Oncolytic viruses (OVs) are a promising class of cancer therapy, exploiting their abilities to selectively infect and kill cancer cells while stimulating antitumor immune responses. The current assessment explores the changing horizons of OV immunotherapy, focusing on recent advances in technology plans to improve OV projects and combined approaches to improve curative efficacy. We discuss how OVs induce direct oncolysis and promote the release of tumor-associated antigens, leading to the activation of both innate and adaptive immunity. Special attention shall be given to programs for arm OVs to express curative genes, modify the tumor microenvironment and overcome immunosuppression. Moreover, we assess the synergies of uniting OVs with other immunotherapeutic techniques, such as immune checkpoint inhibitors and cell therapy, to improve tolerant outcomes. The present assessment provides an understanding of the relevant declaration of the OV analysis, highlighting the main obstacles and the future directions for the development of other capable and targeted cancer immunotherapy.

Regulatory T (Treg) cells are known to impede antitumor immunity, yet the regulatory mechanisms and functional roles of these cells remain poorly understood. In this study, through the characterization of multiple cancer models, we identified a substantial presence of peripherally induced Treg cells in the tumor microenvironment (TME). Depletion of these cells triggered antitumor responses and provided potent therapeutic effects by increasing functional CD8+ T cells. Fate-mapping and transfer experiments revealed that IFN-γ-expressing T helper (Th) 1 cells differentiated into Treg cells in response to TGF-β signaling in tumors. Pseudotime trajectory analysis further revealed the terminal differentiation of Th1-like Treg cells from Th1 cells in the TME. Tumor-resident Treg cells highly expressed T-bet, which was essential for their functions in the TME. Additionally, CD39 was highly expressed by T-bet+ Treg cells in both mouse and human tumors, and was necessary for Treg cell-mediated suppression of CD8+ T cell responses. Our study elucidated the developmental pathway of intratumoral Treg cells and highlighted novel strategies for targeting them in cancer patients.

FoxP3+ regulatory T cells (Tregs) are responsible for immune homeostasis by suppressing excessive anti-self-immunity. Tregs facilitate tumor growth by inhibiting anti-tumor immunity. Here, we explored the targeting of FoxP3 as a basis for new immunotherapies. In a high-throughput phenotypic screening of a drug repurposing library using human primary T cells, we identified quinacrine as a FoxP3 downregulator. In silico searches based on the structure of quinacrine, testing of sub-libraries of analogs in vitro, and validation identified a subset of 9-amino-acridines that selectively abrogated Treg suppressive functions. Mechanistically, these acridines interfered with the DNA-binding activity of FoxP3 and inhibited FoxP3-regulated downstream gene regulation. Release from Treg suppression by 9-amino-acridines increased anti-tumor immune responses both in cancer patient samples and in mice in a syngeneic tumor model. Our study highlights the feasibility of screening for small molecular inhibitors of FoxP3 as an approach to pursuing Treg-based immunotherapy.

Inflammation appears to play a crucial role in the development and progression of penile cancer (PeCa). Two molecular pathways of PeCa are currently described: HPV-dependent and HPV-independent. The tumor immune microenvironment (TIME) of PeCa is characterized by the presence of tumor-associated macrophages, cancer-associated fibroblasts, and tumor-infiltrating lymphocytes. The components of the TIME produce pro-inflammatory cytokines and chemokines, which have been found to be overexpressed in PeCa tissues and are associated with tumor progression and unfavorable prognoses. Additionally, the nuclear factor kappa B (NF-κB) pathway and secreted phosphoprotein 1 (SPP1) have been implicated in PeCa pathogenesis. Elevated C-reactive protein (CRP) levels and the neutrophil-to-lymphocyte ratio (NLR) have been identified as potential prognostic biomarkers in PeCa. This overview presents the complex contribution of the inflammatory process and collates projects aimed at modulating TIME in PeCa.

Breast cancers (BCs) are frequently linked to an immunosuppressive microenvironment that facilitates tumor evasion of anti-cancer immunity. The cells that suppress the immune system such as regulatory B cells (Bregs), regulatory T cells (Tregs), tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), myeloid-derived suppressor cells (MDSCs), play a crucial role in immune resistance. Also, tumor progression and immune evasion of cancers are facilitated by cytokines and factors released by tumor cells or immunosuppressive cells. Targeting these regulatory cells therapeutically, whether through elimination, inactivation, or reprogramming, has resulted in hopeful anti-tumor reactions. Yet, the substantial diversity and adaptability of these cells, both in terms of appearance and function, as well as their variation over time and depending on where they are in the body, have posed significant challenges for using them as reliable biomarkers and creating focused therapies that could target their creation, growth, and various tumor-promoting roles. The immunotherapy approaches in BC and their effectiveness in treating certain subtypes are still in their initial phases. In this review, we thoroughly outlined the characteristics, roles, and possible treatment options for these immune-suppressing cells in the tumor environment.

The host immune system is adapted in a variety of ways by tumour microenvironment and growing tumour interacts to promote immune escape. One of these adaptations is manipulating the metabolic processes of cells in the tumour microenvironment. The growing tumour aggressively utilise glucose, its primary energy source available in tumour site, and produce lactate by Warburg effect. In such a hostile environment, tumour-infiltrating immune cells are unable to survive metabolically. Tumour-infiltrating CD4+ Treg cells, on the other hand, adapted to an alternative energy-generating system, switching from the highly-competitive glucose to the fatty-acid metabolic pathway, by down-regulating glucose-metabolising genes and up-regulating fatty-acid metabolising genes. Tregs with high-levels of the fatty acid scavenger receptor CD36, a key component of the fatty-acid metabolic pathway, aided this metabolic shift. Treg cell formation was hampered when the fatty-acid metabolic pathway was disrupted, showing that it is necessary for Treg cell development. FOXP3, the Treg lineage-specific transcription factor, regulates fatty-acid metabolism by inducing CD36 transcription. A high-fat diet enhanced Treg development while suppressing anti-tumour immunity, whereas a low-fat diet suppressed Treg development. The altered metabolism of tumour-infiltrating Treg cells enables their rapid generation and survival in the hostile tumour microenvironment, aiding cancer progression. Fascinatingly, mice fed with a low-fat diet showed a positive prognosis with chemotherapy than mice fed with a high-fat diet. Thus, a maximum efficacy of chemotherapy might be achieved by altering diet composition during chemotherapy, providing a promising indication for future cancer treatment.

Regulatory T cells (Tregs) are a suppressive CD4+ T cell population that limit the antitumor immune response. In this study, we analyzed the chromatin accessibility of Tregs in the murine tumor microenvironment (TME) to identify tumor-specific accessible peaks and if these are altered over time in the tumor microenvironment, with or without anti-PD-1 immunotherapy. We found that despite little change in chromatin accessibility of Tregs in the tumor over time, Tregs have a distinct chromatin accessibility signature in the TME compared with Tregs in the periphery. This distinct tumor Treg chromatin accessibility profile highlights reduced accessibility at loci important for an CD4+ conventional T cell (CD4+ Foxp3-) effector phenotype. Analysis of chromatin accessibility in Tregs from B16 and MC38 tumor models indicated that Tregs from skin-resident tumors are most similar to naïve skin resident Tregs but still bear key differences attributable to the TME. We also found that Tregs do not alter their transcriptome or chromatin accessibility following immunotherapy. We conclude that although chromatin accessibility in Tregs is somewhat similar to their tissue residency, the TME may drive a unique chromatin accessibility profile. Treg chromatin accessibility in the tumor appears remarkably stable and unaltered by tumor type, over time, or following immunotherapy.

Since its discovery, IL-1β has taken center stage as a key mediator of a very broad spectrum of diseases revolving around immuno-mediated and inflammatory events. Predictably, the pleiotropic nature of this cytokine in human pathology has led to the development of targeted therapeutics with multiple treatment indications in the clinic. Following the accumulated findings of IL-1β's central modulatory role in the immune system and the implication of inflammatory pathways in cancer, the use of IL-1β antagonists was first proposed and then also pursued for oncology disorders. However, this approach has consistently relied on the perceived need of interfering with IL-1β synthesized and secreted by immune cells. Herein, we discuss the importance of IL-1β derived from cancer cells which impacts primary tumors, particularly metastatic lesions, separately from and in addition to its more recognized role in immune-mediated inflammatory events. To this end, we focus on the instrumental contribution of IL-1β in the establishment and progression of advanced prostate adenocarcinoma. Special emphasis is placed on the potential role that the standard-of-care treatment strategies for prostate cancer patients have in unleashing IL-1β expression and production at metastatic sites. We conclude by reviewing the therapeutics currently used for blocking IL-1β signaling and propose a rationale for their concomitant use with standard-of-care treatments to improve the clinical outcomes of advanced prostate cancer.

The purpose of this review is to explore the molecular foundations of ocular surface squamous neoplasia (OSSN), focusing on the genetic and epigenetic aspects. While current management strategies include surgical excision and medical therapies, the understanding of OSSN's molecular basis remains limited, hindering the development of targeted treatments.

A comprehensive MEDLINE search was conducted for literature published between January 1993 and October 2023. Only studies with original data on molecular, genetic, or epigenetic mechanisms, such as mutations, gene expression, and genetic predispositions were included. Articles were excluded if they focused solely on clinical management without addressing these factors, or if they were reviews, editorials, or opinion pieces.

The search yielded a total of 108 articles, out of which 39 articles met the criteria for further analysis. Investigations into OSSN have identified key DNA mutations in the TP53, HGF, EGFR, TERT, and CDKN2A genes, indicating common oncogenic pathways shared with other squamous cell carcinomas (SCCs). Significant epigenetic changes were identified, including DNA methylation, histone modifications, and altered miRNA expression patterns. Epigenetic dysregulation of critical tumor suppressors and oncoproteins, further highlight the complex genetic landscape of OSSN.

The molecular alterations identified in OSSN not only enhance our understanding of its biology but also have potential as novel biomarkers for early detection, prognostic evaluation, and as therapeutic targets. The identification of genetic and epigenetic markers in OSSN signifies progress towards personalized medicine approaches. Further studies and collaborative efforts are essential to validate these molecular markers and translate them into clinical practice, potentially revolutionizing OSSN management and improving patient outcomes.

The emergence of effective immunotherapies has revolutionized therapies for many types of cancer. However, current immunotherapy has limited efficacy in certain patient populations and displays therapeutic resistance after a period of treatment. To address these challenges, a growing number of immunotherapy drugs have been investigated in clinical and preclinical applications. The diverse functionality of peptides has made them attractive as a therapeutic modality, and the global market for peptide-based therapeutics is witnessing significant growth. Peptides can act as immunotherapeutic agents for the treatment of many malignant cancers. However, a systematic understanding of the interactions between different peptides and the host's immune system remains unclear. This review describes in detail the roles of peptides in regulating the function of the immune system for cancer immunotherapy. Initially, we systematically elaborate on the relevant mechanisms of cancer immunotherapy. Subsequently, we categorize peptide-based nanomaterials into the following three categories: peptide-based vaccines, anti-cancer peptides, and peptide-based delivery systems. We carefully analyzed the roles of these peptides in overcoming the current barriers in immunotherapy, including multiple strategies to enhance the immunogenicity of peptide vaccines, the synergistic effect of anti-cancer peptides in combination with other immune agents, and peptide assemblies functioning as immune stimulators or vehicles to deliver immune agents. Furthermore, we introduce the current status of peptide-based immunotherapy in clinical applications and discuss the weaknesses and future prospects of peptide-based materials for cancer immunotherapy. Overall, this review aims to enhance comprehension of the potential applications of peptide-based materials in cancer immunotherapy and lay the groundwork for future research and clinical applications.

The global increase in cancer cases and mortality has been associated with inflammatory processes, in which chemokines play crucial roles. These molecules, a subfamily of cytokines, are essential for the migration, adhesion, interaction, and positioning of immune cells throughout the body. Chemokines primarily originate in response to pathogenic stimuli and inflammatory cytokines. They are expressed by lymphocytes in the bloodstream and are divided into four classes (CC, CXC, XC, and CX3C), playing multifaceted roles in the tumor environment (TME). In the TME, chemokines regulate immune behavior by recruiting cells such as tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), which promote tumor survival. Additionally, they directly influence tumor behavior, promoting pathological angiogenesis, invasion, and metastasis. On the other hand, chemokines can also induce antitumor responses by mobilizing CD8+ T cells and natural killer (NK) cells to the tumor, reducing pro-inflammatory chemokines and enhancing essential antitumor responses. Given the complex interaction between chemokines, the immune system, angiogenic factors, and metastasis, it becomes evident how important it is to target these pathways in therapeutic interventions to counteract cancer progression. In this context, physical exercise emerges as a promising strategy due to its role modulating the expression of anti-inflammatory chemokines and enhancing the antitumor response. Aerobic and resistance exercises have been associated with a beneficial inflammatory profile in cancer, increased infiltration of CD8+ T cells in the TME, and improvement of intratumoral vasculature. This creates an environment less favorable to tumor growth and supports the circulation of antitumor immune cells and chemokines. Therefore, understanding the impact of exercise on the expression of chemokines can provide valuable insights for therapeutic interventions in cancer treatment and prevention.

The T cell response to cancer controls disease progression and response to immunotherapy1-3. Despite extensive knowledge regarding CD8 T cells, how CD4 T cells contribute to this process is less well understood. Here we identified a population of PD1+TCF1+ CD4 T cells with stem-like properties that are capable of self-renewal and differentiation into canonical CD4 effector cells. Primarily residing in tumour-draining lymph nodes (TDLNs), these tumour-specific CD4 T cells are restricted by T regulatory (Treg) cells to a stem-like fate that predominantly generated induced Treg (iTreg) cells, limiting effector CD8 T cell responses to the tumour. By contrast, upon Treg depletion, stem-like CD4 T cells differentiated into T helper 1 (TH1) cells, and via IFNγ production induced robust effector differentiation from TCF1+ CD8 T cells in TDLNs, a state we defined as 'active'. Notably, enforcing TBET expression in transferred stem-like CD4 T cells was sufficient to overcome the established restricted T cell state. Despite the presence of Treg cells, endogenous stem-like CD4 T cells actively generated TH1 cells, which were required to restore TDLN effector CD8 T cell differentiation, enhance tumour control and rescue response to immunotherapy. In agreement, TH1 differentiation in patients with kidney cancer predicted successful immunotherapy responses and improved progression-free survival. Together, these findings identify a stem-like CD4 T cell population that through alternative differentiation fates controls the switch between restricted and active T cell states with implications for cancer immunotherapies.

Glioblastoma (GBM) is an aggressive primary brain tumor with a high recurrence rate and poor prognosis. Necroptosis, a pathological hallmark of GBM, is poorly understood in terms of its role in prognosis, tumor microenvironment (TME) alteration, and immunotherapy.

We assessed the expression of 55 necroptosis-related genes in GBM and normal brain tissues. We identified necroptosis-stratified clusters using Uni-Cox and Least Absolute Shrinkage and Selection Operator (LASSO) regression to establish the 10-gene Glioblastoma Necroptosis Index (GNI). GNI demonstrated significant prognostic efficacy in the TCGA dataset (n = 160) and internal validation dataset (n = 345) and in external validation cohorts (n = 591). The GNI-high subgroup displayed a mesenchymal phenotype, lacking the IDH1 mutation, and MGMT methylation. This subgroup was characterized by significant enrichment in inflammatory and humoral immune pathways with prominent cell adhesion molecules (CD44 and ICAM1), inflammatory cytokines (TGFB1, IL1B, and IL10), and chemokines (CX3CL1, CXCL9, and CCL5). The TME in this subgroup showed elevated infiltration of M0 macrophages, neutrophils, mast cells, and regulatory T cells. GNI-related genes appeared to limit macrophage polarization, as confirmed by immunohistochemistry and flow cytometry. The top 30% high-risk score subset exhibited increased CD8 T cell infiltration and enhanced cytolytic activity. GNI showed promise in predicting responses to immunotherapy and targeted treatment.

Our study highlights the role of necroptosis-related genes in glioblastoma (GBM) and their effects on the tumor microenvironment and patient prognosis. TheGNI demonstrates potential as a prognostic marker and provides insights into immune characteristics and treatment responsiveness.

Healthcare breakthroughs are extending the lives of multiple sclerosis (MS) patients and cancer survivors, creating a growing cohort of individuals navigating a dual diagnosis. Determining the relationship between MS and cancer risk remains challenging, with inconclusive findings confounded by age, risk exposures, comorbidities, genetics and the ongoing introduction of new MS disease-modifying therapies (DMTs) across study periods.This research places significant emphasis on cancer survival, with less attention given to the impact on MS outcomes. Our review explores the existing literature on MS, cancer risk and the intersection of DMTs and cancer treatments. We aim to navigate the complexities of managing MS in cancer survivors to optimise outcomes for both conditions. Continuous research and the formulation of treatment guidelines are essential for guiding future care. Collaboration between neuro-immunology and oncology is crucial, with a need to establish databases for retrospective and ultimately prospective analysis of outcomes in these rapidly evolving fields.

Regulatory T (Treg) cells prevent autoimmunity and facilitate cancer immune evasion. Depletion of Tregs is a promising cancer therapy, but risks of autoimmune reactions hamper its clinical translation. Here, we demonstrate that temporally induced deletion of Ube2n in Tregs (Ube2n Treg-KO ) of adult mice results in a robust expansion and activation of cytotoxic CD8 + T-cells in response to cancer cell challenges, producing a long-lasting survival benefit without autoimmune complications. The anti-tumor effect persists following adoptive T-cell transfer to T-cell-deficient Rag1-knockout mice. Single-cell transcriptomic analysis revealed that UBE2N deletion shifted immunosuppressive Tregs to effector-like T-cells. This shift is characterized by the downregulation of c-Myc target genes, resembling that observed in tumor-infiltrating Tregs of melanoma patients. Further analyses confirm that UBE2N maintains c-Myc protein stability via suppression of K48-Ubiquitin-mediated proteasomal degradation. Taken together, our studies uncover a hitherto unexplored and potentially druggable UBE2N/c-Myc signaling axis to eradicate Treg-enabled cancer immune escape.

High levels of tumor necrosis factor receptor type II (TNFR2) are preferentially expressed by immunosuppressive CD4+Foxp3+ regulatory T cells (Tregs), especially those present in the tumor microenvironment, as initially reported by us. There is compelling evidence that targeting TNFR2 markedly enhances antitumor immune responses. Furthermore, a broad spectrum of human cancers also expresses TNFR2, while its expression by normal tissue is very limited. We thus hypothesized that TNFR2 may be harnessed for tumor-targeted delivery of chemotherapeutic agents. In this study, we performed a proof-of-concept study by constructing a TNFR2-targeted PEGylated poly(dl-lactic-co-glycolic acid) (PLGA-PEG) nanodrug delivery system [designated as TNFR2-PLGA-ADR (Adriamycin)]. The results of in vitro study showed that this TNFR2-targeted delivery system had the properties in cellular binding and cytotoxicity toward mouse colon cancer cells. Further, upon intravenous injection, TNFR2-PLGA-ADR could efficiently accumulate in MC38 and CT26 mouse colon tumor tissues and preferentially bind with tumor-infiltrating Tregs. Compared with ADR and ISO-PLGA-ADR, the in vivo antitumor effect of TNFR2-PLGA-ADR was markedly enhanced, which was associated with a decrease of TNFR2+ Tregs and an increase of IFNγ+CD8+ cytotoxic T lymphocytes in the tumor tissue. Therefore, our results clearly show that targeting TNFR2 is a promising strategy for designing tumor-specific chemoimmunotherapeutic agent delivery system.

Radiotherapy (RT) controls local lesions, meantime it has the capability to induce systemic response to inhibit distant, metastatic, non-radiated tumors, which is referred to as the "abscopal effect". It is widely recognized that radiotherapy can stimulate systemic immune response. This provides a compelling theoretical basis for the combination of immune therapy combined with radiotherapy(iRT). Indeed, this phenomenon has also been observed in clinical treatment, bringing significant clinical benefits to patients, and a series of basic studies are underway to amplify this effect. However, the molecular mechanisms of immune response induced by RT, determination of the optimal treatment regimen for iRT, and how to amplify the abscopal effect. In order to amplify and utilize this effect in clinical management, these key issues require to be well addressed; In this review, we comprehensively summarize the growing consensus and emphasize the emerging limitations of enhancing the abscopal effect with radiotherapy or immunotherapy. Finally, we discuss the prospects and barriers to the current clinical translational applications.

Triple-negative breast cancer is characterized by a worse prognosis compared with other breast cancer subtypes, especially in the case of pretreated metastatic triple-negative breast cancer (mTNBC). Because of the limited treatment options and suboptimal response rates, there is a pressing need to explore novel treatment protocols.

A 48-year-old female patient diagnosed with mTNBC who had not responded to multiple lines of therapy (including surgery, chemotherapy, and radiotherapy) but demonstrated significant efficacy and abscopal effects after enrolling in our clinical trial.

Triple-negative breast cancer with lung metastases.

The clinical trial combined stereotactic body radiotherapy, immunotherapy, granulocyte-macrophage colony-stimulating factor, and thymosin alpha-1 to treat previously treated metastatic solid cancers.

This combined treatment regimen implemented in this clinical trial yielded the patient's notable efficacy, accompanied by abscopal effects. The target lesion and the 3 observed lesions achieved a partial response according to the RECIST v1.1 criteria. reevaluation scans after 2 cycles of immunotherapy indicated a regression rate of -78.97% for the target lesion and -56.73% for the observed lesions. Hematological indexes were stable, and there was no apparent myelosuppression. Also, the tumor marker CA-199 exhibited a downward trend. During the course of treatment, the patient experienced a grade 2 skin reaction, which improved after receiving antiallergic treatment. No further adverse effects were observed.

This treatment regimen may offer a promising treatment strategy for patients with mTNBC and other metastatic solid cancers.

Breast cancer is the most common cancer diagnosed in women worldwide. Early-stage breast cancer is curable in ~70-80% of patients, while advanced metastatic breast cancer is considered incurable with current therapies. Breast cancer is a highly heterogeneous disease categorized into three main subtypes based on key markers orientating specific treatment strategies for each subtype. The complexity of breast carcinogenesis is often associated with epigenetic modification regulating different signaling pathways, involved in breast tumor initiation and progression, particularly by the methylation of arginine residues. Protein arginine methyltransferases (PRMT1-9) have emerged, through their ability to methylate histones and non-histone substrates, as essential regulators of cancers. Here, we present an updated overview of the mechanisms by which PRMT1 and PRMT5, two major members of the PRMT family, control important signaling pathways impacting breast tumorigenesis, highlighting them as putative therapeutic targets.

CD4+CD25+Foxp3+ regulatory T cells (Treg) have been implicated in pain modulation in various inflammatory conditions. However, whether Treg cells hamper pain at steady state and by which mechanism is still unclear. From a meta-analysis of the transcriptomes of murine Treg and conventional T cells (Tconv), we observe that the proenkephalin gene (Penk), encoding the precursor of analgesic opioid peptides, ranks among the top 25 genes most enriched in Treg cells. We then present various evidence suggesting that Penk is regulated in part by members of the Tumor Necrosis Factor Receptor (TNFR) family and the transcription factor Basic leucine zipper transcription faatf-like (BATF). Using mice in which the promoter activity of Penk can be tracked with a fluorescent reporter, we also show that Penk expression is mostly detected in Treg and activated Tconv in non-inflammatory conditions in the colon and skin. Functionally, Treg cells proficient or deficient for Penk suppress equally well the proliferation of effector T cells in vitro and autoimmune colitis in vivo. In contrast, inducible ablation of Penk in Treg leads to heat hyperalgesia in both male and female mice. Overall, our results indicate that Treg might play a key role at modulating basal somatic sensitivity in mice through the production of analgesic opioid peptides.

Gemcitabine is a basic chemotherapy drug for pancreatic cancer (PC), but resistance is common and causes tumor recurrence and metastasis. Therefore, it is significant to explore gemcitabine resistance-related molecules for individualized treatment and prognosis assessment of PC.

In this study, transcriptome sequencing and TCGA database analysis were performed, and a differentiated gene AHNAK2 was screened. MEXPRESS database, tissue microarray analysis, and CIBERSORT and TIMER databases were used to correlate AHNAK2 expression with clinicopathological features and prognosis and immune infiltration of PC. Enrichment analysis was used to investigate the significant biological processes associated with AHNAK2.

AHNAK2 was highly expressed in gemcitabine-resistant cells. High expression of AHNAK2 increased the risk of poor overall survival (OS) and progression-free survival (PFS) in PC. Clinicopathologic analysis revealed that AHNAK2 correlated with KRAS, TP53 mutations, histologic type, short OS, N stage, and elevated CA199 levels in PC. Knockdown of AHNAK2 inhibited the ability of cell proliferation and colony formation and enhanced the toxic effect of gemcitabine in PC. Meanwhile, the knockdown of AHNAK2 expression enhanced cell-ECM adhesion, inhibited cell-cell adhesion, and downregulated the KRAS/p53 signaling pathway in PC. Furthermore, AHNAK2 was correlated with immune infiltration, especially B cells and macrophages.

Our study unveils for the first time the pivotal role of AHNAK2 in PC, particularly its association with gemcitabine resistance, clinical prognosis, and immune infiltration. AHNAK2 not only drives the proliferation and drug resistance of PC cells by potentially activating the KRAS/p53 pathway but also significantly impacts cell-cell and cell- ECM adhesion. Additionally, AHNAK2 plays a crucial role in modulating the tumor immune microenvironment. These insights underscore AHNAK2's unique potential as a novel therapeutic target for overcoming gemcitabine resistance, offering new perspectives for PC treatment strategies.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy that represents a significant challenge in cancer research and clinical management. In this study, we reanalyzed a published single-cell RNA sequencing (scRNA-seq) dataset from PDAC and adjacent tissues to investigate the heterogeneity of tumor and normal tissue, specifically focusing on the regulatory T cells (Tregs) and their interactions with other cells in the tumor microenvironment (TME). Treg cells were identified and clustered into natural Tregs (nTreg) and induced Tregs (iTreg) based on the expression of specific genes. It was found that the number of iTregs was higher in the tumor than in healthy tissues, while the number of n Tregs was higher in healthy tissues. Differential gene expression analysis was performed, and biological process analysis revealed that the Tregs in PDAC were mostly involved in protein targeting and translation pathways. In addition, ligand-receptor pairs between Tregs and other cell types were identified, and the critical communication pathways between Tregs and endothelial and ductal cells were revealed, which could potentially contribute to the immunosuppressive TME of PDAC. These findings provide insights into the role of Tregs in PDAC and their interactions with other cell types in the TME, highlighting potential targets for immunotherapy, such as the inhibitory immune checkpoint receptors CTLA4 and TIGIT, which are known to be expressed on Tregs and have been shown to play a role in suppressing anti-tumor immune responses.

Understanding the underlying mechanisms of HIV pathogenesis is critical for designing successful HIV vaccines and cure strategies. However, achieving this goal is complicated by the virus's direct interactions with immune cells, the induction of persistent reservoirs in the immune system cells, and multiple strategies developed by the virus for immune evasion. Meanwhile, HIV and SIV infections induce a pandysfunction of the immune cell populations, making it difficult to untangle the various concurrent mechanisms of HIV pathogenesis. Over the years, one of the most successful approaches for dissecting the immune correlates of protection in HIV/SIV infection has been the in vivo depletion of various immune cell populations and assessment of the impact of these depletions on the outcome of infection in non-human primate models. Here, we present a detailed analysis of the strategies and results of manipulating SIV pathogenesis through in vivo depletions of key immune cells populations. Although each of these methods has its limitations, they have all contributed to our understanding of key pathogenic pathways in HIV/SIV infection.

A basic mathematical model for IL-2-based cancer immunotherapy is proposed and studied. Our analysis shows that the outcome of therapy is mainly determined by three parameters, the relative death rate of CD4+ T cells, the relative death rate of CD8+ T cells, and the dose of IL-2 treatment. Minimal equilibrium tumor size can be reached with a large dose of IL-2 in the case that CD4+ T cells die out. However, in cases where CD4+ and CD8+ T cells persist, the final tumor size is independent of the IL-2 dose and is given by the relative death rate of CD4+ T cells. Two groups of in silico clinical trials show some short-term behaviors of IL-2 treatment. IL-2 administration can slow the proliferation of CD4+ T cells, while high doses for a short period of time over several days transiently increase the population of CD8+ T cells during treatment before it recedes to its equilibrium. IL-2 administration for a short period of time over many days suppresses the tumor population for a longer time before approaching its steady-state levels. This implies that intermittent administration of IL-2 may be a good strategy for controlling tumor size.

The communication between cells and their microenvironment represents an intrinsic and essential attribute that takes place in several biological processes, including tissue homeostasis and tissue repair. Among these interactions, inflammation is certainly a central biological response that occurs through cytokines and the crosstalk with their respective receptors. In particular, the interaction between CCL2 and its main receptor, CCR2, plays a pivotal role in both harmful and protective inflammatory states, including cancer-mediated inflammation. The activation of the CCL2/CCR2 axis was shown to dictate the migration of macrophages with immune-suppressive phenotype and to aggravate the progression of different cancer types. In addition, this interaction mediates metastasis formation, further limiting the potential therapeutic outcome of anti-cancer drugs. Attempts to inhibit pharmacologically the CCL2/CCR2 axis have yet to show its anti-cancer efficacy as a single agent, but it sheds light on its role as a powerful tool to selectively alleviate pro-tumorigenic and anti-repair inflammation. In this review, we will elucidate the role of CCL2/CCR2 axis in promoting cancer inflammation by activating the host pro-tumorigenic phenotype. Moreover, we will provide some insight into the potential therapeutic benefit of targeting the CCL2/CCR2 axis for cancer and inflammation using novel delivery systems, aiming to sensitize non-responders to currently approved immunotherapies and offer new combinatory approaches.

ATP-binding cassette subfamily G member 1 is mostly known as a transporter for intracellular cholesterol efflux, and a number of studies indicate that ABCG1 also functions actively in tumor initiation and progression. This review aimed to provide an overall review of how ABCG1 acts in tumor progression.

A comprehensive searching about ABCG1 and tumor was conducted up to November 2023 using proper keywords through databases including PubMed and Web of Science.

Overall, ABCG1 plays a crucial role in the development of multiple tumorigenesis. ABCG1 enhances tumor-promoting ability through conferring stem-like properties to cancer cells and mediates chemoresistance in multiple cancers. Additionally, ABCG1 may act as a kinase to phosphorylate downstream molecules and induces tumor growth. In tumor microenvironment, ABCG1 plays a substantial role in immunity response through macrophages to create a tumor-favoring circumstance.

High expression of ABCG1 is usually associated with poor prognosis, which means ABCG1 may be a potential biomarker for early diagnosis and prognosis of various cancers. ABCG1-targeted therapy may provide a novel treatment for cancer patients.

Cancer of the colon and rectum (CRC) has been identified among the three most prevalent types of cancer and cancer-related deaths for both sexes. Even though significant progress in surgical and chemotherapeutic techniques has markedly improved disease-free and overall survival rates in contrast to those three decades ago, recent years have seen a stagnation in these improvements. This underscores the need for new therapies aiming to augment patient outcomes. A number of emerging strategies, such as immune checkpoint inhibitors (ICIs) and adoptive cell therapy (ACT), have exhibited promising outcomes not only in preclinical but also in clinical settings. Additionally, a thorough appreciation of the underlying biology has expanded the scope of research into potential therapeutic interventions. For instance, the pivotal role of altered telomere length in early CRC carcinogenesis, leading to chromosomal instability and telomere dysfunction, presents a promising avenue for future treatments. Thus, this review explores the advancements in CRC immunotherapy and telomere-targeted therapies, examining potential synergies and how these novel treatment modalities intersect to potentially enhance each other's efficacy, paving the way for promising future therapeutic advancements.

Cell-cell interaction factors that facilitate the progression of adenoma to sporadic colorectal cancer (CRC) remain unclear, thereby hindering patient survival.

We performed spatial transcriptomics on five early CRC cases, which included adenoma and carcinoma, and one advanced CRC. To elucidate cell-cell interactions within the tumour microenvironment (TME), we investigated the colocalisation network at single-cell resolution using a deep generative model for colocalisation analysis, combined with a single-cell transcriptome, and assessed the clinical significance in CRC patients.

CRC cells colocalised with regulatory T cells (Tregs) at the adenoma-carcinoma interface. At early-stage carcinogenesis, cell-cell interaction inference between colocalised adenoma and cancer epithelial cells and Tregs based on the spatial distribution of single cells highlighted midkine (MDK) as a prominent signalling molecule sent from tumour epithelial cells to Tregs. Interaction between MDK-high CRC cells and SPP1+ macrophages and stromal cells proved to be the mechanism underlying immunosuppression in the TME. Additionally, we identified syndecan4 (SDC4) as a receptor for MDK associated with Treg colocalisation. Finally, clinical analysis using CRC datasets indicated that increased MDK/SDC4 levels correlated with poor overall survival in CRC patients.

MDK is involved in the immune tolerance shown by Tregs to tumour growth. MDK-mediated formation of the TME could be a potential target for early diagnosis and treatment of CRC.

Japan Society for the Promotion of Science (JSPS) Grant-in-Aid for Science Research; OITA Cancer Research Foundation; AMED under Grant Number; Japan Science and Technology Agency (JST); Takeda Science Foundation; The Princess Takamatsu Cancer Research Fund.

Breast cancer is the most common neoplasm worldwide. Viral infections are involved with carcinogenesis, especially those caused by oncogenic Human Papillomavirus (HPV) genotypes. Despite the detection of HPV in breast carcinomas, the virus's activity against this type of cancer remains controversial. HPV infection promotes remodeling of the host's immune response, resulting in an immunosuppressive profile. This study assessed the individual role of HPV oncogenes in the cell line MDA-MB-231 transfected with the E5, E6, and E7 oncogenes and co-cultured with peripheral blood mononuclear cells. Immunophenotyping was conducted to evaluate immune system modulation. There was an increase in CD4+ T cell numbers when compared with non-transfected and transfected MDA-MB-231, especially in the Treg profile. Pro-inflammatory intracellular cytokines, such as IFN-γ, TNF-α, and IL-17, were impaired by transfected cells, and a decrease in the cytolytic activity of the CD8+ and CD56+ lymphocytes was observed in the presence of HPV oncogenes, mainly with E6 and E7. The E6 and E7 oncogenes decrease monocyte expression, activating the expected M1 profile. In the monocytes found, a pro-inflammatory role was observed according to the cytokines released in the supernatant. In conclusion, the MDA-MB-231 cell lineage transfected with HPV oncogenes can downregulate the number and function of lymphocytes and monocytes.

Interleukin-2 (IL-2) exhibits the unique capacity to modulate immune functions, potentially exerting antitumor effects by stimulating immune responses, making it highly promising for immunotherapy. However, the clinical use of recombinant IL-2 protein faces significant limitations due to its short half-life and systemic toxicity. To overcome these challenges and fully exploit IL-2's potential in tumor immunotherapy, this study reports the development of a tumor-activated IL-2 mRNA, delivered via lipid nanoparticles (LNPs). Initially, ionizable lipid U-101 derived nanoparticles (U-101-LNP) were prepared using microfluidic technology. Subsequent in vitro and in vivo delivery tests demonstrated that U-101-LNP achieved more effective transfection than the approved ALC-0315-LNP. Following this, IL-2F mRNAs, encoding fusion proteins comprising IL-2, a linker, and CD25 (IL-2Rα), were designed and synthesized through in vitro transcription. A cleavable linker, consisting of the peptide sequence SGRSEN↓IRTA, was selected for cleavage by matrix metalloproteinase-14 (MMP-14). IL-2F mRNA was then encapsulated in U-101-LNP to create U-101-LNP/IL-2F mRNA complexes. After optimization, assessments of expression efficiency, masking, and release characteristics revealed that IL-2F with linker C4 demonstrated superior performance. Finally, the antitumor activity of IL-2F mRNA was evaluated. The results indicated that U-101-LNP/IL-2F mRNA achieved the strongest antitumor effect, with an inhibition rate of 70.3%. Immunohistochemistry observations revealed significant expressions of IL-2, IFN-γ, and CD8, suggesting an up-regulation of immunomodulation in tumor tissues. This effect could be ascribed to the expression of IL-2F, followed by the cleavage of the linker under the action of MMP-14 in tumor tissue, which sustainably releases IL-2. H&E staining of tissues treated with U-101-LNP/IL-2F mRNA showed no abnormalities. Further evaluations indicated that the U-101-LNP/IL-2F mRNA group maintained proper levels of inflammatory factors without obvious alterations in liver and renal functions. Taken together, the U-101-LNP/IL-2F mRNA formulation demonstrated effective antitumor activity and safety, which suggests potential applicability in clinical immunotherapy.

This retrospective study aimed to investigate the changes in peripheral blood lymphocyte subsets before and after immunotherapy in patients with advanced gastric cancer and their relationship n with the therapeutic efficacy and clinical prognosis.

Peripheral blood lymphocyte subsets, including CD4 + T cells, CD8 + T cells, CD4+/CD8 + ratio, NK cells, Treg cells, and B cells, were collected from 195 patients with advanced gastric cancer who were admitted to the First Hospital of Shanxi Medical University with immunotherapy from January 2020 to October 2021, at the time of diagnosis of advanced gastric cancer, before immunotherapy and after 3 cycles of immunotherapy. T-tests were used to examine the factors influencing the patients' peripheral blood lymphocyte subsets and the changes after immunotherapy. To examine the relationship between lymphocyte subsets and treatment outcomes, ROC curves were plotted using a logistic regression. Kaplan-Meier curve was drawn, and the Log Rank test was carried out to compare the differences in PFS between the different groups. Cox proportional hazards regression model was used to analyze the factors affecting PFS after calibration of other variables.

The proportion of peripheral blood lymphocyte subsets in patients with advanced gastric cancer was affected by age and PD-L1 level. Compared to the baseline, the treatment effective group had higher proportions of CD4 + T cells, a higher CD4+/CD8 + ratio, NK cells and Treg cells, and lower proportions of CD8 + T cells and B cells in the peripheral blood after three cycles of immunotherapy. In the treatment-naive group, there were no significant differences in the lymphocyte subsets. With cut-off values of 30.60% and 18.00%, baseline CD4 + T cell and NK cell ratios were independent predictors of immunotherapy efficacy and PFS. Treg cell ratio, gender, PD-L1 levels, and MMR status all predicted PFS independently.

The proportion of peripheral blood lymphocyte subsets was modified in patients who responded to PD-1 inhibitors. Different lymphocyte subpopulation levels can be used as biomarkers to predict immunotherapy efficacy and clinical prognosis in patients with advanced gastric cancer.

Immunotherapy targeting the toll-like receptor 7 (TLR7) is a promising strategy for cancer treatment. Herein, we describe the design and synthesis of a series of imidazoquinoline-based TLR7 agonists and assess NF-κB pathway activation using HEK-Blue hTLR7 cells to identify the most potent small-molecule TLR7 agonist, SMU-L11 (EC50 = 0.024 ± 0.002 μM). In vitro experiments demonstrated that SMU-L11 specifically activated TLR7, resulting in recruitment of the MyD88 adaptor protein and activation of the NF-κB and MAPK signaling pathways. Moreover, SMU-L11 was found to exert immune-enhancing effects by significantly inducing the secretion of proinflammatory cytokines in murine dendritic cells, macrophages, and human peripheral blood mononuclear cells while promoting M1 macrophage polarization. In vivo studies using a B16-F10 mouse tumor model showed that SMU-L11 significantly enhanced immune cell activation and augmented CD4+ T and CD8+ T-cell proliferation, directly killing tumor cells and inhibiting tumor growth.

Advances in cancer immunotherapy over the last decade have led to the development of several agents that affect immune checkpoints. Inhibitory receptors expressed on T cells that negatively regulate the immune response include cytotoxic T‑lymphocyte antigen 4 (CTLA4) and programmed cell death protein 1 (PD1), which have been studied more than similar receptors. Inhibition of these proteins and other immune checkpoints can stimulate the immune system to attack cancer cells, and prevent the tumor from escaping the immune response. However, the administration of anti-PD1 and anti-CTLA4 antibodies has been associated with adverse inflammatory responses similar to autoimmune diseases. The current review discussed the role of the NF-κB pathway as a tumor promoter, and how it can govern inflammatory responses and affect various immune checkpoints. More precise knowledge about the communication between immune checkpoints and NF-κB pathways could increase the effectiveness of immunotherapy and reduce the adverse effects of checkpoint inhibitor therapy.

Isocitrate dehydrogenase (IDH)-wild-type (WT) high-grade gliomas, especially glioblastomas, are highly aggressive and have an immunosuppressive tumor microenvironment. Although tumor-infiltrating immune cells are known to play a critical role in glioma genesis, their heterogeneity and intercellular interactions remain poorly understood. In this study, we constructed a single-cell transcriptome landscape of immune cells from tumor tissue and matching peripheral blood mononuclear cells (PBMC) from IDH-WT high-grade glioma patients. Our analysis identified two subsets of tumor-associated macrophages (TAM) in tumors with the highest protumorigenesis signatures, highlighting their potential role in glioma progression. We also investigated the T-cell trajectory and identified the aryl hydrocarbon receptor (AHR) as a regulator of T-cell dysfunction, providing a potential target for glioma immunotherapy. We further demonstrated that knockout of AHR decreased chimeric antigen receptor (CAR) T-cell exhaustion and improved CAR T-cell antitumor efficacy both in vitro and in vivo. Finally, we explored intercellular communication mediated by ligand-receptor interactions within the tumor microenvironment and PBMCs and revealed the unique cellular interactions present in the tumor microenvironment. Taken together, our study provides a comprehensive immune landscape of IDH-WT high-grade gliomas and offers potential drug targets for glioma immunotherapy.

Ovarian cancer (OC) is a malignancy associated with poor prognosis and has been linked to regulatory T cells (Tregs) in the immune microenvironment. Nevertheless, the association between Tregs-related genes (TRGs) and OC prognosis remains incompletely understood. The xCell algorithm was used to analyze Tregs scores across multiple cohorts. Weighted gene co-expression network analysis (WGCNA) was utilized to identify potential TRGs and molecular subtypes. Furthermore, we used nine machine learning algorithms to create risk models with prognostic indicators for patients. Reverse transcription-quantitative polymerase chain reaction and immunofluorescence staining were used to demonstrate the immunosuppressive ability of Tregs and the expression of key TRGs in clinical samples. Our study found that higher Tregs scores were significantly correlated with poorer overall survival. Recurrent patients exhibited increased Tregs infiltration and reduced CD8+ T cell. Moreover, molecular subtyping using seven key TRGs revealed that subtype B exhibited higher enrichment of multiple oncogenic pathways and had a worse prognosis. Notably, subtype B exhibited high Tregs levels, suggesting immune suppression. In addition, we validated machine learning-derived prognostic models across multiple platform cohorts to better distinguish patient survival and predict immunotherapy efficacy. Finally, the differential expression of key TRGs was validated using clinical samples. Our study provides novel insights into the role of Tregs in the immune microenvironment of OC. We identified potential therapeutic targets derived from Tregs (CD24, FHL2, GPM6A, HOXD8, NAP1L5, REN, and TOX3) for personalized treatment and created a machining learning-based prognostic model for OC patients, which could be useful in clinical practice.

Double-stranded DNA (dsDNA) in the cytoplasm of eukaryotic cells is abnormal and typically indicates the presence of pathogens or mislocalized self-DNA. Multiple sensors detect cytosolic dsDNA and trigger robust immune responses via activation of type I interferons. Several cancer immunotherapy treatments also activate cytosolic nucleic acid sensing pathways, including oncolytic viruses, nucleic acid-based cancer vaccines, and pharmacological agonists. We report here that cytosolic dsDNA introduced into malignant cells can robustly upregulate expression of CCL22, a chemokine responsible for the recruitment of regulatory T cells (Tregs). Tregs in the tumor microenvironment are thought to repress anti-tumor immune responses and contribute to tumor immune evasion. Surprisingly, we found that CCL22 upregulation by dsDNA was mediated primarily by interferon regulatory factor 3 (IRF3), a key transcription factor that activates type I interferons. This finding was unexpected given previous reports that type I interferon alpha (IFN-α) inhibits CCL22 and that IRF3 is associated with strong anti-tumor immune responses, not Treg recruitment. We also found that CCL22 upregulation by dsDNA occurred concurrently with type I interferon beta (IFN-β) upregulation. IRF3 is one of two transcription factors downstream of the STimulator of INterferon Genes (STING), a hub adaptor protein through which multiple dsDNA sensors transmit their signals. The other transcription factor downstream of STING, NF-κB, has been reported to regulate CCL22 expression in other contexts, and NF-κB has also been associated with multiple pro-tumor functions, including Treg recruitment. However, we found that NF-κB in the context of activation by cytosolic dsDNA contributed minimally to CCL22 upregulation compared with IRF3. Lastly, we observed that two strains of the same cell line differed profoundly in their capacity to upregulate CCL22 and IFN-β in response to dsDNA, despite apparent STING activation in both cell lines. This finding suggests that during tumor evolution, cells can acquire, or lose, the ability to upregulate CCL22. This study adds to our understanding of factors that may modulate immune activation in response to cytosolic DNA and has implications for immunotherapy strategies that activate DNA sensing pathways in cancer cells.