Immunosuppressive Mechanisms Research Articles

Computational Identification of Migrating T cells in Spatial Transcriptomics Data.

T cells are the central players in antitumor immunity, and effective tumor killing depends on their ability to infiltrate into the tumor microenvironment (TME) while maintaining normal cytotoxicity. However, late-stage tumors develop immunosuppressive mechanisms that impede T cell movement and induce exhaustion. Investigating T cell migration in human tumors in vivo could provide novel insights into tumor immune escape, although it remains a challenging task. In this study, we developed ReMiTT, a computational method that leverages spatial transcriptomics data to track T cell migration patterns within tumor tissue. Applying ReMiTT to multiple tumor samples, we identified potential migration trails. On these trails, chemokines that promote T-cell trafficking display an increasing trend. Additionally, we identified key genes and pathways enriched on these migration trails, including those involved in cytoskeleton rearrangement, leukocyte chemotaxis, cell adhesion, leukocyte migration, and extracellular matrix (ECM) remodeling. Furthermore, we characterized the phenotypes of T cells along these trails, showing that the migrating T cells are highly proliferative. Our findings introduce a novel approach for studying T cell migration and interactions within the tumor microenvironment (TME), offering valuable insights into tumor-immune dynamics.

Reversing NK cell exhaustion: a novel strategy combining immune checkpoint blockade with drug sensitivity enhancement in the treatment of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common lethal cancers worldwide. Natural killer cells (NK cells) play a key role in liver immunosurveillance, but in the tumor microenvironment, NK cells are readily depleted, as evidenced by down-regulation of activating receptors, reduced cytokine secretion, and attenuated killing function. The up-regulation of inhibitory receptors, such as PD-1, TIM-3, and LAG-3, further exacerbates the depletion of NK cells. Combined blockade strategies targeting these immunosuppressive mechanisms, such as the combination of PD-1 inhibitors with other inhibitory pathways (eg. TIM-3 and LAG-3), have shown potential to reverse NK cell exhaustion in preclinical studies. This article explores the promise of these innovative strategies in HCC immunotherapy, providing new therapeutic directions for optimizing NK cell function and improving drug sensitivity.

Human cornea-derived mesenchymal stromal cells inhibit T cells through indoleamine 2,3 dioxygenase.

Human cornea-derived mesenchymal stromal cells inhibit T cells through indoleamine 2,3 dioxygenase.

Harnessing Extracellular Vesicles for Stabilized and Functional IL-10 Delivery in Macrophage Immunomodulation.

Extracellular vesicles (EVs) are gaining recognition as promising therapeutic carriers for immune modulation. We investigated the potential of EVs derived from HEK293FT cells to stabilize and deliver interleukin-10 (IL-10), a key anti-inflammatory cytokine. Using minicircle (MC) DNA vectors, we achieved IL-10 overexpression and efficient incorporation into EVs, yielding superior stability compared to free, recombinant IL-10 protein. Detailed biophysical and functional analyses revealed that IL-10+ EVs contain both monomeric and oligomeric forms of IL-10 on their external surface and encapsulated within vesicles. IL-10+ EVs suppressed inflammatory cytokine expression in pro-inflammatory macrophages (from two to 14-fold compared to naïve EVs) without inducing anti-inflammatory polarization, demonstrating a distinct immunosuppressive mechanism. Interestingly, naïve EVs from non-transfected cells also exhibited significant anti-inflammatory effects, suggesting that the intrinsic bioactive cargo of EVs substantially contributes to their function, complicating the interpretation of IL-10-specific effects. Size-based fractionation analyses of IL-10+ large EVs (lEVs), small EVs (sEVs), and non-vesicular extracellular particles (NVEPs) revealed IL-10 presence across all fractions, predominantly in monomeric form, with anti-inflammatory activity distributed among subpopulations. Anion exchange chromatography successfully enriched IL-10+ exosomes while retaining immunomodulatory effects. However, the shared properties of naïve and IL-10+ exosomes underscore the complexity of their immunomodulatory functions. These findings highlight the therapeutic potential of EVs while emphasizing the need to disentangle the contributions of engineered cytokines from endogenous vesicular components.

Regulation of Stress-Induced Immunosuppression in the Context of Neuroendocrine, Cytokine, and Cellular Processes.

Understanding the regulatory mechanisms of stress-induced immunosuppression and developing reliable diagnostic methods are important tasks in clinical medicine. This will allow for the development of effective strategies for the prevention and treatment of conditions associated with immune system dysfunction induced by chronic stress. The purpose of this review is to conduct a comprehensive analysis and synthesis of existing data on the regulatory mechanisms of stress-induced immunosuppression. The review is aimed at identifying key neuroendocrine, cytokine, and cellular processes underlying the suppression of the immune response under stress. This study involved a search of scientific literature covering the neuroendocrine, cellular, and molecular mechanisms of stress-induced immunosuppression regulation, as well as modern methods for its diagnosis. Major international bibliographic databases covering publications in biomedicine, psychophysiology, and immunology were selected for the search. The results of the analysis identified key mechanisms regulating stress-induced immunosuppression. The reviewed publications provided detailed descriptions of the neuroendocrine and cytokine processes underlying immune response suppression under stress. A significant portion of the data confirms that the activation of the hypothalamic-pituitary-adrenal (HPA) axis and subsequent elevation of cortisol levels exert substantial immunosuppressive effects on immune cells, particularly macrophages and lymphocytes, leading to the suppression of innate and adaptive immune responses. The data also highlight the crucial role of cortisol and catecholamines (adrenaline and noradrenaline) in initiating immunosuppressive mechanisms under chronic stress.

Mechanisms of myeloid-derived suppressor cells-mediated immunosuppression in melanoma

Melanoma is a malignant tumor with immunosuppression. Its immunosuppression is mostly due to myeloid-derived suppressor cells (MDSCs). At present, many studies have found that the generation of tumors is accompanied by the upregulation of certain factors and call them tumor markers. Some markers that cause tumor immunosuppression have been found in melanin. However, it is not clear how these markers work at the molecular level. The production of MDSCs, their migration into the tumor microenvironment (TME), their impact on T cells, and their unique function in the signal regulation pathway are all examined in this article. This study provides some references on pathways such as TLR4/NF-B, STAT3/Arg1 mRNA, such as STAT3/CCR5mRNA, etc. For the future research on the immunosuppression of melanoma. The pathways discovered so far are only a small part, and there are more pathways to be discovered. Future research can focus on the discovery of new pathways.

DAMPs prognostic signature predicts tumor immunotherapy, and identifies immunosuppressive mechanism of pannexin 1 channels in pancreatic ductal adenocarcinoma.

Damage-associated molecular patterns (DAMPs) induced by immunogenic cell death (ICD) may be useful for the immunotherapy to patients undergoing pancreatic ductal adenocarcinoma (PDAC). The aim of this study is to predict the prognosis and immunotherapy responsiveness of PDAC patients using DAMPs-related genes. K-means analysis was used to identify the DAMPs-related subtypes of 175 PDAC cases. The significance of gene mutation and immune status in different subtypes was detected. LASSO regression was used to construct a DAMPs-related prognostic signature to predict the immunotherapy responsiveness of PDAC. Subsequently, in vivo and in vitro experiments and Bulk-RNA seq were used to verify the effect of hub gene pannexin 1 (PANX1) on PDAC. Two subtypes were clustered based on the expression levels of DAMPs genes from 175 PDAC patients. Besides, the prognosis and immune landscape in up-regulated DAMPs expression subtypes was poor. In addition, we constructed a DAMPs-related prognostic signature that correlated with immune cell infiltration and predicted immunotherapy or chemotherapy responsiveness of patients with PDAC. Mechanically, through Bulk-RNA sequencing and experiments, we found that PANX1 promoted tumor progression and immune regulation via the ATP release to active NOD1/NFκB signaling pathway in PDAC. Our in silico analyses established a classification system based on ICD-related DAMPs genes in PDAC, and constructed a DAMPs-related prognostic model to predict the efficacy of immunotherapy. This study will provide a new perspective for targeting the DAMPs-related molecule PANX1 in the treatment of PDAC.

Divergent Effects of Circoviridae Capsid Proteins on Type I Interferon Signaling.

Viruses in the Circoviridae family can infect mammals and birds. Porcine circovirus type 2 (PCV2) significantly affects the livestock industry by causing porcine circovirus-associated diseases, such as postweaning multisystem wasting syndrome, respiratory disease complex, and dermatitis nephropathy syndrome. Additionally, beak and feather disease virus in parrots, canine circovirus in dogs, and columbid circovirus (pigeon circovirus) in racing pigeons induce immunosuppression, followed by secondary infections in these hosts. Although the PCV2 capsid protein has been demonstrated to inhibit type I interferon (IFN) signaling, the molecular mechanisms of Circoviridae-induced immunosuppression are largely unknown. In this study, we examined whether these functions are conserved across Circoviridae capsid proteins. Our results illustrated that although the nuclear localization of capsid proteins is conserved, their effects on IFN-β signaling vary by species, revealing the diverse roles of Circoviridae capsid proteins in modulating immune responses.

A novel mitochondrial-related risk model for predicting prognosis and immune checkpoint blockade therapy response in uterine corpus endometrial carcinoma

Uterine Corpus Endometrial Carcinoma (UCEC) represents a common malignant neoplasm in women, with its prognosis being intricately associated with available therapeutic interventions. In the past few decades, there has been a burgeoning interest in the role of mitochondria within the context of UCEC. Nevertheless, the development and application of prognostic models predicated on mitochondrial-related genes (MRGs) in UCEC remains in the exploratory stages. This study utilized RNA sequencing data and clinical information from the TCGA database to identify differentially expressed MRGs (DEMRGs) between UCEC and normal groups that are associated with overall survival (OS). Patients were randomly assigned to training and testing cohorts in a 1:1 ratio. In the training cohort, a risk model based on DEMRGs was developed using Lasso Cox regression analysis. Subsequently, patients in both cohorts were stratified into high-risk and low-risk groups based on their median risk scores. The prognostic performance of the model was validated through Kaplan-Meier survival analysis, ROC curves, and nomograms. Additionally, further analyses including functional enrichment, immune landscape assessment, prediction of response to ICB therapy, mutation profiling, and drug sensitivity analysis elucidated biological distinctions between the identified risk groups. We established a risk model incorporating eight MRGs. Patients classified within he high-risk group exhibited significantly poorer prognoses relative to those in the low-risk group. Functional enrichment analysis identified substantial differences in biological processes and signaling pathways between the high-risk and low-risk cohorts. Immune landscape analysis showed that patients with elevated risk scores exhibited significant immunosuppressive and immune evasion mechanisms. Conversely, low-risk patients exhibited higher expression of human leukocyte antigen (HLA) family members and immune checkpoint genes (ICGs) compared to their high-risk counterparts.Consequently, low-risk patients showed greater responsiveness to immunotherapy and potential small molecule drugs, whereas high-risk patients were more susceptible to chemotherapy. The mitochondrial-related risk model formulated in this study demonstrates efficacy in predicting both prognosis and response to immunotherapy in patients with UCEC, thereby providing a scientific basis for personalized treatment strategies. Future research endeavors should focus on further validating the clinical utility of this model and investigate the specific mechanisms of the identified MRGs in UCEC.

PD-L1, PD-1, and CTLA-4 mRNA InSitu Expression by Canine Oral Melanoma Cells and Immune Cells of the Tumour Microenvironment.

Canine oral melanoma (OM) exhibits poor prognosis and limited treatment options. The success of immune checkpoint inhibitors (ICIs) in human melanoma has driven interest in similar therapeutic approaches in the dog, although the immunosuppressive mechanisms adopted by canine OM remain unclear. This study aimed to evaluate the expression of the immune checkpoints PD-1/PD-L1 and CTLA-4 by RNAscope insitu hybridization (ISH) in canine OM, to investigate their expression pattern and explore their potential role in melanoma progression. Twenty-four formalin-fixed, paraffin-embedded canine OM were included in the study. PD-L1 expression by tumour cells was detected in 100% melanomas (score 1-3), especially at the host-tumour interface. PD-1 and CTLA-4 expression by tumour cells was detected in 13/24 (54%, score 1-2) and 18/24 (75%, score 1) melanomas, respectively. Dual ISH-immunohistochemistry with Melanoma Triple Cocktail, CD3, CD20 and Iba1 demonstrated the expression of tested immune checkpoints in neoplastic and immune cells. Notably, PD-1 and CTLA-4 were predominantly expressed by tumour-infiltrating T lymphocytes, while PD-L1 was primarily expressed by tumour-associated macrophages. PD-1 expression in neoplastic cells was significantly correlated with mitotic count (p < 0.05), while no associations were found between immune checkpoint expression and disease-free interval or overall survival. Whole tumour PD-L1 and PD-1 expression, assessed by image analysis, correlated to PD-L1 scores in neoplastic cells and the grade of tumour-infiltrating lymphocytes, respectively. Collectively, PD-L1, PD-1 and CTLA-4 likely contribute to immunosuppression in canine OM. Further studies are warranted to investigate whether ISH can serve as a biomarker for selecting patients suitable for ICI treatment.

Advancing brain immunotherapy through functional nanomaterials.

Glioblastoma (GBM), a highly aggressive brain tumor, poses significant treatment challenges due to its highly immunosuppressive microenvironment and the brain immune privilege. Immunotherapy activating the immune system and T lymphocyte infiltration holds great promise against GBM. However, the brain's low immunogenicity and the difficulty of crossing the blood-brain barrier (BBB) hinder therapeutic efficacy. Recent advancements in immune-actuated particles for targeted drug delivery have shown the potential to overcome these obstacles. These particles interact with the BBB by rapidly and reversibly disrupting its structure, thereby significantly enhancing targeting and penetrating delivery. The BBB targeting also minimizes potential long-term damage. At GBM, the particles demonstrated effective chemotherapy, chemodynamic therapy, photothermal therapy (PTT), photodynamic therapy (PDT), radiotherapy, or magnetotherapy, facilitating tumor disruption and promoting antigen release. Additionally, components of the delivery system retained autologous tumor-associated antigens and presented them to dendritic cells (DCs), ensuring prolonged immune activation. This review explores the immunosuppressive mechanisms of GBM, existing therapeutic strategies, and the role of nanomaterials in enhancing immunotherapy. We also discuss innovative particle-based approaches designed to traverse the BBB by mimicking innate immune functions to improve treatment outcomes for brain tumors.

JNK1 inhibitors target distal B cell receptor signaling and overcome BTK-inhibitor resistance in CLL.

Inhibition of the proximal B cell receptor (BCR) signaling pathway by BTK inhibitors is highly effective in the treatment of CLL, but drug resistance or intolerance occurs. Here, we investigated c-Jun N-terminal protein kinase 1 (JNK1) as an alternative drug target in the distal BCR pathway. JNK1 was preferentially overexpressed and activated in poor prognostic CLL with unmutated IGHV. Proximal BCR inhibition (BTK, PI3K, or SYK inhibitors) or SYK knockdown efficiently dephosphorylated JNK1, identifying JNK1 as a critical BCR downstream kinase in CLL. JNK1 inhibition induced apoptosis in primary CLL cells, resulting in the downregulation of BCL2, MCL1, and c-JUN. JNK1 inhibition in patient-derived CLL xenografted mice and Eµ-TCL1-tg mice prevented CLL progression, reduced splenic infiltration, and restored T cell function and normal hematopoiesis. JNK1 inhibitors even remained effective in ibrutinib refractory CLL. In conclusion, our study revealed JNK1 as a promising drug target in CLL downstream of the BCR, overcoming ibrutinib resistance, blocking the protective microenvironment, and improving CLL-specific immunosuppressive mechanisms.

Phosphoenolpyruvate carboxykinase 2 is a promising prognostic biomarker that correlates with peritumoral dendritic cell infiltration in glioblastoma.

Background: Despite the growing interest in Phosphoenolpyruvate carboxykinase 2 (PCK2) as a potential biomarker in cancer research, studies on its clinical relevance and biological processes in glioblastoma are still unexplored. Methods: Three main glioma cohorts (TCGA, CGGA, Rembrandt) were extracted to exploit the association between PCK2 expression and clinical relevance through Kaplan-Meier survival analysis, univariate and multivariate cox regression analysis. Immunohistochemistry was used to detect PCK2 expression in glioma samples. GSEA, Pearson correlation and ROC analysis were performed to verify the specificity of PCK2 in mesenchymal GBM. Gene set variation analysis and CIBERSORT were used to explore the correlation of tumor-infiltrating immune cells according to PCK2 expression. Double immunofluorescence was performed to testify the co-expression patterns across PCK2, CD11C and PD-L1 in GBM tissues. Results: PCK2 is increasingly expressed in GBM tissues and could serve as an independent poor prognostic indicator for glioma patients. PCK2 is preferentially expressed in mesenchymal subtype and correlates with immune infiltrates and immunosuppression in glioblastoma. Furthermore, PCK2 exhibits a positive correlation with dendritic cell infiltration and is co-expressed with CD11C and PD-L1 in the peritumoral region of the GBM tissues. Additionally, the enrichment of dendritic cell signature is associated with poor prognosis in glioblastoma patients. Conclusion: Our study highlights the potential therapeutic applicability of PCK2 and PCK2 mediated dendritic cell infiltration as a mechanism for glioblastoma immunosuppression.

Tumor-intrinsic PRMT5 upregulates FGL1 via methylating TCF12 to inhibit CD8+ T-cell-mediated antitumor immunity in liver cancer

Tumor-intrinsic PRMT5 upregulates FGL1 via methylating TCF12 to inhibit CD8+ T-cell-mediated antitumor immunity in liver cancer

Navigating glioblastoma therapy: A narrative review of emerging immunotherapeutics and small-molecule inhibitors

Glioblastoma multiforme (GBM) is the most common malignant primary tumor of the central nervous system (CNS), accounting for the majority of brain tissue tumors and CNS neoplasms. GBM has an incidence rate of 3.2/100,000 people in the United States, with an abysmal survival rate of 15 months with treatment and under 3 months for untreated patients. GBM remains incurable, with no disease-modifying treatment available. As a grade IV astrocytoma, GBM is highly aggressive, characterized by rapid proliferation, high metabolic demands, substantial angiogenesis, and diffuse infiltration of healthy parenchyma. The GBM genome is highly heterogeneous, with unpredictable amplification patterns, dysregulation, and mutational activation of receptor tyrosine kinase genes, tumor suppressor genes, and growth factor signaling. GBM&amp;rsquo;s indistinct tumor margins, its highly adaptive interaction with the brain microenvironment, and the existence of the blood-brain barrier and the blood-brain tumor barrier further limit effective anti-GBM therapeutic strategies. Hence, anti-GBM drug discoveries and molecular techniques that aim for patient-specific treatment stratification are of profound clinical and therapeutic significance. The current paper aims to outline the fundamental pathophysiology, tumorigenicity, and immunosuppressive mechanism of GBMs, review current treatment options for GBMs, and examine the contemporary challenges and advances in anti-GBM drug discovery and delivery. Finally, the paper aims to shed light on the emergence of small-molecule inhibitors, immune checkpoint inhibitors, and vaccination therapy as potentially efficacious therapeutic strategies for treating GBM.

Immune Privilege in the Central Nervous System: Implications for Neuroinflammatory Diseases

The central nervous system (CNS) has long been considered an immune-privileged site, where immune responses are tightly regulated to protect neural tissue from inflammation-induced damage. Immune privilege in the CNS is maintained through various mechanisms, including the blood-brain barrier (BBB), the absence of conventional lymphatic drainage, the specialized function of CNS-resident immune cells, and the expression of immunosuppressive molecules like TGF-β and IL-10. These protective systems are essential for preserving CNS homeostasis, as uncontrolled immune activity in the CNS can lead to irreversible damage to neurons and glial cells. However, immune privilege is not absolute. In neuroinflammatory diseases such as multiple sclerosis (MS), neuromyelitis optica (NMO), and Alzheimer’s disease, immune privilege is breached, resulting in the infiltration of immune cells, chronic inflammation, and progressive neural damage. The breakdown of the BBB, immune cell activation, and dysregulated inflammation contribute to the pathophysiology of these diseases. This review examines the mechanisms that underlie immune privilege in the CNS, how these systems are compromised in neuroinflammatory conditions, and the therapeutic implications for modulating immune responses in the CNS. Targeted therapies aimed at restoring immune regulation and preserving CNS function offer promising prospects for treating neuroinflammatory diseases and maintaining CNS health. Keywords: Immune Privilege, Central Nervous System, Neuroinflammatory Diseases, Blood-Brain Barrier, Multiple Sclerosis, Immunosuppressive Mechanisms

Abstract PR003: Structure-guided design and optimization of small molecule CD73 inhibitors with excellent drug-like properties: discovery of quemliclustat

Abstract In the tumor microenvironment, high concentrations of extracellular adenosine promote tumor proliferation through various immunosuppressive mechanisms. High expression of CD73—an ecto-nucleotidase that produces adenosine from adenosine monophosphate—has been associated with poorer prognosis in several tumor types. Herein, we describe the drug discovery efforts that resulted in the discovery of quemliclustat, a highly potent and selective inhibitor of CD73. As a small molecule with excellent drug-like properties, quemliclustat offers several advantages over CD73 antibodies in development, such as greater inhibition of CD73 enzymatic activity (both soluble and membrane-bound), deeper tumor penetration, and the potential for both IV and oral formulations. Quemliclustat was the first small molecule CD73 inhibitor to enter clinical development and is currently being evaluated in various Phase 1/2 studies in advanced solid tumors, including lung and pancreatic cancers. Recent data in metastatic pancreatic cancer are supportive of further study in this disease setting. Citation Format: Jenna Jeffrey Structure-guided design and optimization of small molecule CD73 inhibitors with excellent drug-like properties: discovery of quemliclustat. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr PR003

Adenosine Uptake through the Nucleoside Transporter ENT1 Suppresses Antitumor Immunity and T-cell Pyrimidine Synthesis.

Immunosuppression by adenosine is an important cancer immune checkpoint. Extracellular adenosine signals through specific receptors and can be transported across the cell membrane through nucleoside transporters. Although adenosine receptors are well-known to regulate tumor immunity, the impact of adenosine transporters remains unexplored. In this study, we investigated the effect on tumor immunity of equilibrative nucleoside transporter-1 (ENT1), the major regulator of extracellular adenosine concentrations. Blocking or deleting host ENT1 significantly enhanced CD8+ T-cell-dependent antitumor responses. Tumors inoculated into ENT1-deficient mice showed increased infiltration of effector CD8+ T cells with an enhanced cytotoxic transcriptomic profile and significant upregulation of granzyme B, IFNγ, IL2, TNFα, and CXCL10. ENT1 deficiency was further associated with decreased tumor-infiltrating T regulatory cells and CD206high macrophages and suppressed CCL17 production. ENT1 deficiency notably potentiated the therapeutic activity of PD-1 blockade. T cells upregulated ENT1 upon activation, and blocking ENT1 enhanced their function when cocultured with cognate antigen/HLA-matched melanoma cells. Mechanistically, ENT1-mediated adenosine uptake inhibited the activity of phosphoribosyl pyrophosphate synthetase in activated T cells, thereby suppressing production of uridine 5'-monophosphate and its derivatives required for DNA and RNA synthesis. In summary, this study identified ENT1-mediated adenosine uptake as an important mechanism of adenosine-mediated immunosuppression and pyrimidine starvation that can be targeted to enhance antitumor T-cell responses. Significance: ENT1 is a potential therapeutic target to overcome immunosuppression induced by extracellular adenosine and to increase the activity of PD-1 blockade.

Resistance mechanisms of non-small cell lung cancer and improvement of treatment effects through nanotechnology: a narrative review.

Lung cancer continues to be the leading cause of cancer-related deaths globally. Non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer cases. Although targeted therapies and immune checkpoint inhibitors have improved clinical outcomes for NSCLC patients, primary and acquired resistance remain significant obstacles to effective treatment. This review aims to elucidate the molecular mechanisms of NSCLC resistance and explore the potential of nanotechnology-based drug delivery systems in overcoming these resistance barriers. The research team conducted a comprehensive literature search in PubMed, Cochrane Library, Google Scholar, Embase, Web of Science, China National Knowledge Internet (CNKI), and Wanfang Database, covering the period from January 1st, 2007 to January 1st, 2024. This review summarizes the molecular mechanisms of NSCLC resistance, including target alterations, bypass signaling pathways, phenotypic transformations, and immunosuppressive mechanisms. It discusses the use of nanotechnology-based drug delivery systems (such as polymeric nanoparticles, liposomes, dendrimers, and inorganic nanoparticles) to overcome various resistance barriers. Additionally, it highlights the role of nanotechnology-based immunotherapeutic strategies in modulating tumor immunity. The review also explores methods for rationally designing combination nanomedicine strategies to address resistance issues at multiple levels, thereby enhancing the effectiveness of NSCLC treatment. A deep understanding of the mechanisms of NSCLC resistance and the innovative application of nanotechnology-based delivery strategies are crucial for improving patient survival. Rationally designing combination nanomedicine strategies that target multiple resistance mechanisms simultaneously holds promise for overcoming NSCLC resistance and enhancing treatment effectiveness. Further research is needed to investigate the clinical translation of emerging nanotechnologies, providing more effective treatment strategies for NSCLC patients.

Harnessing Tumor Cell-Derived Exosomes for Immune Rejection Management in Corneal Transplantation.

Transplantation remains the definitive treatment for end-stage organ failures, but its efficacy is frequently compromised by immune rejection. This study introduces a novel strategy by utilizing tumor-derived exosomes from B16-F10 melanoma cells (B16-Exo), diverging from the conventional use of immune cell-derived exosomes, to alleviate post-transplantation immune rejection. Utilizing murine corneal transplantation as a model, it is demonstrated that B16-Exo significantly reduces immune rejection, evidenced by decreased corneal opacity, neovascularization, and immune dysregulation, while enhancing postoperative survival. Proteomic analyses reveal differential expression of pivotal proteins in B16-Exo, notably the JAK2 protein within the JAK-STAT signaling pathway, which has been mechanistically demonstrated to amplify the activity of myeloid-derived suppressor cells (MDSCs) and inhibit T cell proliferation. These findings demonstrate the significant immunomodulatory effect of B16-Exo in transplant immunology, supporting the continued exploration of tumor-derived exosomes as a platform to uncover novel immunosuppressive mechanisms in transplantation.