miR-15a-5p, and miR-106a-5p in osteosarcoma, lung cancer, and prostate cancer, respectively. This review explains a bidirectional interplay between ncRNAs and apelin in cancers to provide insights concerning the molecular mechanisms underlying this crosstalk and potential implications for cancer therapy.

Leptin/lipopolysaccharide-treated dendritic cell vaccine improved cellular immune responses in an animal model of breast cancer.

PURPOSE: In dendritic cells (DCs), leptin as an immune-regulating hormone, increases the IL-12 generation whereas it reduces the IL-10 production, thus contributing to TH1 cell differentiation. Using a murine model of breast cancer (BC), we evaluated the impacts of the Leptin and/or lipopolysaccharide (LPS)-treated DC vaccine on various T-cell-related immunological markers. MATERIALS AND METHODS: Tumors were established in mice by subcutaneously injecting 7 × 105 4T1 cells into the right flank. Mice received the DC vaccines pretreated with Leptin, LPS, and both Leptin/LPS, on days 12 and 19 following tumor induction. The animals were sacrificed on day 26 and after that the frequency of the splenic cytotoxic T lymphocytes (CTLs) and TH1 cells; interferon gamma (IFN-γ), interleukin 12 (IL-12) and tumor growth factor beta (TGF-ß) generation by tumor lysate-stimulated spleen cells, and the mRNA expression of T-bet, FOXP3 and Granzyme B in the tumors were measured with flow cytometry, ELISA and real-time PCR methods, respectively. RESULTS: Leptin/LPS-treated mDC group was more efficient in blunting tumor growth (p = .0002), increasing survival rate (p = .001), and preventing metastasis in comparison with the untreated tumor-bearing mice (UT-control). In comparison to the UT-control group, treatment with Leptin/LPS-treated mDC also significantly increased the splenic frequencies of CTLs (p < .001) and TH1 cells (p < .01); promoted the production of IFN-γ (p < .0001) and IL-12 (p < .001) by splenocytes; enhanced the T-bet (p < .05) and Granzyme B (p < .001) expression, whereas decreased the TGF-ß and FOXP3 expression (p < .05). CONCLUSION: Compared to the Leptin-treated mDC and LPS-treated mDC vaccines, the Leptin/LPS-treated mDC vaccine was more effective in inhibiting BC development and boosting immune responses against tumor.

Natural killer cells and their exosomes in viral infections and related therapeutic approaches: where are we?

Innate immunity is the first line of the host immune system to fight against infections. Natural killer cells are the innate immunity lymphocytes responsible for fighting against virus-infected and cancerous cells. They have various mechanisms to suppress viral infections. On the other hand, viruses have evolved to utilize different ways to evade NK cell-mediated responses. Viruses can balance the response by regulating the cytokine release pattern and changing the proportion of activating and inhibitory receptors on the surface of NK cells. Exosomes are a subtype of extracellular vesicles that are involved in intercellular communication. Most cell populations can release these nano-sized vesicles, and it was shown that these vesicles produce identical outcomes to the originating cell from which they are released. In recent years, the role of NK cell-derived exosomes in various diseases including viral infections has been highlighted, drawing attention to utilizing the therapeutic potential of these nanoparticles. In this article, the role of NK cells in various viral infections and the mechanisms used by viruses to evade these important immune system cells are initially examined. Subsequently, the role of NK cell exosomes in controlling various viral infections is discussed. Finally, the current position of these cells in the treatment of viral infections and the therapeutic potential of their exosomes are reviewed. Video Abstract.

Evaluation of the interaction between tumor growth factor-ß and interferon type I pathways in patients with COVID-19: focusing on ages 1 to 90 years.

BACKGROUND: Evidence revealed that age could affect immune responses in patients with the acute respiratory syndrome of coronavirus 2 (SARS-CoV-2) infection. This study investigated the impact of age on immune responses, especially on the interaction between the tumor growth factor-ß (TGF-ß) and interferon type-I (IFN-I) axes in the pathogenesis of novel coronavirus disease 2019 (COVID-19). METHODS: This age-matched case-control investigation enrolled 41 COVID-19 patients and 40 healthy controls categorized into four groups, including group 1 (up to 20 years), group 2 (20-40 years), group 3 (40-60 years), and group 4 (over 60 years). Blood samples were collected at the time of admission. The expression of TGF-ßRI, TGF-ßRII, IFNARI, IFNARII, interferon regulatory factor 9 (IRF9), and SMAD family member 3 (SMAD3) was measured using the real-time PCR technique. In addition, serum levels of TGF-ß, IFN-α, and SERPINE1 were measured by the enzyme-linked immunosorbent assay (ELISA) technique. All biomarkers were measured and analyzed in the four age studies groups. RESULTS: The expression of TGF-ßRI, TGF-ßRII, IFNARI, IFNARII, IRF9, and SMAD3 was markedly upregulated in all age groups of patients compared with the matched control groups. Serum levels of IFN-α and SERPINE1 were significantly higher in patient groups than in control groups. While TGF-ß serum levels were only significantly elevated in the 20 to 40 and over 60 years patient group than in matched control groups. CONCLUSIONS: These data showed that the age of patients, at least at the time of admission, may not significantly affect TGF-ß- and IFN-I-associated immune responses. However, it is possible that the severity of the disease affects these pathway-mediated responses, and more studies with a larger sample size are needed to verify it.

Purinergic signaling: decoding its role in COVID-19 pathogenesis and promising treatment strategies.

The pathogenesis of coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2), is complex and involves dysregulated immune responses, inflammation, and coagulopathy. Purinergic signaling, mediated by extracellular nucleotides and nucleosides, has emerged as a significant player in the pathogenesis of COVID-19. Extracellular adenosine triphosphate (ATP), released from damaged or infected cells, is a danger signal triggering immune responses. It activates immune cells, releasing pro-inflammatory cytokines, contributing to the cytokine storm observed in severe COVID-19 cases. ATP also promotes platelet activation and thrombus formation, contributing to the hypercoagulability seen in COVID-19 patients. On the other hand, adenosine, an immunosuppressive nucleoside, can impair anti-viral immune responses and promote tissue damage through its anti-inflammatory effects. Modulating purinergic receptors represents a promising therapeutic strategy for COVID-19. Understanding the role of purinergic signaling in COVID-19 pathogenesis and developing targeted therapeutic approaches can potentially improve patient outcomes. This review focuses on the part of purinergic signaling in COVID-19 pathogenesis and highlights potential therapeutic approaches targeting purinergic receptors.

Immunopathological similarities between COVID-19 and influenza: Investigating the consequences of Co-infection.

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been a global public health emergency since December 2019, and so far, more than 980,000 people (until September 24, 2020) around the world have died. SARS-CoV-2 mimics the influenza virus regarding methods and modes of transmission, clinical features, related immune responses, and seasonal coincidence. Accordingly, co-infection by these viruses is imaginable because some studies have reported several cases with SARS-CoV-2 and influenza virus co-infection. Given the importance of the mentioned co-infection and the coming influenza season, it is essential to recognize the similarities and differences between the symptoms, immunopathogenesis and treatment of SARS-CoV-2 and influenza virus. Therefore, we reviewed the virology, clinical features, and immunopathogenesis of both influenza virus and SARS-CoV-2 and evaluated outcomes in cases with SARS-CoV-2 and influenza virus co-infection.

Assessing the expression of immunosuppressive cytokines in the newly diagnosed systemic lupus Erythematosus patients: a focus on B cells.

BACKGROUND: The immunosuppressive effects of regulatory B-cells (Bregs) and their immunosuppressive cytokines on immune responses in autoimmune disorders, mainly systemic lupus erythematosus (SLE), have been recently established. Therefore, the purpose of this article has been the exploration of the expressions of cytokines produced by B cells in newly diagnosed SLE patients. RESULTS: The findings demonstrated that the gene expression of IL-10, TGF-ß, IL-35, PD-L1, and FasL was significantly up-regulated in SLE patients compared to healthy subjects (P < 0.05). Additionally, the results revealed that serum levels of IL-10, TGF-ß, IL-35, PD-L1 were remarkably increased in patients with SLE compared to healthy subjects (P < 0.0001). However, serum levels of IL-10 and TGF-ß decreased significantly with increasing SLEDAI score in studied patients (P < 0.05). CONCLUSION: It was concluded that the release of anti-inflammatory cytokines, particularly IL-10 and TGF-ß, might inhibit immune responses and autoreactive immune cells in a compensatory manner in SLE patients with mild to moderate disease activity.

Role(s) of cytokines in pulpitis: Latest evidence and therapeutic approaches.

Pulpitis is known as a typical inflammation of dental pulp tissue, and microorganisms of the oral microbiome are involved in this opportunistic infection. Studies indicated that several factors related to host response have a crucial role in pulpitis. Among these factors, inflammatory mediators of the immune system such as cytokines and chemokines contribute to pulpal defense mechanisms. A wide range of cytokines have been observed in dental pulp and these small molecules are able to trigger inflammation and participate in immune cell trafficking, cell proliferation, inflammation, and tissue damage in pulp space. Therefore, the aim of this review was to describe the role of cytokines in the pathogenesis of pulpitis.

Indole itself and its novel derivative affect PML cells proliferation via controlling the expression of cell cycle genes.

Recently the role of indole and pyran rings in carcinogenesis has been well studied. Here we studied the effects and the possible mechanisms of the action of basal indole (I3A) and its novel indole derivative (C19H15F3N2O) on inhibition of proliferation cells in acute promyelocytic leukemia NB4 cell line by examining the expression of cell cycle genes. We treated NB4 cells with concentration of C19H15F3N2O for 24-72 h. The MTT and PI/Annexin V examinations were employed for assessment of the proliferation and apoptosis of NB4 cells. Both of Cyclin D and P21 were detected by the Real-time PCR. The western blotting analysis was also performed to show the protein levels for P21. A difference was regarded significant if p-value was less than 0.05. MTT assay showed that 15.12-1000 µg/mL C19H15F3N2O caused a time and concentration-dependent inhibition of NB4 cell proliferation. Exposure to higher concentrations of C19H15F3N2O resulted in significantly increased apoptosis rate in NB4 cells. RT PCR showed that C19H15F3N2O has up-regulated the expression of P21 and down-regulated the expression of Cyclin D. Western blotting experiments also demonstrated that the P21 expression in C19H15F3N2O treated cells has significantly increased, where compared with either untreated control cells or I3A treated cells. This newly (C19H15F3N2O) was able to inhibit NB4 cells proliferation and causes apoptosis of these cells more than I3A, and these effects are probably facilitated via cell cycle arrest. C19H15F3N2O might probably be introduced as a promising organic therapeutic reagent against APL.

A brief look at the role of monocyte chemoattractant protein-1 (CCL2) in the pathophysiology of psoriasis.

Psoriasis (PsO) is a chronic skin disorder resulting from the imbalanced interactionbetween infiltrating immune cells and keratinocytes. These immune cells, including monocytes, are able to mediate the immune responses in inflamed skin lesions. Chemokines are responsible for the recruitment of leukocytes to sites of inflammation. In patients with PsO, the keratinocytes are the main source of monocyte chemotactic protein 1 (MCP-1/CCL2), which is a CC chemokine. After CCL2 binds to the chemokine receptor CCR2, which mainly is expressed on the surface of monocytes, the monocytes differentiate into macrophages and migrate from the blood stream to sites of inflammation. This process can cause the formation of lesions. Accordingly, it has been hypothesized that CCL2 could be a potential biomarker to monitor the progression of PsO. Thus, evidence suggests that there could be a potential role for CCR2 and CCL2 during treatment of PsO and to prevent its further development. For example, to modify the course of PsO, efforts have been made to inhibit or modulate the CCR2/CCL2 axis. However, before exploring the targeting of the CCR2/CCL2 axis in a clinical setting, better understanding of the different molecular aspects of PsO is required.

CXCL12 and CXCR4 in the Peripheral Blood of Patients with Parkinson's Disease.

OBJECTIVE: The role of CXCL12 and its receptor CXCR4 has not been fully examined in Parkinson's disease (PD). The purpose of this study was to investigate the role of CXCL12/CXCR4 in the peripheral blood of patients with PD and healthy controls. METHODS: CXCL12 serum levels and CXCR4 mRNA levels were measured in 30 PD patients and 40 controls using ELISA and real-time PCR, respectively. RESULTS: CXCL12 serum levels were significantly higher in PD patients compared to controls (p < 0.0001). Moreover, CXCR4 expression in peripheral blood mononuclear cells (PBMC) of PD patients was significantly increased compared to controls (p < 0.0001). CONCLUSIONS: Our findings provide new information on the expression of CXCL12/CXCR4 in PD. CXCR4 expression in PBMC or CXCL12 serum levels may be potential biomarkers of inflammation in PD patients.

Correction to: Biological/pathological functions of the CXCL12/CXCR4/CXCR7 axes in the pathogenesis of bladder cancer.

Following the publication from the original article, it came to our attention that we unintentionally neglected to acknowledge some text overlap with previous publications.

Biological/pathological functions of the CXCL12/CXCR4/CXCR7 axes in the pathogenesis of bladder cancer.

CXC chemokine ligand 12 (CXCL12) is an important member of the CXC subfamily of chemokines, and has been extensively studied in various human body organs and systems, both in physiological and clinical states. Ligation of CXCL12 to CXCR4 and CXCR7 as its receptors on peripheral immune cells gives rise to pleiotropic activities. CXCL12 itself is a highly effective chemoattractant which conservatively attracts lymphocytes and monocytes, whereas there exists no evidence to show attraction for neutrophils. CXCL12 regulates inflammation, neo-vascularization, metastasis, and tumor growth, phenomena which are all pivotally involved in cancer development and further metastasis. Generation and secretion of CXCL12 by stromal cells facilitate attraction of cancer cells, acting through its cognate receptor, CXCR4, which is expressed by both hematopoietic and non-hematopoietic tumor cells. CXCR4 stimulates tumor progression by different mechanisms and is required for metastatic spread to organs where CXCL12 is expressed, thereby allowing tumor cells to access cellular niches, such as the marrow, which favor tumor cell survival and proliferation. It has also been demonstrated that CXCL12 binds to another seven-transmembrane G-protein receptor or G-protein-coupled receptor, namely CXCR7. These studies indicated critical roles for CXCR4 and CXCR7 mediation of tumor metastasis in several types of cancers, suggesting their contributions as biomarkers of tumor behavior as well as potential therapeutic targets. Furthermore, CXCL12 itself has the capability to stimulate survival and growth of neoplastic cells in a paracrine fashion. CXCL12 is a supportive chemokine for tumor neovascularization via attracting endothelial cells to the tumor microenvironment. It has been suggested that elevated protein and mRNA levels of CXCL12/CXCR4/CXCR7 are associated with human bladder cancer (BC). Taken together, mounting evidence suggests a role for CXCR4, CXCR7, and their ligand CXCL12 during the genesis of BC and its further development. However, a better understanding is still required before exploring CXCL12/CXCR4/CXCR7 targeting in the clinic.

CXC chemokine CXCL12 tissue expression and circulating levels in peptic ulcer patients with Helicobacter pylori infection.

Helicobacter pylori (H. pylori) infection is among the most prevalent human infections. CXCL12 is a well-known CXC chemokine involved in inflammation and play major roles in angiogenesis. There is currently very limited data on the role of CXCL12 in peptic ulcer disease. Hence, we aimed to explore whether CXCL12 is involved in the pathogenesis of peptic ulcer induced by H. pylori. In this study, we enrolled 102 H. pylori-infected patients, including 51 with active ulcer (GA) and 51 with healing ulcer (GH). We also recruited 50 healthy subjects as control, which did not show any sign or symptoms of chronic inflammatory diseases, infection, or immune-related disorders. Endoscopy was performed to determine the stage of the disease. ELISA was used for detection of H. pylori infection and CXCL12 measurement. We also employed western blotting to detect CXCL12 in ulcerative lesions of H. pylori. Demographic data were also collected by questionnaire. Our results demonstrated that CXCL12 serum levels in GA group (151.8±18.31pg/mL) were significantly higher than those in GH (36.89±6.78pg/mL) and control groups (33.77±9.12pg/mL) (P<0.0001). However, we did not observe a significant difference between GH and control groups. Moreover, overexpression of CXCL12 in gastric lesions of patients in GA group was confirmed by Western blot analysis. According to the result of the present study, it could be concluded that CXCL12 is involved in the pathogenesis and healing of H. pylori-induced peptic ulcer. CXCL12 serum levels may also be used to distinguish between GA and GH phases of the disease.

All eotaxins CCL11, CCL24 and CCL26 are increased but to various extents in pulmonary tuberculosis patients.

BACKGROUND: Mycobacterium tuberculosis is a pulmonary pathogen responsible for tuberculosis. Tuberculosis (TB) is characterized histologically by granulomas at the site of disease activity. Primary pathologic feature of TB is formation of a granuloma, and chemokines are known to play an important role in the formation of granulomas during infection. Therefore, the aim of this study was to evaluate the serum levels of CCL11, CCL24, and CCL26 in the TB patients in comparison to healthy controls. METHODS: The population of this cross-sectional study included 300 patients suffering from TB and 100 healthy controls. Concentrations of CCL11, CCL24, and CCL26 were measured by enzyme linked immunosorbent assay (ELISA) technique. The results were analyzed using SPSS software package version 18. Differences were considered significant where p was less than 0.05. RESULTS: The results showed significant elevated serum levels of CCL11, CCL24, and CCL26 in TB patients compared to controls. CONCLUSIONS: According to the present results it can be concluded that CCL11, CCL24, and CCL26 (which are produced by Th2 cells and other cells which induce Th2 development) are increased in TB patients; hence, it seems that TB suppresses Th1 and the classic function of macrophages subsequently by inducing the chemokines' expression.

Harmonizing hope: navigating the osteoarthritis melody through the CCL2/CCR2 axis for innovative therapeutic avenues.

Osteoarthritis (OA) is characterized by a complex interplay of molecular signals orchestrated by the CCL2/CCR2 axis. The pathogenesis of OA has been revealed to be influenced by a multifaceted effect of CCL2/CCR2 signaling on inflammation, cartilage degradation, and joint homeostasis. The CCL2/CCR2 axis promotes immune cell recruitment and tips the balance toward degeneration by influencing chondrocyte behavior. Insights into these intricate pathways will offer novel therapeutic approaches, paving the way for targeted interventions that may redefine OA management in the future. This review article explores the molecular symphony through the lens of the CCL2/CCR2 axis, providing a harmonious blend of current knowledge and future directions on OA treatment. Furthermore, in this study, through a meticulous review of recent research, the key players and molecular mechanisms that amplify the catabolic cascade within the joint microenvironment are identified, and therapeutic approaches to targeting the CCL2/CCR axis are discussed.

The story of clobenpropit and CXCR4: can be an effective drug in cancer and autoimmune diseases?

Clobenpropit is a histamine H3 receptor antagonist and has developed as a potential therapeutic drug due to its ability to inhibit CXCR4, a chemokine receptor involved in autoimmune diseases and cancer pathogenesis. The CXCL12/CXCR4 axis involves several biological phenomena, including cell proliferation, migration, angiogenesis, inflammation, and metastasis. Accordingly, inhibiting CXCR4 can have promising clinical outcomes in patients with malignancy or autoimmune disorders. Based on available knowledge, Clobenpropit can effectively regulate the release of monocyte-derived inflammatory cytokine in autoimmune diseases such as juvenile idiopathic arthritis (JIA), presenting a potential targeted target with possible advantages over current therapeutic approaches. This review summarizes the intricate interplay between Clobenpropit and CXCR4 and the molecular mechanisms underlying their interactions, comprehensively analyzing their impact on immune regulation. Furthermore, we discuss preclinical and clinical investigations highlighting the probable efficacy of Clobenpropit for managing autoimmune diseases and cancer. Through this study, we aim to clarify the immunomodulatory role of Clobenpropit and its advantages and disadvantages as a novel therapeutic opportunity.

Current and future immunotherapeutic approaches in pancreatic cancer treatment.

Pancreatic cancer is a major cause of cancer-related death, but despondently, the outlook and prognosis for this resistant type of tumor have remained grim for a long time. Currently, it is extremely challenging to prevent or detect it early enough for effective treatment because patients rarely exhibit symptoms and there are no reliable indicators for detection. Most patients have advanced or spreading cancer that is difficult to treat, and treatments like chemotherapy and radiotherapy can only slightly prolong their life by a few months. Immunotherapy has revolutionized the treatment of pancreatic cancer, yet its effectiveness is limited by the tumor's immunosuppressive and hard-to-reach microenvironment. First, this article explains the immunosuppressive microenvironment of pancreatic cancer and highlights a wide range of immunotherapy options, including therapies involving oncolytic viruses, modified T cells (T-cell receptor [TCR]-engineered and chimeric antigen receptor [CAR] T-cell therapy), CAR natural killer cell therapy, cytokine-induced killer cells, immune checkpoint inhibitors, immunomodulators, cancer vaccines, and strategies targeting myeloid cells in the context of contemporary knowledge and future trends. Lastly, it discusses the main challenges ahead of pancreatic cancer immunotherapy.