Targeting Ferroptosis for Cancer Immunotherapy: Molecular Mechanisms, Immune Microenvironment Crosstalk, and Clinical Translation Prospects

Epithelial ovarian cancer (EOC) is a cancer that affects the female reproductive system and is highly lethal. It poses significant challenges in terms of treatment and often has a poor prognosis. In recent years, with the advent of PARPi, the treatment of ovarian cancer has entered a new stage of full-process management. Although more and more drugs have been approved, the therapeutic effect of PARPi is still very limited. With the rapid development of PD-1/PD-L1, CTLA-4, oncolytic viruses, cancer vaccines, adoptive cell therapy, etc., tumor immunotherapy has provided new opportunities for the treatment of ovarian cancer. This study used comprehensive transcriptome analysis across multiple databases to gather gene transcripts and clinical features of normal ovarian samples and tissue samples from ovarian cancer. The aim was to explore the mechanisms underlying tumor immunotherapy resistance and to reveal the relationship between ovarian cancer's immune microenvironment and genes linked to inflammation. Various R packages were used for differential gene analysis, enrichment analysis, co-expression network construction, and prognostic model building. It has been found that the prognosis of ovarian cancer patients is closely associated with sets of genes involved in inflammation. The immune infiltration microenvironment, clinicopathological features, and survival rates differed significantly between two inflammatory gene expression patterns identified using cluster and immune microenvironment analyses. Further analysis revealed that the high-risk group had a higher abundance of M2-type macrophage infiltration, more active anti-tumor immune response, higher tumor stemness score, potentially worse prognosis, and lower response rates to multiple chemotherapy drugs and immune checkpoint inhibitors. These findings provide new perspectives and potential targets for immunotherapy and prognostic evaluation of ovarian cancer and offer new strategies and directions for clinical treatment and patient management. This study provides crucial information to further our comprehension of drug response mechanisms and tumor immunotherapy. It offers new strategies and methods for the treatment and prognostic improvement of ovarian cancer.

Chronic infections by pathogenic microorganisms play a significant role in cancer development, disrupting the body's immune system and microenvironment. This interference impairs the body's ability to eliminate these microorganisms promptly, allowing them to persist by evading immune defenses. This study aimed to explore how chronic pathogenic infections influence the immune microenvironment, impacting tumorigenesis, cancer progression, and treatment strategies. Additionally, it seeks to investigate the effects of these infections on specific immune checkpoints and identify potential targets for immunotherapy. We conducted searches, readings, and detailed analyses of key terms in databases like PubMed and Web of Science to evaluate the impact of chronic infections by pathogenic microorganisms on the immune microenvironment. Our analysis demonstrates a significant association between persistent chronic infections by pathogenic microorganisms and tumorigenesis. Notable impacts on the immune microenvironment include changes in immune cell function and the regulation of immune checkpoints, offering insights into potential targets for cancer immunotherapy. This study highlights the complex relationship between chronic infections and cancer development, presenting new opportunities for cancer immunotherapy by understanding their effects on the immune microenvironment. The influence of these infections on immune checkpoints emphasizes the crucial role of the immune system in cancer treatment. Chronic infections by pathogenic microorganisms greatly affect the immune microenvironment, tumorigenesis, and cancer treatment. Unraveling the underlying mechanisms can unveil potential targets for immunotherapy, improving our comprehension of the immune response to cancer and potentially leading to more effective cancer treatments in the future.

Every day, more evidence is revealed regarding the importance of the relationship between the response to cancer immunotherapy and the cancer immune microenvironment. It is well established that a profound characterization of the immune microenvironment is needed to identify prognostic and predictive immune biomarkers. To this end, we find phenotyping cells by multiplex immunofluorescence (mIF) a powerful and useful tool to identify cell types in biopsy specimens. Here, we describe the use of mIF tyramide signal amplification for labeling up to eight markers on a single slide of formalin-fixed, paraffin-embedded tumor tissue to phenotype immune cells in tumor tissues. Different panels show different markers, and the different panels can be used to characterize immune cells and relevant checkpoint proteins. The panel design depends on the research hypothesis, the cell population of interest, or the treatment under investigation. To phenotype the cells, image analysis software is used to identify individual marker expression or specific co-expression markers, which can differentiate already selected phenotypes. The individual-markers approach identifies a broad number of cell phenotypes, including rare cells, which may be helpful in a tumor microenvironment study. To accurately interpret results, it is important to recognize which receptors are expressed on different cell types and their typical location (i.e., nuclear, membrane, and/or cytoplasm). Furthermore, the amplification system of mIF may allow us to see weak marker signals, such as programmed cell death ligand 1, more easily than they are seen with single-marker immunohistochemistry (IHC) labeling. Finally, mIF technologies are promising resources for discovery of novel cancer immunotherapies and related biomarkers. In contrast with conventional IHC, which permits only the labeling of one single marker per tissue sample, mIF can detect multiple markers from a single tissue sample, and at the same time, deliver extensive information about the cell phenotypes composition and their spatial localization. In this matter, the phenotyping process is critical and must be done accurately by a highly trained personal with knowledge of immune cell protein expression and tumor pathology.

The immune microenvironment is of great significance in cervical cancer. However, there is still a lack of systematic research on the immune infiltration environment of cervical cancer. We obtained cervical cancer transcriptome data and clinical information from the Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases, evaluated the immune microenvironment of cervical cancer, determined immune subsets, constructed an immune cell infiltration scoring system, screened key immune-related genes, and performed single-cell data analysis and cell function analysis of key genes. We combined the TCGA and GEO data sets and obtained three different immune cell populations. We obtained two gene clusters, extracted 119 differential genes, and established an immune cell infiltration (ICI) scoring system. Finally, three key genes, IL1B, CST7, and ITGA5, were identified, and single-cell sequencing data were mined to distribute these key genes in different cell types. By up-regulating CST7 and down-regulating IL1B and ITGA5, cervical cancer cells' proliferation ability and invasion ability were successfully reduced. We conducted a comprehensive assessment of the state of the tumor immune microenvironment in cervical cancer, constructed the ICI scoring system, and identified the ICI scoring system as a potential indicator of susceptibility to immunotherapy for cervical cancer, identifying key genes suggesting that IL1B, CST7, and ITGA5 play an essential role in cervical cancer.

Extracellular vesicles (EVs) are secreted by almost all cells. They contain proteins, lipids, and nucleic acids which are delivered from the parent cells to the recipient cells. Thereby, they function as mediators of intercellular communication and molecular transfer. Recent evidences suggest that exosomes, a small subset of EVs, are involved in numerous physiological and pathological processes and play essential roles in remodeling the tumor immune microenvironment even before the occurrence and metastasis of cancer. Exosomes derived from tumor cells and host cells mediate their mutual regulation locally or remotely, thereby determining the responsiveness of cancer therapies. As such, tumor‐derived circulating exosomes are considered as noninvasive biomarkers for early detection and diagnosis of tumor. Exosome‐based therapies are also emerging as cutting‐edge and promising strategies that could be applied to suppress tumor progression or enhance anti‐tumor immunity. Herein, the current understanding of exosomes and their key roles in modulating immune responses, as well as their potential therapeutic applications are outlined. The limitations of current studies are also presented and directions for future research are described.

Tumor-derived exosomes in the cancer immune microenvironment and cancer immunotherapy

BackgroundUnderstanding the tumor microenvironment (TME) is essential for the advancement of immunotherapy for ovarian cancer (OC). Nonetheless, predicting transcription factor (TF) regulation from the TME using single-cell RNA sequencing (scRNA-seq) data is challenging.MethodsThe OC scRNA-seq data were analyzed with a specialized scRNA-seq transcriptome analysis application. The OC TME was utilized to instruct the SCENIC procedure for TF regulation. We built a risk model using Lasso regression and identified immunological subgroups using ConsensusClusterPlus. To analyze the percentage of invading immune cells, the algorithms CIBERSORT, ESTIMATE, and xCell were used. We computed the stromal score, immunological score, estimate score, and tumor purity to evaluate the risk model's capacity to predict the tumor immune microenvironment. Additionally, the expression of immunological checkpoints was examined, and for pertinent evaluation, the imvigor 210 dataset of the immunotherapy cohort was used. pRophetic predicted the sensitivity of 138 GDSC database drugs. In addition, we examined the expression of unproven risk model genes using qPCR and immunohistochemistry (JCHAIN, UBD, and RARRES1). Cell proliferation was assessed by colony formation assays. Transwell experiments were used to examine the invasion and migration ability of OC cells.ResultsSix immunologically malignant cell subpopulations have been identified within the cancer immune microenvironment (referred to as TC0-6). Unique in its immunological profile, TC0 demonstrates the most intimate interactions with immune cells. Following a meta gene screen in the TC0 subpopulation using the top 30 targets of 14 transcription factor (TF) factors, two distinct immunological molecular subtypes—the C1 and C2 subtypes—with notable survival differences were discovered. On the basis of nine genes whose expression differs between the C1 and C2 subtypes, a risk model was constructed. The risk model is an accurate method for forecasting the effectiveness of immunotherapies, clinicopathological characteristics, and survival. JCHAIN and UBD expression in OC tissues was found to be low according to qPCR and IHC analyses, whereas RARRES1 expression was found to be high. The functional experiment results indicated that downregulation of JCHAIN and UBD and overexpression of RARRES1 could suppress the proliferation, migration, and invasion of OC cells in vitro.ConclusionBased on TF regulatory networks in the tumor microenvironment, this study developed a 9-gene risk model for the prognosis of ovarian cancer. This model may aid in the future promotion of personalized OC immunotherapy. In addition, JCHAIN, UBD, and RARRES1 were identified as three novel immune-related biomarkers for OC.

Cancer immunotherapy has revolutionized oncology by harnessing the body’s immune system to target and eradicate malignant cells. This review delves into emerging strategies in cancer immunotherapy, focusing on novel approaches and future directions of this rapidly evolving field. Key areas of exploration include immune checkpoint inhibitors (ICIs), chimeric antigen receptor (CAR) T-cell therapy, and cancer vaccines. ICIs, which target proteins such as cytotoxic T-lymphocyte antigen-4 and programmed cell death-1/programmed cell death ligand 1, have shown significant efficacy in various cancers, transforming clinical outcomes. CAR-T cell therapy, with its ability to genetically modify T-cells to attack cancer cells, has demonstrated remarkable success in hematologic malignancies and is being adapted for solid tumors. Cancer vaccines designed to stimulate an immune response against specific tumor antigens are also advancing with promising clinical results. Despite these advances, challenges such as immunogenicity, side effects, and treatment resistance remain. This review provides a comprehensive overview of the latest developments, clinical trials, and future perspectives in cancer immunotherapy, highlighting the potential for these strategies to redefine cancer treatment.

Ferroptosis in cancer immunity and immunotherapy: Multifaceted interplay and clinical implications

ATM in immunobiology: From lymphocyte development to cancer immunotherapy.

Cancer immunotherapy has developed rapidly in recent years and stands as one of the most promising techniques for combating cancer. To develop and optimize cancer immunotherapy, it is crucial to comprehend the interactions between immune cells and tumor cells in the tumor microenvironment (TME). The TME is complex, with the distribution and function of immune cells undergoing dynamic changes. There are several research techniques to study the TME, and intravital imaging emerges as a powerful tool for capturing the spatiotemporal dynamics, especially the movement behavior and the immune function of various immune cells in real physiological state. Intravital imaging has several advantages, such as high spatio-temporal resolution, multicolor, dynamic and 4D detection, making it an invaluable tool for visualizing the dynamic processes in the TME. This review summarizes the workflow for intravital imaging technology, multi-color labeling methods, optical imaging windows, methods of imaging data analysis and the latest research in visualizing the spatio-temporal dynamics and function of immune cells in the TME. It is essential to investigate the role played by immune cells in the tumor immune response through intravital imaging. The review deepens our understanding of the unique contribution of intravital imaging to improve the efficiency of cancer immunotherapy.

Tumor microenvironment (TME) is formed as a result of interaction and cross-linking between the tumor cell and different types of surrounding cells. Recent studies have shown that the tumor reprograms the microenvironment so that TME promotes the development of primary tumors, their metastasis and becomes an important regulator of oncogenesis. Under the influence of the tumor, the immune profile in the TME undergoes significant changes, “editing". An immunosuppressive network is formed, which suppresses the activity of the main effector of cellular immunity — T lymphocytes. T cells in TMA are in a state of anergy and exhaustion. T cells in TME are characterized by increased expression of inhibitory receptors, decreased secretion of cytokines and cytolytic activity. Blocking inhibitory receptors with specific antibodies can lead to the restoration of the functions of exausted T cells. Therefore, the restoration of the functional activity of T lymphocytes is one of the important strategies in cancer immunotherapy. The formation of the immune profile is influenced by genetic aberrations accumulating in the tumor. They play an important role in creating a specific, characteristic only for this tumor immune environment in the TME. Genetic changes in tumor cells lead to phenotypic and functional rearrangements of lymphocytes, which allows the tumor to escape the reaction of immune cells. Since many tumors occur after prolonged inflammation or exhibit characteristics of chronic inflammation as they progress, inflammation is considered an important factor in the formation of immune profile in TME. Immune infiltrates from different human tumors associated with inflammation may contain valuable prognostic and pathophysiological information. Macrophages in the TME now began to be regarded as descriptive marker and as a therapeutic target. One of the main mechanisms by which tumor cells reprogram surrounding cells is the release of exosomes — small vesicles that carry and deliver proteins and nucleic acids to other cells. When exosomal cargo is absorbed, molecular, transcriptional and translational changes occur in the recipient non-tumor cells in the TME. Therefore, tumor exosomes are an effective means by which the functions of immune cells in TME are purposefully changed. Thus, along with individual molecular and genomic testing of the tumor, attention should be paid to a deeper analysis of the immune profile of TME. It is a large resource of biomarkers and targets for immunotherapy.

In the tumor immune microenvironment (TIME), tumor cells interact with various cells and operate various strategies to avoid antitumor immune responses. These immune escape strategies often make the TIME resistant to cancer immunotherapy. Neutralizing immune escape strategies is necessary to overcome resistance to cancer immunotherapy. Immune checkpoint receptors (ICRs) expressed in effector immune cells inhibit their effector function via direct interaction with immune checkpoint ligands (ICLs) expressed in tumor cells. Therefore, blocking ICRs or ICLs has been developed as a promising cancer immunotherapy by reinvigorating the function of effector immune cells. Among the ICRs, programmed cell death 1 (PD-1) has mainly been antagonized to enhance the survival of human patients with cancer by restoring the function of tumor-infiltrating (TI) CD8+ T cells. It has been demonstrated that PD-1 is expressed not only in TI CD8+ T cells, but also in other TI immune cells and even tumor cells. While PD-1 suppresses the function of TI CD8+ T cells, it is controversial whether PD-1 suppresses or amplifies the suppressive function of TI-suppressive immune cells (e.g., regulatory T cells, tumor-associated macrophages, and myeloid cells). There is also controversy regarding the role of tumor-expressing PD-1. Therefore, a precise understanding of the expression pattern and function of PD-1 in each cell subset is important for improving the efficacy of cancer immunotherapy. Here, we review the differential role of PD-1 expressed by various TI immune cells and tumor cells. We focused on how cell-type-specific ablation or blockade of PD-1 affects tumor growth in a murine tumor model. Furthermore, we will also describe how the blockade of PD-1 acts on TI immune cells in human patients with cancer.

Cancer immunotherapy has shown promising results in the clinic, but it faces great challenges such as low response rates and low efficacy in solid tumors. c-Rel, a member of the nuclear factor (NF)-κB family, is a newly described immune checkpoint for myeloid-derived suppressor cells (MDSCs), which contribute to the formation of immune-suppressive tumor microenvironment and resistance to cancer immunotherapy. How to selectively target myeloid c-Rel for the treatment of cancer is not well established. In this study, we investigated the feasibility and efficacy of knocking down myeloid c-Rel with siRNA-loaded peptide-based nanoparticles as a new cancer immunotherapy strategy. The knockdown of c-Rel gene by the siRNA-loaded peptide nanoparticles was confirmed on MDSCs in vitro and in vivo. The effects of c-Rel silencing on cell number and immune suppressive function of the murine bone marrow-derived MDSCs were then investigated. To evaluate the anti-tumor efficacy of the c-Rel siRNA loaded nanoparticles, female C57BL/6 mice with subcutaneous B16 tumor were treated with PBS, c-Rel siRNA loaded nanoparticles, control siRNA loaded nanoparticles or empty nanoparticles. The tumor growth and body weight of mice were monitored, and the numbers and immune activities of tumor infiltrated immune cells in different groups were analyzed at the end of the experiment. The immune function of MDSCs isolated from tumor bearing mice received different treatments were further investigated ex vivo by T cell proliferation assays. The c-Rel siRNA nanoparticles significantly reduced c-Rel expression in MDSCs, diminished both the number and immune suppressive function of MDSCs, and enhanced intratumor CD8+ T cell responses. Significantly reduced tumor growth was observed in mice treated with the c-Rel siRNA nanoparticles compared to control mice. Our data indicates that peptide-based nanoparticles can be successfully utilized to target the myeloid immune checkpoint c-Rel for the treatment of cancer.

Introduction: A cross-sectional design study demonstrated several predictor factors for cervical cancer associated with sociodemographic, psychosocial, and psychosexual variables linked with the percentage distribution age group human papillomavirus (HPV)-positive. Papillomaviruses can be used as viral vectors in gene therapy. Future messenger ribonucleic acid (mRNA) vaccines and new mRNA-based medicines are the potential of the future. Objective: To describe the development of mRNA vaccines in phase of clinical trials for colorectal cancer, head and neck carcinoma to exploring several strategies for cancer Immunotherapy. Methods: Research was carried out in meta-analysis using databases as a molecular tool. There are different types of RNA expression vectors used in mRNA cancer vaccines as circular RNA (circ RNA), self-amplifying RNA and comb-structured mRNA involved hybridizing short double-stranded RNA (dsRNA) with single stranded mRNA as vaccine platforms. Biomarkers tumor associated antigens (TAAs) and chimeric protein derived from the fusion of the HPV-16 have been developed. Results: The self-amplification RNA (saRNA) targeting the HPV exhibited high antitumor effects. Deoxyribonucleic acid (DNA)-based vaccines, recombinant proteins, nanoparticles, synthetic peptides, viral and non-viral vectors may be novel therapeutic targets for HPV vaccination. Conclusion: Several potential benefits of mRNA-based vaccine may be mitigating risks in HPV related diseases as anus-genital, head, and neck cancer, colorectal tumors, penile cancer, and recurring respiratory papillomatosis.