The exploration of therapeutic targets in neuroblastoma (NB), which needs more attempts, can benefit patients with high-risk NB. Based on metabolomic and transcriptomic data in mediastinal NB tissues, we found that the content of long-chain acylcarnitine (LCAC) was increased and positively associated with leptin expression in advanced NB. Leptin over-expression forced naïve CD4+ T cells to differentiate into Treg cells instead of Th17 cells, which benefited from NB cell proliferation, migration, and drug resistance. Mechanically, leptin in NB cells blunted the activity of carnitine palmitoyltransferase 2 (CPT2), the key enzyme for LCAC catabolism, by inhibiting sirtuin 3-mediated CPT2 deacetylation, which depresses oxidative phosphorylation (OXPHOS) for energy supply and increases lactic acid (LA) production from glycolysis to modulate CD4+ T cell differentiation. These findings highlight that excess leptin contributes to lipid metabolism dysfunction in NB cells and subsequently misdirects CD4+ T cell differentiation in tumor micro-environment (TME), indicating that targeting leptin could be a therapeutic strategy for retarding NB progression.

In recent years, the discovery of IL-12 family cytokines, which includes IL-12, IL-23, IL-27, IL-35, and IL-39, whose biological functions directly or indirectly affect various autoimmune diseases. In autoimmune diseases, IL-12 family cytokines are aberrantly expressed to varying degrees. These cytokines utilize shared subunits to influence T-cell activation and differentiation, thereby regulating the balance of T-cell subsets, which profoundly impacts the onset and progression of autoimmune diseases. In such conditions, IL-12 family members are aberrantly expressed to varying degrees. By exploring their immunomodulatory functions, researchers have identified varying therapeutic potentials for each member. This review examines the physiological functions of the major IL-12 family members and their interactions, discusses their roles in several autoimmune diseases, and summarizes the progress of clinical studies involving monoclonal antibodies targeting IL-12 and IL-23 subunits currently available for treatment.

The treatment landscape of non-small-cell lung cancer (NSCLC) is evolving rapidly, driven by advances in the development of targeted agents and immunotherapies. Despite this progress, some patients have suboptimal responses to treatment, highlighting the need for new therapeutic strategies. In the past decade, the important role of the tumour microenvironment (TME) in NSCLC progression, metastatic dissemination and response to treatment has become increasingly evident. Understanding the complexity of the TME and its interactions with NSCLC can propel efforts to improve current treatment modalities, overcome resistance and develop new treatments, which will ultimately improve the outcomes of patients. In this Review, we provide a comprehensive view of the NSCLC TME, examining its components and highlighting distinct archetypes characterized by spatial niches within and surrounding tumour nests, which form complex neighbourhoods. Next, we explore the interactions within these components, focusing on how inflammation and immunosuppression shape the dynamics of the NSCLC TME. We also address the emerging influences of patient-related factors, such as ageing, sex and health disparities, on the NSCLC-TME crosstalk. Finally, we discuss how various therapeutic strategies interact with and are influenced by the TME in NSCLC. Overall, we emphasize the interconnectedness of these elements and how they influence therapeutic outcomes and tumour progression.

Regulatory T cells (Tregs), previously referred to as suppressor T cells, represent a distinct subset of CD4+ T cells that are uniquely specialized for immune suppression. They are characterized by the constitutive expression of the transcription factor FoxP3 in their nuclei, along with CD25 (the IL-2 receptor α-chain) and CTLA-4 on their cell surface. Tregs not only restrict natural killer cell-mediated cytotoxicity but also inhibit the proliferation of CD4+ and CD8+ T-cells and suppress interferon-γ secretion by immune cells, ultimately impairing an effective antitumor immune response. Treg cells are widely recognized as a significant barrier to the effectiveness of tumor immunotherapy in clinical settings. Extensive research has consistently shown that Treg cells play a pivotal role in facilitating tumor initiation and progression. Conversely, the depletion of Treg cells has been linked to a marked delay in tumor growth and development.

The tumor microenvironment (TME) plays a crucial role in cancer development and spreading being considered as "the dark side of the tumor". Within this term tumor cells, immune components, supporting cells, extracellular matrix and a myriad of bioactive molecules that synergistically promote tumor development and therapeutic resistance, are included. Recent findings revealed the profound impacts of TME on cancer development, serving as physical support, critical mediator and biodynamic matrix in cancer evolution, immune modulation, and treatment outcomes. TME targeting strategies built on vasculature, immune checkpoints, and immuno-cell therapies, have paved the way for revolutionary clinical interventions. On this basis, the relevance of pre-clinical and clinical investigations has rapidly become fundamental for implementing novel therapeutical strategies breaking cell-cell and cell -mediators' interactions between TME components and tumor cells. This review summarizes the key players in the breast and pancreatic TME, elucidating the intricate interactions among cancer cells and their essential role for cancer progression and therapeutic resistance. Different tumors such breast and pancreatic cancer have both different and similar stroma features, that might affect therapeutic strategies. Therefore, this review aims to comprehensively evaluate recent findings for refining breast and pancreatic cancer therapies and improve patient prognoses by exploiting the TME's complexity in the next future.

Gastric cancer (GC) remains a major challenge due to its high mortality and morbidity, despite extensive research. Dysregulated host immunity plays a critical role in carcinogenesis, particularly among susceptible cohorts. In the gastric mucosa of GC patients, a reduction in IL-34 and TAM1, accompanied by an increase in TAM2 via M-CSF, enhances Th2 cell function, reduces pro-inflammatory activity, and elevates anti-inflammatory responses. Consequently, TAM2 acts in both paracrine and autocrine manners to polarize and boost TAM2, creating a tumour-favourable microenvironment that supports GC progression. High levels of TAM2, observed during advanced GC stages, suppress gastric IL-34 production, further promoting GC development. In contrast, IL-35, a cytokine involved in immune regulation and suppression, is produced by activated T cells and/or B cells in the affected gastric mucosa. Persistent H. pylori infection in GC tissues is associated with significant infiltration of IL-35-producing B cells and regulatory T cells (Tregs), which enhance the immunosuppressive and pro-tumour microenvironment by disrupting the local immune balance. Upregulated mucosal IL-35 promotes the polarization of TAM2 and Tregs while suppressing TAM1 cells, fostering a tumour-friendly environment that allows transformed gastric mucosal cells to evade immune surveillance, particularly in chronic H. pylori-infected patients. This cascade enhances proliferation and invasion while suppressing differentiation and apoptosis of GC cells. Together, the differential regulation of these cytokines creates an environment that supports cancer progression and resistance to therapy. Targeting the IL-34 and IL-35 pathways may offer a novel therapeutic strategy for improving outcomes in GC patients.

Lymphoma is a malignancy of the immune system, which originates from lymphatic tissues and lymph nodes. Diffuse large B‑cell lymphoma (DLBCL) is a common type of non‑Hodgkin lymphoma, occurring in 30‑40% of all cases, which has persistent clinical challenges. The treatment of DLBCL is challenging due to its diverse genetic and biological characteristics and complex clinical physiology. Despite advancements in overall prognosis, 20‑25% of patients continue to experience relapse and 10‑15% of patients experience refractory disease. Vitamin C is a water‑soluble vitamin with antioxidant properties and notable pharmacological activity, with potential applications in cancer therapy. Pharmacological doses of vitamin C (1‑4 g/kg) can induce apoptosis in malignant cells by inhibiting and/or reversing gene mutations that are associated with hematological malignancies. For example, 10‑25% of patients with myeloid malignancies have tet methylcytosine dioxygenase 2 (TET2) gene mutations and vitamin C can regulate blood stem cell frequency and leukemia production by enhancing TET2 function. Consequently, pharmacological doses of vitamin C can inhibit the development and progression of hematological malignancies. Therefore, the present review aimed to investigate the role of vitamin C in the pathophysiology and treatment of DLBCL, whilst highlighting the potential challenges and future perspectives.

Radiotherapy (RT) induced abscopal effect has garnered substantial attention, nevertheless, it is rarely observed in clinics, due to the tumor hypoxia-related radioresistance, inadequate immune stimulation, and immunosuppressive tumor microenvironment. Herein, we construct a radiotherapy-immunomodulated nanoplatform (THUNDER), which synergizes with RT and greatly triggers the generation of both hypoxic and normoxic tumor cells-derived tumor-associated antigens (TAAs), resulting in robust abscopal effect and sustained immune memory. THUNDER exhibits prolonged blood circulation and high tumor retention capacity. When combined with RT, THUNDER effectively destructs both hypoxic and normoxic tumor cells, facilitating the substantial release of TAAs from both cell types, which further promotes the maturation of dendritic cells (DCs), thus forming powerful immune stimulation and initiating systemic anti-tumor immunity. In murine models, the combination of THUNDER and RT efficiently suppresses the growth of triple-negative breast cancer. In addition, the further combination with PD-L1 blockade yields noteworthy suppression of distant metastasis and tumor recurrence, resulting in a 5.2-fold augmentation in CD8+ T lymphocytes within distant tumors and a 2.8-fold increase in effector memory T cells in the spleen. In conclusion, the radiotherapy-immunomodulated nanoplatform presents an effective strategy for combating tumor metastases and recurrence by eliciting both hypoxic and normoxic TAAs, offering a significant avenue for radioimmunotherapy.

Cancer immunotherapy has transformed oncology by harnessing the immune system to specifically target cancer cells, offering reduced systemic toxicity compared to traditional therapies. This review highlights key strategies, including adoptive cell transfer (ACT), immune checkpoint inhibitors, oncolytic viral (OV) therapy, monoclonal antibodies (mAbs), and mRNA-based vaccines. ACT reinfuses enhanced immune cells like tumor-infiltrating lymphocytes (TILs) to combat refractory cancers, while checkpoint inhibitors (eg, PD-1 and CTLA-4 blockers) restore T-cell activity. OV therapy uses engineered viruses (eg, T-VEC) to selectively lyse cancer cells, and advanced mAbs improve targeting precision. mRNA vaccines introduce tumor-specific antigens to trigger robust immune responses. Despite significant progress, challenges like immune-related side effects, high costs, and immunosuppressive tumor microenvironments persist. This review underscores the need for combination strategies and precision medicine to overcome these barriers and maximize the potential of immunotherapy in personalized cancer treatment.

Gut microbiota can significantly alter the risk or progression of cancer by maintaining gut immune system homeostasis. However, the exact mechanism by which the gut microbiota and its metabolites influence colorectal tumorigenesis is unclear.

The roles of tryptophan metabolite indole-3-acetic acid (IAA) in inflammation and tumor development were investigated in dextran sodium sulfate (DSS) and azoxymethane (AOM)-DSS mouse models with or without IAA supplementation and with or without Lactobacillus reuteri-produced IAA. Pregnane X receptor (PXR) knockout (KO) mice and aryl hydrocarbon receptor KO mice were used to explore the mechanism by which IAA regulates interleukin (IL)-35 expression. IL-35+ immune cells were stimulated in vitro and analyzed by flow cytometry. Additionally, metabolites were analyzed by liquid chromatography-mass spectrometry.

We found that IAA, a metabolite of tryptophan produced in the gut by L. reuteri, can inhibit the development of colitis by inducing IL-35 expression in immunosuppressant cells. HuREG3αIECtg mice had high levels of intestinal microbiota-derived IAA, and these mice were resistant to AOM-DSS-induced cancer. Patients with colorectal cancer also had low peripheral blood levels of IAA. Further studies revealed that IAA-producing L. reuteri alleviated colitis symptoms and inhibited colon tumors by inducing macrophages, T cells, and B cells to produce IL-35. Finally, PXR KO completely abolished the effects of IAA on immune cells.

We demonstrate that gut microbiota-derived IAA can improve the precancerous colon inflammatory environment through IL-35, thereby inhibiting tumorigenesis, suggesting that IAA may be a preventive factor for colitis-related cancers.

The relationship between immune cells and colorectal cancer (CRC) development has been extensively studied; however, the mediating role of gut microbiota in this relationship remains poorly understood.

We utilized summary data from genome-wide association studies (GWAS) to analyze 731 immune cell phenotypes, 473 gut microbiota, and CRC-related data. A two-step mediation analysis was employed to identify mediating gut microbiota. The primary analysis method was inverse variance weighting (IVW), supplemented by MR-Egger, simple mode, weighted median, and weighted mode analyses. Robustness of the results was ensured through systematic sensitivity analyses.

Our analysis identified 13 immune cell phenotypes significantly associated with CRC, including 10 protective factors and 3 risk factors. Additionally, 13 gut microbiota showed significant associations with CRC, comprising 8 protective factors and 5 risk factors. Mediation analysis revealed that 4-gut microbiota (1 order, 1 family, 1 genus, and 1 unclassified) mediated the relationship between immune cells and CRC. For instance, unclassified CAG - 977 mediated the effects of FSC-A on NK and NKT %lymphocyte on CRC risk, with mediation proportions of 11% and 12.3%, respectively. Notably, 22.3% of the protective effect of EM CD8br %CD8br on CRC was mediated through order Francisellales.

This study provides evidence for a potential causal relationship between immune cells, gut microbiota, and CRC, highlighting the mediating role of specific gut microbiota. These findings offer new insights into the pathogenesis of CRC and may inform future therapeutic strategies.

Colorectal cancer (CRC) is among the most prevalent and lethal cancers globally, accounting for approximately 10% of all cancer cases and deaths. Regulatory T (Treg) cells, which accumulate in CRC tissue, suppress anti-tumor immune responses and facilitate tumor progression. This review discusses Treg cell origins and functions, along with the mechanisms by which Tregs influence CRC development. In addition, we highlight therapeutic strategies targeting Tregs-such as immune checkpoint inhibitors and combinatorial approaches-to enhance effector T cell responses. A deeper understanding of Treg-mediated immunosuppression in CRC may inform the design of more effective immunotherapies and precision medicine strategies.

Regulatory T cell (Treg) heterogeneity exists in lymphoid and non-lymphoid tissues, but we have limited understanding of context-dependent functions and spatiotemporal regulators of heterogenous Treg states, especially during perinatal life when immune tolerance is established. Here, we revealed that the class III PI3K Vps34 orchestrates effector Treg (eTreg) transitional heterogeneity during perinatal life. We found that loss of Vps34 reduced terminal eTreg accumulation in lymphoid tissues, associated with decreased Treg generation in non-lymphoid tissues and development of an early-onset autoimmune-like disease. After perinatal life, Vps34-deficient eTreg accumulation was further impaired due to reduced cell survival, highlighting temporal regulation of eTreg heterogeneity and maintenance by Vps34. Accordingly, inhibition of Vps34 in mature Tregs disrupted immune homeostasis but boosted anti-tumor immunity. Mechanistically, multiomics profiling approaches uncovered that Vps34-orchestrated transcriptional and epigenetic remodeling promotes terminal eTreg programming. Further, via genetic deletion of the Vps34-interacting proteins Atg14 or Uvrag in Tregs, we established that Atg14 but not Uvrag was required for the overall survival, but not terminal differentiation, of eTregs, suggesting that autophagy but not endocytosis partly contributed to Vps34-dependent effects. Accordingly, mice with Treg-specific loss of Atg14, but not Uvrag, had moderately disrupted immune homeostasis and reduced tumor growth, with Vps34- or Atg14-dependent gene signatures also being elevated in intratumoral Tregs from human cancer patients. Collectively, our study reveals distinct Vps34-orchestrated signaling events that regulate eTreg heterogeneity and functional adaptation and the pathophysiological consequences on autoimmunity versus anti-tumor immunity.

CD8 T cells play a critical role in antitumor immunity. However, over time, they often become dysfunctional or exhausted and ultimately fail to control tumor growth. To effectively harness CD8 T cells for cancer immunotherapy, a detailed understanding of the mechanisms that govern their differentiation and function is crucial. This review summarizes our current knowledge of the molecular pathways that regulate CD8 T cell heterogeneity and function in chronic infection and cancer and outlines how T cells respond to therapeutic checkpoint blockade. We explore how T cell-intrinsic and -extrinsic factors influence CD8 T cell differentiation, fate choices, and functional states and ultimately dictate their response to therapy. Identifying cells that orchestrate long-term antitumor immunity and understanding the mechanisms that govern their development and persistence are critical steps toward improving cancer immunotherapy.

As immunosuppressive cells, Regulatory T cells (Tregs) exert their influence on tumor immune escape within the tumor microenvironment (TME) by effectively suppressing the activity of other immune cells, thereby significantly impeding the anti-tumor immune response. In recent years, the metabolic characteristics of Tregs have become a focus of research, especially the important role of lipid metabolism in maintaining the function of Tregs. Consequently, targeted interventions aimed at modulating lipid metabolism in Tregs have been recognized as an innovative and promising approach to enhance the effectiveness of tumor immunotherapy. This review presents a comprehensive overview of the pivotal role of lipid metabolism in regulating the function of Tregs, with a specific focus on targeting Tregs lipid metabolism as an innovative approach to augment anti-tumor immune responses. Furthermore, we discuss potential opportunities and challenges associated with this strategy, aiming to provide novel insights for enhancing the efficacy of cancer immunotherapy.

Cutaneous melanoma (CM) poses a therapeutic challenge due to its aggressive nature and often limited response to conventional treatments. Exploring novel therapeutic targets is essential, and natural compounds have emerged as potential candidates. This study aimed to elucidate the impact of curcumin, a natural compound known for its anti-inflammatory, antioxidant, and anti-tumor properties, on metastatic melanoma cells, focusing on the purinergic system and immune responses. Human melanoma cell line SK-Mel-28 were exposed to different curcumin concentrations for either 6 or 24 h, after which we assessed components related to the purinergic system and the inflammatory cascade. Using RT-qPCR, we assessed the gene expression of CD39 and CD73 ectonucleotidases, as well as adenosine deaminase (ADA). Curcumin effectively downregulated CD39, CD73, and ADA gene expression. Flow cytometry analysis revealed that curcumin significantly reduced CD39 and CD73 protein expression at specific concentrations. Moreover, the A2A receptor's protein expression decreased across all concentrations. Enzymatic activity assays demonstrated that curcumin modulated CD39, CD73, and ADA activities, with effects dependent on concentration and duration of treatment. Extracellular ATP levels increased after 24 h of curcumin treatment, emphasizing its role in modulating hydrolytic activity. Curcumin also displayed anti-inflammatory properties by reducing NLRP3 gene expression and impacting the levels of key inflammatory cytokines. In conclusion, this study unveils the potential of curcumin as a promising adjuvant in CM treatment. Curcumin modulates the expression and activity of crucial components of the purinergic system and exhibits anti-inflammatory effects, indicating its potential therapeutic role in combating CM. These findings underscore curcumin's promise and warrant further investigation in preclinical and clinical settings for melanoma management.

Regulatory T cells (Tregs) play an immunosuppressive role in tumor microenvironment (TME) in various of cancer types. However, how different Treg subsets influence and effect on head and neck squamous cell carcinoma (HNSCC) remain unclear. Here, using single-cell RNA sequencing (scRNA-seq), we identified an IL1R2+Treg subset which promoted the progression of HNSCC. Via tissue microassay (TMA) and enzyme-linked immunosorbent assay (ELISA), we verified the clinical diagnostic value of the IL1R2+Treg and soluble IL1R2 (sIL1R2). In addition, we constructed tumor-bearing mouse models to explore the antitumor effects of combined targeting IL1R2 and CTLA4. For mechanism, we found IL-1β promoted the expression of IL1R2 and CTLA4 in Tregs, and upregulated CTLA4 though NR4A1 translocation. These results revealed that IL1R2+Treg and serum IL1R2 level had potential diagnostic and prognostic value of HNSCC and combined targeting of IL1R2 and CTLA4 might be an effective strategy to inhibit tumor progression.

Gliomas are the most prevalent malignant tumors in the adult central nervous system (CNS). Glioblastoma (GBM) accounts for approximately 60-70% of primary gliomas. It is a great challenge to human health because of its high degree of malignancy, rapid progression, short survival time, and susceptibility to recurrence. Owing to the specificity of the CNS, the glioma microenvironment often contains numerous glial cells. Astrocytes are most widely distributed in the human brain and form reactive astrocyte proliferation regions around glioma tissue. In addition, astrocytes are activated under pathological conditions and regulate tumor and microenvironmental cells through cell-to-cell contact or the secretion of active substances. Therefore, astrocytes have attracted attention as important components of the glioma microenvironment. Here, we focus on the mechanisms of reactive astrocyte activation under glioma conditions, their contribution to the mechanisms of glioma genesis and progression, and their potential value as targets for clinical intervention in gliomas.

Chimeric antigen receptor (CAR) T-cell therapy has shown remarkable efficacy in treating hematological malignancies and is expanding into other indications such as autoimmune diseases, fibrosis, aging and viral infection. However, clinical challenges persist in treating solid tumors, including physical barriers, tumor heterogeneity, poor in vivo persistence, and T-cell exhaustion, all of which hinder therapeutic efficacy. This review focuses on the critical role of tonic signaling in CAR-T therapy. Tonic signaling is a low-level constitutive signaling occurring in both natural and engineered antigen receptors without antigen stimulation. It plays a pivotal role in regulating immune cell homeostasis, exhaustion, persistence, and effector functions. The "Peak Theory" suggests an optimal level of tonic signaling for CAR-T function: while weak tonic signaling may result in poor proliferation and persistence, excessively strong signaling can cause T cell exhaustion. This review also summarizes the recent progress in mechanisms underlying the tonic signaling and strategies to fine-tune the CAR tonic signaling. By understanding and precisely modulating tonic signaling, the efficacy of CAR-T therapies can be further optimized, offering new avenues for treatment across a broader spectrum of diseases. These findings have implications beyond CAR-T cells, potentially impacting other engineered immune cell therapies such as CAR-NK and CAR-M.

This review explores the emerging role of T cell exhaustion in allergic diseases and allergen immunotherapy (AIT). It aims to synthesize current knowledge on the mechanisms of T cell exhaustion, evaluate its potential involvement in allergic inflammation, and assess its implications as a novel biomarker for predicting and monitoring AIT efficacy.

Recent studies highlight that T cell exhaustion, characterized by co-expression of inhibitory receptors (e.g., PD-1, CTLA-4, TIM-3), diminished cytokine production, and altered transcriptional profiles, may suppress type 2 inflammation in allergic diseases. In allergic asthma, exhausted CD4 + T cells exhibit upregulated inhibitory receptors, correlating with reduced IgE levels and airway hyperreactivity. During AIT, prolonged high-dose allergen exposure drives allergen-specific Th2 and T follicular helper (Tfh) cell exhaustion, potentially contributing to immune tolerance. Notably, clinical improvements in AIT correlate with depletion of allergen-specific Th2 cells and persistent expression of exhaustion markers (e.g., PD-1, CTLA-4) during maintenance phases. Blockade of inhibitory receptors (e.g., PD-1) enhances T cell activation, underscoring their dual regulatory role in allergy. T cell exhaustion represents a double-edged sword in allergy: it may dampen pathological inflammation in allergic diseases while serving as a mechanism for AIT-induced tolerance. The co-expression of inhibitory receptors on allergen-specific T cells emerges as a promising biomarker for AIT efficacy. Future research should clarify the transcriptional and metabolic drivers of exhaustion in allergy, validate its role across diverse allergic conditions, and optimize strategies to harness T cell exhaustion for durable immune tolerance. These insights could revolutionize therapeutic approaches and biomarker development in allergy management.

Breast cancer is a leading malignancy in women, with mortality disparities between developed and underdeveloped regions. Accumulating evidence suggests that the competitive endogenous RNA (ceRNA) regulatory networks play paramount roles in various human cancers. However, the complexity and behavior characteristics of the ceRNA network in breast cancer progression have not been fully elucidated. The expression profiles of three RNAs (long non-coding RNAs [lncRNAs], microRNAs [miRNAs], and mRNAs) were extracted from breast cancer and adjacent samples were sourced from the TCGA database. The SLC26A4-AS1- hsa-miR-19a-3p-NTRK2 ceRNA network related to the prognosis of breast cancer was obtained by performing bioinformatics analysis. Importantly, we identified the SLC26A4-AS1/NTRK2 axis within the ceRNA network through correlation analysis and found it to be a potential prognostic model in clinical outcomes based on Cox regression analysis. Moreover, methylation analysis suggests that the aberrant downregulation of the SLC26A4-AS1/NTRK2 axis might be attributed to hypermethylation at specific sites. Immune infiltration analysis indicates that the SLC26A4-AS1/NTRK2 axis may have implications for the alteration of the tumor immune microenvironment and the emergence and progression of immune evasion in breast cancer. Finally, we validated the expression of SLC26A4-AS1-hsa-miR-19a-3p-NTRK2 in breast cancer cell lines. In summary, the present study posits that the SLC26A4-AS1/NTRK2 axis, based on the ceRNA network, could be a novel and significant prognostic factor associated with breast cancer diagnosis and outcomes.

The tumor microenvironment (TME) contains tumor cells, surrounding cells, and secreted factors. It provides a favorable environment for the maintenance of cancer stem cells (CSCs), the spread of cancer cells to metastatic sites, angiogenesis, and apoptosis, as well as the growth, proliferation, invasion, and drug resistance of cancer cells. Cancer cells rely on the activation of oncogenes, inactivation of tumor suppressors, and the support of a normal stroma for their growth, proliferation, and survival, all of which are provided by the TME. The TME is characterized by the presence of various cells, including cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), CD8 + cytotoxic T cells (CTLs), regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), mesenchymal stem cells (MSCs), endothelial cells, adipocytes, and neuroendocrine (NE) cells. The high expression of inflammatory cytokines, angiogenic factors, and anti-apoptotic factors, as well as drug resistance mechanisms in the TME, contributes to the poor therapeutic efficacy of anticancer drugs and tumor progression. Hence, this review describes the mechanisms through which the TME is involved in apoptosis, angiogenesis, metastasis, and drug resistance in tumor cells.

Background and Objective: The discovery of novel molecular biomarkers via next-generation sequencing technologies has revolutionized how glioblastomas (GBMs) are classified nowadays. This has resulted in more precise diagnostic, prognostic, and therapeutic approaches to address this malignancy. The present work examines the applications of single-cell RNA sequencing (scRNA-seq) in GBM, focusing on its potential to address tumor complexity and therapeutic resistance and improve patient outcomes. Methods: A scoping review of original studies published between 2009 and 2024 was conducted using the PUBMED and EMBASE databases. Studies in English or Spanish related to single-cell analysis and GBM were included. Key Findings: The database search yielded 453 publications. Themes related to scRNA-seq applied for the diagnosis, prognosis, treatment, and understanding of the cancer biology of GBM were used as criteria for article selection. Of the 24 studies that were included in the review, 11 focused on the tumor microenvironment and cell subpopulations in GBM samples, 5 investigated the use of sequencing to elucidate the GBM cancer biology, 3 examined disease prognosis using sequencing models, 3 applied translational research through scRNA-seq, and 2 addressed treatment-related problems in GBM elucidated by scRNA-seq. Conclusions: This scoping review explored the various clinical applications of scRNA-seq technologies in approaching GBM. The findings highlight the utility of this technology in unraveling the complex cellular and immune landscapes of GBM, paving the way for improved diagnosis and personalized treatments. This cutting-edge approach might strengthen treatment strategies against tumor progression and recurrence, setting the stage for multi-targeted interventions that could significantly improve outcomes for patients with aggressive, treatment-resistant GBMs.

Epstein-Barr virus (EBV), the first identified human tumor virus, significantly influences the immune microenvironment of associated cancers. EBV-induced expression of viral antigens by tumor cells triggers immune recognition and elicits a pro-inflammatory response. While mild inflammation may help eliminate malignant cells, intense inflammation can accelerate tumor progression. Moreover, EBV can establish lifelong latency in human hosts, characterized by low immunogenicity of its proteins and noncoding RNAs. This enables tumor cells to evade immune detection and impair immune cell function, disrupting immune homeostasis. Consequently, EBV-associated malignancies pose a considerable public health challenge globally, often complicating the prognosis of cancer patients under conventional treatment. With deeper research into the oncogenic expressions and mechanisms of EBV, novel targeted therapies against EBV are gaining prominence. This review discusses recent advancements in understanding how EBV helps tumor cells evade immune surveillance and induce immune dysfunction. It also examines the clinical potential of targeting EBV-associated tumors, providing fresh perspectives on the mechanisms and therapeutic strategies for these cancers.

Cytokines influence cell-fate decisions of naïve lymphocytes and determine outcome of immune responses by transducing signals that regulate the initiation, intensity and duration of immune responses. However, aberrant regulation of physiological levels of cytokines contribute to the development of autoimmune and other inflammatory diseases. The Interleukin 6 (IL-6)/IL-12 superfamily of cytokines have a profound influence on all aspects of host immunity and our focus in this review is on the signaling pathways that mediate their functions, with emphasis on how this enigmatic family of cytokines promote or suppress inflammation depending on the physiological context. We also describe regulatory lymphocyte populations that suppress neuroinflammatory diseases by producing cytokines, such as IL-27 (i27-Breg) or IL-35 (i35-Breg and iTR35). We conclude with emerging immunotherapies like STAT-specific Nanobodies, Exosomes and Breg therapy that ameliorate CNS autoimmune diseases in preclinical studies.

Lack of sustained response to oncogenic Kras (Kras*) inhibition in preclinical models and patients with pancreatic ductal adenocarcinoma (PDAC) emphasizes the need to identify impactful synergistic combination therapies to achieve robust clinical benefit. Kras* targeting results in an influx of global T cell infiltrates including Tregs, effector CD8 + T cells and exhausted CD8 + T cells expressing several immune checkpoint molecules in PDAC. Here, we probe whether the T cell influx induced by diverse Kras* inhibitors open a therapeutic window to target the adaptive immune response in PDAC. We show a specific synergy of anti-CTLA4 immune checkpoint blockade with Kras* targeting primed by Kras G12D allele specific inhibitor, MRTX1133 and multi-selective pan-RAS inhibitor, RMC-6236, both currently in clinical testing phase. In contrast, attempted therapeutic combination following Kras* targeting with multiple checkpoint inhibitors, including anti-PD1, anti-Tim3, anti-Lag3, anti-Vista and anti-4-1BB agonist antibody failed due to compensatory mechanisms mediated by other checkpoints on exhausted CD8 + T cells. Anti-CTLA4 therapy in Kras* targeted PDAC transcriptionally reprograms effector T regs to a naïve phenotype, reverses CD8 + T cell exhaustion and is associated with recruitment of tertiary lymphoid structures (TLS) containing interferon (IFN)-stimulated/ activated B cells and germinal center B cells to enable immunotherapy efficacy and overcome resistance with long-term survival. Single cell ATAC sequencing analysis revealed that transcriptional reprogramming of Tregs is epigenetically regulated by downregulation of AP-1 family of transcription factors including Fos, Fos-b, Jun-b, Jun-d in the IL-35 promoter region. This study reveals an actionable vulnerability in the adaptive immune response in Kras* targeted PDAC with important clinical implications.

Regulatory T (Treg) cells are a specialized CD4+ T cell lineage with essential anti-inflammatory functions. Analysis of Treg cell adaptations to non-lymphoid tissues that enable their specialized immunosuppressive and tissue-supportive functions raises questions about the underlying mechanisms of these adaptations and whether they represent stable differentiation or reversible activation states. Here, we characterize distinct colonic effector Treg cell transcriptional programs. Attenuated T cell receptor (TCR) signaling and acquisition of substantial TCR-independent functionality seems to facilitate the terminal differentiation of a population of colonic effector Treg cells that are distinguished by stable expression of the immunomodulatory cytokine IL-10. Functional studies show that this subset of effector Treg cells, but not their expression of IL-10, is indispensable for colonic health. These findings identify core features of the terminal differentiation of effector Treg cells in non-lymphoid tissues and their function.

Immunotherapy has improved the survival rate of patients with head and neck squamous cell carcinoma (HNSCC), but less than 20 % of them have a durable response to these treatments. Excessive local recurrence and lymph node metastasis ultimately lead to death, making the 5-year survival rate of HNSCC still not optimistic. Cell metabolism has become a key determinant of the viability and function of cancer cells and immune cells. In order to maintain the enormous anabolic demand, tumor cells choose a specialized metabolism different from non-transformed somatic cells, leading to changes in the tumor microenvironment (TME). In recent years, our understanding of immune cell metabolism and cancer cell metabolism has gradually increased, and we have begun to explore the interaction between cancer cell metabolism and immune cell metabolism in a way which is meaningful for treatment. Understanding the different metabolic requirements of different cells that constitute the immune response to HNSCC is beneficial for revealing metabolic heterogeneity and plasticity, thereby enhancing the effect of immunotherapy. In this review, we have concluded that the relevant metabolic processes that affect the function of immune cells in HNSCC TME and proposed our own opinions and prospects on how to use metabolic intervention to enhance anti-tumor immune responses.

Neuroblastoma (NB) is an immunologically "cold" tumor with poor or no inflamed substrates as most of solid pediatric tumors (SPT). Consistent data indicate that NB tumor microenvironment (TME) is dominated by myeloid cells, with little (but variable) T cell infiltration. The obstacles to lymphocyte infiltration and to their anti-tumor activity are due to different tumor immune evasion strategies, including loss of HLA Class I molecules, high expression of immune checkpoint molecular ligands leading to exhaustion of T effector (and NK) cells, induction of T regulatory, myeloid and stromal cells and secretion of immunosuppressive mediators. In odds with adult solid tumors, NB displays weak immunogenicity caused by intrinsic low mutational burden and scant expression of neoepitopes in the context of MHC-class I antigens which, in turn, are particularly poorly expressed on NB cells, thus inducing low anti-tumor T cell responses. In addition, NB is generated from embryonal cells and is the result of transcriptional abnormalities and not of the accumulation of genetic mutations over time, thus further explaining the low immunogenicity. The poor expression of immunogenic molecules on tumor cells is associated with the high production of immunosuppressive factors which further downregulate lymphocyte infiltration and activity, thus explaining the limited efficacy of new drugs in NB, as immune checkpoint inhibitors. This review is focused on examining the role of T effector and regulatory cells infiltrating TME of NB, taking into account their repertoire, phenotype, function, plasticity and, importantly, predictive value for defining novel targets for therapy.

Post-translational modifications such as SUMOylation are crucial for the functionality and signal transduction of a diverse array of proteins. Analogous to ubiquitination, SUMOylation has garnered significant attention from researchers and has been implicated in the pathogenesis of various human diseases in recent years, such as cancer, neurological lesions, cardiovascular diseases, diabetes mellitus, and so on. The pathogenesis of diabetes, particularly type 1 and type 2 diabetes, has been closely associated with immune dysfunction, which constitutes the primary focus of this review. This review will elucidate the process of SUMOylation and its impact on diabetes mellitus development and associated complications, focusing on its regulatory effects on the immune microenvironment. This article summarizes various signaling pathways at both cellular and molecular levels that are implicated in these processes. Furthermore, it proposes potential new targets for drug development aimed at the prevention and treatment of diabetes mellitus based on insights gained from the SUMOylation process.

Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment for aggressive hematologic malignancies. However, the risk of developing graft-versus-host disease (GVHD) is a significant barrier to allo-HSCT. GVHD is a debilitating condition with high mortality rates and current therapeutic options for GVHD are limited, with corticosteroids being the standard treatment. However, the adverse effects of steroids make prolonged use difficult, necessitating the development of safer therapies. IL-35-producing B-cells (i35-Bregs) have emerged as critical regulators of immunity during autoimmune diseases. In this study, we investigated whether i35-Bregs immunotherapy can suppress and mitigate GVHD. Methods: We administered a single dose of i35-Bregs (1.5×106) to mice undergoing allo-HSCT and monitored disease severity and survival of GVHD mice over 90 days post-transplantation. We discovered that i35-Bregs secrete exosomes containing membrane-bound IL-35 (i35-Exosomes) and investigated whether ex-vivo generated i35-exosomes can be used as stand-alone immunotherapy for GVHD. i35-Breg-induced expression of cytokines or checkpoint proteins (PD-1, LAG-3, CTLA-4) was analyzed by Flow cytometry, ELISA, and RNA-seq analysis. Characterization of membrane-bound IL-35 was by Proximity ligation assay (PLA), immunohistochemistry/Confocal microscopy and Alpha Fold-Multimer modeling. Results: A single dose of 1.5×106 i35-Breg reduced severity of GVHD and prolonged GVHD survival, with more than 70% i35-Breg-treated mice surviving beyond day-90 post-transplantation while observing 100% mortality among untreated mice by day-45. Contrary to the view that IL-35 is secreted cytokine, we show here that i35-Bregs mitigate GVHD via membrane-bound IL-35 and by secreting i35-exosomes. Furthermore, i35-Bregs or ex-vivo generated i35-exosomes induce alloreactive T-cells to upregulate checkpoint proteins associated with T-cell exhaustion and anergy, inhibiting alloreactive responses and propagating infectious-tolerance mechanisms that suppress GVHD. Importantly, i35-Bregs or i35-exosomes suppresses GVHD by increasing bystander lymphocytes coated with immunosuppressive i35-exosomes. Conclusions: This study demonstrates that i35-Bregs and i35-exosomes play a critical role in mitigating GVHD. The combination of i35-Breg and i35-exosome immunotherapy may be an effective strategy for treating GVHD and other inflammatory diseases.

Regulatory T (Treg) cells contribute to solid organ cancer progression, except in colorectal cancer (CRC) despite being abundantly present. Here, we demonstrate that two distinct tumoral IL-10⁺ and IL-10⁻ Treg cell subsets exert opposing functions by counteracting and promoting CRC tumor growth, respectively. The tumor restraining activity of IL-10⁺ Treg cells was mediated by their suppression of effector CD4 T cell production of IL-17, which directly stimulates CRC tumor cell proliferation. Consistently, IL-10⁻ Treg cells were more abundant in both mouse and human CRC tumors than in tumor-adjacent normal tissues, whereas IL-10+ Treg cells exhibited the opposite distribution. Furthermore, relative abundance of IL-10⁺ and IL-10⁻ Treg cells correlated with better and worse disease prognoses in human CRC, respectively. This functional dichotomy between Treg cell subsets provides a rationale for therapeutic strategies to selectively target pro-tumoral Treg cells while preserving their anti-tumoral counterparts across barrier tissue cancers that harbor both subsets.

Inspired by the remarkable success of CAR-T therapy in hematologic malignancies, research is increasingly focused on adapting this treatment for solid tumors. However, CAR-T efficacy remains limited due to its exhaustion and shortened persistence. Transcription factors and epigenetic modifications play pivotal roles in modulating T cell differentiation and functionality, which have been leveraged in numerous strategies to promote the formation of long-lasting memory cells with stem-like properties and supercharging CAR-T performance. This review highlights pivotal transcriptional factors, such as c-Jun and FOXO1, which enhance and sustain T cell effector function, diminishes exhaustion, and epigenetic regulators like TET2 and DNMT3A, whose knockout promotes memory T subsets formation. We explore their interconnections, downstream targets, biological impacts, and the potential application risks of certain candidates, providing a comprehensive theoretical framework for supercharging CAR-T therapies through transcriptional and epigenetic interventions.

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.

Endothelial dysfunction is a significant factor in the pathogenesis of various diseases. In pathological states, endothelial cells (ECs) undergo activation, resulting in dysfunction characterized by the stimulation of inflammatory responses, oxidative stress, cell proliferation, blood coagulation, and vascular adhesions. Interleukin-35 (IL-35), a novel member of the IL-12 family, is primarily secreted by regulatory T cells (Tregs) and regulatory B cells (Bregs). The role of IL-35 in immunomodulation, antioxidative stress, resistance to apoptosis, control of EC activation, adhesion, and angiogenesis in ECs remains incompletely understood, as the specific mechanisms of IL-35 action and its regulation have yet to be fully elucidated. Therefore, this systematic review aims to comprehensively investigate the impact of IL-35 on ECs and their physiological roles in a range of conditions, including cardiovascular diseases, tumors, sepsis, and rheumatoid arthritis (RA), with the objective of elucidating the potential of IL-35 as a therapeutic target for these ailments.

Given the limitations of immunotherapy for treating non-small cell lung cancer (NSCLC), we investigated the phenotype and function of exhausted CD8+T cells and analyzed a novel combination immunotherapy to restore the effector killing function of tumor-infiltrating CD8+T lymphocyte (TIL).

We examined the expression and function of immunosuppressive molecules on CD8+T cells of peripheral blood mononuclear cells (PBMCs) and TILs by using prospectively collected peripheral blood, pleural effusions, and tumor tissues from patients with NSCLC and correlated the results with clinical data. We then evaluated the effect of interleukin 6 (IL-6) stimulation on CD8+T cells. Finally, we assessed the effects of combined blockade of PD1 and IL-6 on macrophage recruitment in a zebrafish macrophage model and CD8+ T cell function and tumor growth in PBMC humanized mouse model.

The expression of exhaustion markers on CD8+ T cells was found to be notably higher in both tumor and paraneoplastic tissues compared to peripheral blood. Furthermore, the degree of CD8+ T cell exhaustion exhibited a progressive increase with proximity to the tumor. When CD8+ T cells from peripheral blood and tumor tissues of NSCLC patients were stimulated with IL-6, the expression level of exhaustion markers, especially PD1, was further elevated. In the in vitro experiment, the combined inhibition of IL-6 and PD1 substantially enhanced the effector killing function of CD8+ T cells in NSCLC pleural effusion samples. In a macrophage-labeled zebrafish model, combined blockade of IL-6 and PD1 enhanced the recruitment of macrophages. In PBMC humanized mouse model, combined blockade of IL-6 and PD1 enhanced the inhibition of tumor growth.

Our data suggest that CD8+ T cells in NSCLC patients were in a state of exhaustion and combined blockade of IL-6 and PD1 to restore CD8+ T cell function to inhibit tumor growth may be an effective clinical strategy for the treatment of NSCLC.

Cancer stem cells (CSCs) are a small subset within the tumor mass significantly contributing to cancer progression through dysregulation of various oncogenic pathways, driving tumor growth, chemoresistance and metastasis formation. The aggressive behavior of CSCs is guided by several intracellular signaling pathways such as WNT, NF-kappa-B, NOTCH, Hedgehog, JAK-STAT, PI3K/AKT1/MTOR, TGF/SMAD, PPAR and MAPK kinases, as well as extracellular vesicles such as exosomes, and extracellular signaling molecules such as cytokines, chemokines, pro-angiogenetic and growth factors, which finely regulate CSC phenotype. In this scenario, tumor microenvironment (TME) is a key player in the establishment of a permissive tumor niche, where CSCs engage in intricate communications with diverse immune cells. The "oncogenic" immune cells are mainly represented by B and T lymphocytes, NK cells, and dendritic cells. Among immune cells, macrophages exhibit a more plastic and adaptable phenotype due to their different subpopulations, which are characterized by both immunosuppressive and inflammatory phenotypes. Specifically, tumor-associated macrophages (TAMs) create an immunosuppressive milieu through the production of a plethora of paracrine factors (IL-6, IL-12, TNF-alpha, TGF-beta, CCL1, CCL18) promoting the acquisition by CSCs of a stem-like, invasive and metastatic phenotype. TAMs have demonstrated the ability to communicate with CSCs via direct ligand/receptor (such as CD90/CD11b, LSECtin/BTN3A3, EPHA4/Ephrin) interaction. On the other hand, CSCs exhibited their capacity to influence immune cells, creating a favorable microenvironment for cancer progression. Interestingly, the bidirectional influence of CSCs and TME leads to an epigenetic reprogramming which sustains malignant transformation. Nowadays, the integration of biological and computational data obtained by cutting-edge technologies (single-cell RNA sequencing, spatial transcriptomics, trajectory analysis) has significantly improved the comprehension of the biunivocal multicellular dialogue, providing a comprehensive view of the heterogeneity and dynamics of CSCs, and uncovering alternative mechanisms of immune evasion and therapeutic resistance. Moreover, the combination of biology and computational data will lead to the development of innovative target therapies dampening CSC-TME interaction. Here, we aim to elucidate the most recent insights on CSCs biology and their complex interactions with TME immune cells, specifically TAMs, tracing an exhaustive scenario from the primary tumor to metastasis formation.

Esophageal squamous cell carcinoma (ESCC) is a highly heterogeneous and aggressive malignancy. The progression, invasiveness, and metastatic potential of ESCC are shaped by a multitude of cells within the tumor microenvironment (TME), including tumor cells, immune cells, endothelial cells, as well as fibroblasts and other cell types. Recent advancements in single-cell sequencing technologies have significantly enhanced our comprehension of the diverse landscape of ESCC. Single-cell multi-omics technology, particularly single-cell transcriptome sequencing, have shed light on the expression profiles of individual cells and the molecular characteristics of distinct tumor cell populations. This review summarizes the latest literature on single-cell research in the field of ESCC, aiming to elucidate the heterogeneity of tumor cells, immune cells, and stromal cells at the single-cell level. Furthermore, it explores the impact of cellular interactions within the TME on the progression of ESCC. By compiling a comprehensive overview of single-cell omics research on ESCC, this article aims to enhance our understanding of ESCC diagnosis and treatment by elucidating the intricate interplay within the TME. It explores the cellular composition, spatial arrangement, and functional attributes of the ESCC TME, offering potential therapeutic targets and biomarkers for personalized treatment strategies.

T lymphocytes are among the immunological cells that make up the tumor microenvironment (TME), and they are essential in the growth of tumors and anti-tumor reactions. Regulatory T cells (Treg cells) are a subset of CD4+ T cells in the immune system that suppress the immune system. They are distinguished by their expression of the master transcription factor forkhead box protein P3 (FOXP3). Furthermore, Treg cells are essential for maintaining immunological homeostasis, inhibiting inflammation, and maintaining self-tolerance. In a variety of malignancies within the TME, Treg cells demonstrate notable flexibility and functional diversity. Highly plastic Treg cells can change into Th-like Treg cells in specific circumstances, which allow them to secrete particular pro-inflammatory cytokines. Interleukin 35 (IL-35) is a part of the immunosuppressive cytokines that belong to the IL-12 family. Treg cells release IL-35, which was elevated in the peripheral blood and TME of numerous cancer patients, implying that IL-35 in the TME may be an intriguing target for cancer therapy. In cancer, IL-35 is a two-edged sword; it promotes tumorigenicity in cancer cells while shielding them from apoptosis. Nonetheless, other investigations have mentioned its conflicting effects on cancer prevention. Herein, we provide an updated understanding of the critical mechanisms behind the anticancer immunity mediated by Treg cells plasticity, the role of IL-35, and tactics to strengthen the immune response against malignancies, outlining major clinical trials that used Treg cells/IL-35 therapies in the three main cancer types (lung, breast, and colorectal cancers).

Spatially resolved gene expression profiling provides insight into tissue organization and cell-cell crosstalk; however, sequencing-based spatial transcriptomics (ST) lacks single-cell resolution. Current ST analysis methods require single-cell RNA sequencing data as a reference for rigorous interpretation of cell states, mostly do not use associated histology images and are not capable of inferring shared neighborhoods across multiple tissues. Here we present Starfysh, a computational toolbox using a deep generative model that incorporates archetypal analysis and any known cell type markers to characterize known or new tissue-specific cell states without a single-cell reference. Starfysh improves the characterization of spatial dynamics in complex tissues using histology images and enables the comparison of niches as spatial hubs across tissues. Integrative analysis of primary estrogen receptor (ER)-positive breast cancer, triple-negative breast cancer (TNBC) and metaplastic breast cancer (MBC) tissues led to the identification of spatial hubs with patient- and disease-specific cell type compositions and revealed metabolic reprogramming shaping immunosuppressive hubs in aggressive MBC.