Cancer immunotherapy has evolved into a new generation strategy in the field of anti-tumor treatment. Polysaccharides derived from Traditional Chinese Medicine (TCM) are gaining recognition as powerful immunomodulators in cancer therapy, noted for their multi-target and multi-pathway actions. Owing to their beneficial properties such as water solubility, biocompatibility, and chemical structure modifiability, TCM polysaccharides can also serve as carriers for hydrophobic drugs in the development of innovative drug delivery systems, enhancing synergistic antitumor effects. In this article, we summarize the diverse mechanisms of immunoregulation by TCM polysaccharides in tumor therapy. The applications of these polysaccharides as both active ingredients and drug carriers within nanodelivery systems for cancer immunotherapy are also introduced. Additionally, extensive research on TCM polysaccharides in clinical settings has been collected. Furthermore, discussions are presented on the development prospects and challenges faced by these polysaccharides in the field of tumor immunotherapy. Our goal is to improve researchers' comprehension of TCM polysaccharides in cancer immunotherapy, providing promising strategies to optimize cancer treatment and benefit diverse patient populations.

Osteosarcoma predominantly affects adolescents and young adults and is characterized as a malignant bone tumor. In recent decades, substantial advancements have been achieved in both diagnosing and treating osteosarcoma. Resulting in enhanced survival rates. Despite these advancements, the intricate relationship between ferroptosis and cuproptosis genes in osteosarcoma remains inadequately understood. Leveraging TARGET and GEO datasets, we conducted Cox regression analysis to select prognostic genes from a cohort of 71 candidates. Subsequently, a novel prognostic model was engineered using the LASSO algorithm. Kaplan-Meier analysis demonstrated that patients stratified as low risk had a substantially better prognosis compared with their high-risk counterparts. The model's validity was corroborated by the area under the receiver operating characteristic (ROC) curve. Additionally, we ascertained independent prognostic indicators, including clinical presentation, metastatic status, and risk scores, and crafted a clinical scoring system via nomograms. The tumor immune microenvironment was appraised through ESTIMATE, CIBERSORT, and single-sample gene set enrichment analysis. Gene expression within the model was authenticated through PCR validation. The prognostic model, refined by Cox regression and the LASSO algorithm, comprised two risk genes. Kaplan-Meier curves confirmed a significantly improved prognosis for the low-risk group in contrast to those identified as high-risk. For the training set, the ROC area under the curve (AUC) values stood at 0.636, 0.695, and 0.729 for the 1-, 3-, and 5-year checkpoints, respectively. Although validation set AUCs were 0.738, 0.668, and 0.596, respectively. Immune microenvironmental analysis indicated potential immune deficiencies in high-risk patients. Additionally, sensitivity to three small molecule drugs was investigated in the high-risk cohort, informing potential immunotherapeutic strategies for osteosarcoma. PCR analysis showed increased mRNA levels of the genes FDX1 and SQLE in osteosarcoma tissues. This study elucidates the interaction of ferroptosis and cuproptosis genes in osteosarcoma and paves the way for more targeted immunotherapy.

To investigate the role of neuroinflammation in the substantia nigra pars compacta (SNc) across different parkinsonian disorders-Parkinson's disease (PD), progressive supranuclear palsy (PSP), and multiple system atrophy (MSA)-by examining SNc dopaminergic neuron counts, neuroinflammatory T cells, and microglial activity.

Postmortem neuropathological samples were collected from 79 individuals (PD, n = 38; PSP, n = 15; MSA, n = 14; controls, n = 12). The density of SNc tyrosine hydroxylase (TH)-positive neurons, T cells (CD3+, CD4+, and CD8+), and Iba1 expression (Iba1-positive microglia/macrophages) were examined in the SNc and crus cerebri. Demographic and clinical data were gathered from patient histories.

PSP patients had 89 to 212% more nigral CD3+, CD4+, and CD8+ T cells compared to MSA patients (p < 0.04), 125 to 178% more CD3+ and CD4+ T cells than healthy controls (p < 0.002), and 95% more CD4+ T cells than PD patients (p = 0.001). Iba1 expression in the SNc was higher in PD patients than in MSA patients (p = 0.004), with no significant differences observed across other conditions. There was a negative association between disease duration and SNc CD3+ T cell density (p = 0.002), and a positive correlation between nigral dopaminergic neuron density and CD3+ density, CD8+ density, and Iba1 expression in PD patients.

The study reveals distinctive neuroinflammatory patterns in the SNc, with T cell-mediated inflammation prominent in PSP and microglia-mediated inflammation in PD. PSP and MSA show greater SNc dopaminergic neuron loss compared to PD. Increased neuroinflammatory response is seen in earlier disease stages, diminishing with greater neuron loss, which may inform disease progression understanding and therapeutic strategies. ANN NEUROL 2025;97:1096-1109.

The utilization of transcriptome technology in the identification of pivotal regulatory genes associated with immunity is of paramount importance. Previous studies have shown that undomesticated gayal (Bos frontalis) may have higher humoral responses which is comparable to yaks. However, research on immune function of gayal is limited, and comparisons with different breeds are rarely reported. The objective of this study was to inspect the immune status and compare splenic differential expression genes (DEGs) through comparative transcriptome analysis of gayal and domesticated local cattle (Yunan yellow cattle).

Serum immunological status investigation showed the better humoral immune status and lower levels of pro-inflammatory cytokines of gayal when compared to the local cattle. Spleen RNA-seq showed that 708 DEGs (365 up- and 343 down-regulated genes) were obtained between the gayal and local cattle. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analysis showed that immune system pathways, immune disease pathways, and chemotaxis-related molecular function of gayal were significantly enriched, whereas T cell-related cellular component and biological process were downregulated in the gayal. Correlation analysis shown that CD1, CD36, CD38, CD179a, CD179b, CXCL8, IGCGAMMA, IGH, IGHG1, IGLL1, IL1R2, SERPINB, and SERPINB4 had positive correlations with splenic IgA, IgD, IgE, IgG, and IgM, respectively (R > 0.5, P < 0.05). ANPEP, BVD1.23, CD1E, CD3D, CD3E, CD3G, CD5, CD8 A, HBB, IDO1, LCK, MGC126945, MHC1, TRAV, TRBV, and ZAP70 had negative correlations with splenic IgA, IgD, IgE, IgG, and IgM, respectively (R < -0.5, P < 0.05).

Our results reveal the immunological mode of gayal with high-level humoral immunity and enhanced splenic immunoglobulin gene expression and B cell differentiation, which may enable gayal to adapt to the harsh environments.

The tumor microenvironment (TME) influences cancer cell metabolism and survival. However, how immune and stromal cells respond to metabolic stress in vivo, and how nutrient limitations affect therapy, remains poorly understood. Here, we introduce Dual Ribosome Profiling (DualRP) to simultaneously monitor translation and ribosome stalling in multiple tumor cell populations. DualRP reveals that cancer-fibroblast interactions trigger an inflammatory program that reduces amino acid shortages during glucose starvation. In immunocompetent mice, we show that serine and glycine are essential for optimal T cell function and that their deficiency impairs T cell fitness. Importantly, immune checkpoint blockade therapy imposes amino acid restrictions specifically in T cells, demonstrating that therapies create distinct metabolic demands across TME cell types. By mapping codon-resolved ribosome stalling in a cell‑type‑specific manner, DualRP uncovers metabolic crosstalk that shapes translational programs. DualRP thus offers a powerful, innovative approach for dissecting tumor cell metabolic interplay and guiding combined metabolic-immunotherapeutic strategies.

Probiotics such as Lactobacillus and Bifidobacterium spp. have been shown to be critical for maintaining host homeostasis. In recent years, key compounds of postbiotics derived from probiotic metabolism and cellular secretion have been identified for their role in maintaining organ immunity and regulating intestinal inflammation. In particular, probiotic-derived extracellular vesicles (PEVs) can act as postbiotics, maintaining almost the same functional activity as probiotics. They also have strong biocompatibility and loading capacity to carry exogenous or parental active molecules to reach distal organs to play their roles. This provides a new direction for understanding the intrinsic microbiota-host communication mechanism. However, most current studies on PEVs are limited to their functional effects/benefits, and their specific physicochemical properties, composition, intrinsic mechanisms for maintaining host homeostasis, and possible threats remain to be explored. Here, we review and summarize the unique physicochemical properties of PEVs and their bioactivities and mechanisms in mediating microbiota-host communication, and elucidate the limitations of the current research on PEVs and their potential application as postbiotics.

Due to the limitations of current treatment strategies, hepatocellular carcinoma (HCC) continues to impose a severe burden on people's health. In the process of exploring novel therapies, T cell receptor-engineered T cell (TCR-T) therapy has been extensively developed in HCC immunotherapy. Melanoma-associated antigen family A member 10 (MAGE-A10) is a cancer-testis antigen (CTA), specifically expressed on HCC cells. However, the identification of TCR-T targeting MAGE-A10 in HCC remains rarely discussed. In this study, single-cell RNA sequencing (scRNA-seq) and TCR sequencing (scTCR-seq) were performed on samples from HCC patients. The cellular landscape of HCC was illustrated through a single-cell atlas. Reactive T cells were defined based on the matched T cells. Additionally, most reactive T cells were enriched in CD4_CD69_Th, CD4_FOXP3_Treg, CD4_CXCL13_TEX, and CD8_CXCL13_TEX. GLIPH2 was utilized to cluster TCRs from reactive T cells, enabling the identification of reactive TCRs. TCRMatch predicted MAGE-A10 as a specific antigen recognized by one of the reactive TCRs. Furthermore, the affinity assessments between human leukocyte antigen (HLA), epitope of MAGE-A10, and the identified TCR were performed with NetMHCpan and DLpTCR. Finally, cytotoxicity assays indicated the specific recognition and killing of MAGE-A10-TCR-T cells against HCC cells, paving the way for TCR-T immunotherapy in HCC.

T cells and their T cell receptors (TCRs) play crucial roles in the adaptive immune system's response against pathogens and tumors. However, immunosenescence, characterized by declining T cell function and quantity with age, significantly impairs antitumor immunity. Recent years have witnessed remarkable progress in T cell-based cancer treatments, driven by a deeper understanding of T cell biology and innovative screening technologies. This review comprehensively examines T cell maturation mechanisms, T cell-mediated antitumor responses, and the implications of thymic involution on T cell diversity and cancer prognosis. We discuss recent advances in adoptive T cell therapies, including tumor-infiltrating lymphocyte (TIL) therapy, engineered T cell receptor (TCR-T) therapy, and chimeric antigen receptor T cell (CAR-T) therapy. Notably, we highlight emerging DNA-encoded library technologies in mammalian cells for high-throughput screening of TCR-antigen interactions, which are revolutionizing the discovery of novel tumor antigens and optimization of TCR affinity. The review also explores strategies to overcome challenges in the solid tumor microenvironment and emerging approaches to enhance the efficacy of T cell therapy. As our understanding of T cell biology deepens and screening technologies advances, T cell-based immunotherapies show increasing promise for delivering durable clinical benefits to a broader patient population.

Glioblastoma multiforme (GBM) is the most prevalent brain tumor that remains incurable up to now. The rapid advancement of immunotherapy makes vaccines a promising therapeutic approach for GBM. However, current vaccine platforms, such as peptides, dendritic cells, mRNA, and viral vectors, are subject to limitations such as inadequate antigen loading, insufficient immune system activation, ineffective vector delivery, complicated fabrication process, and complex formulation. Here, we developed a GBM tumor cell derived homologous exosomal nanovaccine that does not need to carry any additional tumor antigens and leads to the activation of antigen-presenting cells (APCs) in lymph nodes, increasing the proportion of immune cells (matured dendritic cells, cytotoxic T cells, and memory T cells) and in turn promoting the expression of cytokines (TNF-α, IL-6, and IFN-γ), which effectively stimulates innate immunity to trigger durable protective immunity against tumor cell insult. Our nanovaccine platform possesses efficient dual-targeting capability to lymph nodes and the brain. More importantly, the developed exosomal nanovaccines protected 100% of treated mice by inducing sustained and strong immunity against GL261-luc GBM tumor cells, resulting in 100% mouse survival (8/8) up to 5 months. Our nanovaccines also induced antitumor immune responses in the immunosuppressed CT2A-luc GBM mouse model with greatly improved survival compared to control mice. Exosomal nanovaccines also demonstrated effectiveness in preventing brain metastasis in the B16F10-luc melanoma malignant brain metastasis mouse model, and the mice showed notably improved survival rates. Our simple and potent exosomes offer a versatile platform for clinical translation as individualized vaccine therapy.

T cell activation requires a substantial increase in NAD+ production, often exceeding the capacity of oxidative phosphorylation (OXPHOS). To investigate how T cells adapt to this metabolic challenge, we generate T cell-specific ADP/ATP translocase-2 knockout (Ant2-/-) mice. Loss of Ant2, a crucial protein mediating ADP/ATP exchange between mitochondria and cytoplasm, induces OXPHOS restriction by limiting ATP synthase activity, thereby impeding NAD+ regeneration. Interestingly, Ant2-/- naïve T cells exhibit enhanced activation, proliferation and effector functions compared to wild-type controls. Metabolic profiling reveals that these T cells adopt an activated-like metabolic program with increased mitobiogenesis and anabolism. Lastly, pharmacological inhibition of ANT in wild-type T cells recapitulates the Ant2-/- phenotype and improves adoptive T cell therapy of cancer in mouse models. Our findings thus suggest that Ant2-deficient T cells bypass the typical metabolic reprogramming required for activation, leading to enhanced T cell function and highlighting the therapeutic potential of targeting ANT for immune modulation.

Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of lymphoproliferative disorders characterised by skin infiltration by malignant memory T cells. While most patients will present with an indolent disease, others will follow a highly aggressive clinical course. Currently, defining disease prognosis remains challenging. Ectopic expression of gametocyte-specific factor 1 (GTSF1) has emerged as a potential prognostic biomarker. However, its contribution to CTCL carcinogenesis remains unknown. Here, we report that GTSF1 contributes to carcinogenesis by partially modifying the memory/effector phenotype of the malignant T cells. GTSF1 knockdown in CTCL cells led to T-cell activation and production of IFNγ and TNFα. Advanced stages of the disease are associated with decreased production of these cytokines. Notably, we show that patients classified with high expression of GTSF1 are associated with a worse disease prognosis. Taken together, our findings indicate that GTSF1 expression in CTCL cells allows them to acquire memory T-cell phenotype. Malignant memory T cells have a decreased production of immune-responsive cytokines, leading to a diminished immune response and disease progression. GTSF1 is an important candidate as a prognostic biomarker. Furthermore, understanding the specific function of GTSF1 might help develop novel targeted treatment options for CTCL patients.

Curcumin, a compound isolated from turmeric, has been found to have promising anti-tumor effects in various cancers, including anaplastic thyroid carcinoma (ATC). However, the molecular mechanism of curcumin in ATC remains largely unclear. CD8 +T cells could eliminate rapidly proliferating malignant cells, whereas interaction between programmed death-1 (PD-1) and programmed cell death ligand 1 (PD-L1) could inhibit the activation and functions of CD8 + T cells. Thus, we aimed to explore whether curcumin could inhibit ATC progression via regulating CD8 + T cells and PD-L1 expression. The protein expression of PD-L1 in ATC cells was detected by western blot assay. Additionally, a syngeneic mouse model was used to assess the effect of curcumin or/and anti-PD-1 treatment on tumorigenesis in vivo. The effect of curcumin on CD8 +T cell function was investigated by flow cytometry in vitro and in vivo. The results indicated curcumin notably suppressed ATC cell proliferation, migration and invasion and induced cell apoptosis. Additionally, curcumin could reduce PD-L1 level in ATC cells through inactivating AKT/mTORC1/STAT3 signaling. Meanwhile, curcumin obviously elevated CD8 + T cell function by elevating the number of IFN-γ producing CD8 + T cells. Furthermore, curcumin or anti-PD-L1 treatment could enhance anti-tumor immunity by increasing infiltration of CD8 + T cells in tumor tissues in vivo. As expected, compared to the single treatment, combination curcumin and anti-PD-1 treatment further elevated CD8 + T cell function in vivo, thereby potentiating anti-tumor immunity in ATC. Collectively, curcumin could enhance anti-tumor immunity in ATC by elevating CD8 + T cell function and inactivating the AKT/mTORC1/STAT3/PD-L1 axis. Our findings demonstrated a novel mechanism of the anti-tumor effects of curcumin in ATC.

Alopecia areata (AA) is a complex, chronic inflammatory skin disorder characterized by unpredictable, nonscarring hair loss, affecting millions worldwide. Its pathogenesis remains poorly understood, driven by intricate interactions among immune dysregulation, genetic predisposition, and environmental triggers. Despite significant advances in identifying these contributing factors, substantial gaps persist in our understanding of the full spectrum of AA's molecular mechanisms and in the development of effective therapeutic approaches. This review aims to comprehensively explore the immunological, genetic, epigenetic, and environmental factors underlying AA, with a focus on immune-mediated mechanisms. We also evaluate diagnostic approaches and recent advancements in assessing disease severity. Furthermore, the review discusses evolving therapeutic options, including traditional therapies, biologics, small-molecule agents, and emerging treatments. The academic value of this work lies in its synthesis of current knowledge on the multifaceted nature of AA, providing insights for future research and clinical practice. By elucidating the interconnected factors underlying AA, this review seeks to advance both understanding and management of this prevalent, clinically challenging disorder.

Cardiac arrhythmias are a significant cause of morbidity and mortality worldwide. Emerging evidence has demonstrated that resident and infiltrating cardiac immune cells play direct, mechanistic roles in arrhythmia onset and progression. In this review, we provide a comprehensive summary and expert commentary on the role of each immune cell subtype in the pathogenesis of atrial and ventricular arrhythmias.

Alzheimer's disease (AD) represents the most prevalent form of dementia, characterized by progressive cognitive impairment and chronic neuroinflammation. Immune checkpoint inhibitors (ICIs), including anti-programmed cell death (PD)-1 and anti-PD-L1, signify a revolutionary advancement in cancer treatment by preventing T-cell exhaustion; however, their therapeutic application in AD presents a conundrum. Hypothesis: Recent preclinical studies indicate that PD-1 inhibition in AD mouse models induces an interferon-gamma (IFN-γ)-mediated response, leading to increased recruitment of monocyte-derived macrophages into the brain, enhanced clearance of amyloid-beta (Aβ) plaques, and improved cognitive performance. Nonetheless, this therapeutic effect is counterbalanced by the potential for exacerbated neuroinflammation, as PD-1/PD-L1 blockade may potentiate pro-inflammatory T helper (Th)1 and Th17 responses. In this review, we critically discuss the pertinent pro-inflammatory and neuroprotective facets of T cell biology in the pathogenesis of AD, emphasizing the potential for modulation of the PD-1/PD-L1 axis to influence both Aβ clearance and the dynamics of neuroinflammatory processes. In summary, we determine that ICIs are promising tools for reducing AD pathology and improving cognition. However, it is essential to refine treatment protocols and carefully select patients to optimize neuroprotective effects while adequately considering inflammatory risks.

Objective: This study aimed to analyze the relevant risk factors for nosocomial infection (NI) in patients who were admitted to an emergency department, explore the correlation between each influencing factor and the risk of NI, and evaluate the application value of immunological indicators on the patient prognosis, all of which can provide reference for clinical guidance. Methods: We prospectively enrolled 128 patients meeting the inclusion criteria who visited the emergency department of Dongzhimen Hospital, Beijing University of Chinese Medicine, from January 1 to December 31, 2019. Basic information and serum samples were collected from the patients, and flow cytometry was used. T lymphocyte subgroups, CD3+CD4+and CD3+CD8+, and natural killer (NK) cells were measured. Patients were divided into infection group and control group according to whether nosocomial infection occurred within 48 h of admission. Age, gender, type of disease, APACHE II score, Charlton score, T lymphocyte subtypes, and NK cell values were compared, and a logistic multivariate regression analysis was conducted. A multifactor regression analysis was performed on various risk factors. The nomogram website was used to draw a nomogram model of meaningful indicators, and the receiver-operating characteristic (ROC) curve was based on experimental results. Results: Logistics multivariate regression analysis showed the Charlton score and NK cell count were independent risk factors for nosocomial infection. Cell counts for subsets CD3+CD4+ and CD3+CD8+ were protective factors, and the OR value and 95% CI were 5.199 (1.933-13.983), 1.248 (1.055-1.475), 0.851 (0.790-0.916), and 0.832 (0.711-0.973), p < 0.05. respectively. Statistical significance was set at p < 0.05.The nomogram model suggested that the area under the curve for predicting the risk of nosocomial infection was 0.920 (0.872-0.967), p < 0.001. Conclusion: Patients with low CD3+CD4+ and CD3+CD8+ T lymphocyte or high NK cell count as well as high Charlton score are more likely to have nosocomial infection. Then, we speculate that the risk of nosocomial infection within 48 h is also high for patients with underlying diseases and immune function that is affected and suppressed on admission, regardless of whether infection occurs during hospitalization.

T cells play a central role in anti-tumor immunity, yet their function is often compromised within the immunosuppressive tumor microenvironment, leading to cancer progression and resistance to immunotherapies. T-cell activation and differentiation require dynamic metabolic shifts, with mitochondrial metabolism playing a crucial role in sustaining their function. Research in cancer immunometabolism has revealed key mitochondrial abnormalities in tumor-infiltrating lymphocytes, including reduced mitochondrial capacity, depolarization, structural defects, and elevated reactive oxygen species. While these mitochondrial disruptions are well-characterized in solid tumors and linked to T-cell exhaustion, their impact on T-cell immunity in lymphoproliferative disorders remains underexplored. Chronic lymphocytic leukemia (CLL), the most prevalent chronic adult leukemia, is marked by profound T-cell dysfunction that limits the success of adoptive cell therapies. Emerging studies are shedding light on the role of mitochondrial disturbances in CLL-related T-cell dysfunction, but significant knowledge gaps remain. This review explores mitochondrial metabolism in T-cell exhaustion, emphasizing recent findings in CLL. We also discuss therapeutic strategies to restore T-cell mitochondrial function and identify key research gaps.

Immunotherapy has demonstrated potential in the treatment of esophageal cancer (EC); however, the overall response rate (ORR) remains below 30% among EC patients. Herein, the use of peripheral blood lymphocyte subsets as biomarkers was explored to evaluate the efficacy of immunotherapy in this patient population.

Sixty-three patients were enrolled. The patients were diagnosed with EC and treated with immune checkpoint inhibitors (ICIs) at The Fourth Hospital of Hebei Medical University from December 2019 to June 2023. Kaplan-Meier (KM) survival curves were used to reflect differences in survival benefit. The prognostic factors of survival were investigated using the Cox proportional hazards regression model for both univariate and multivariate analyses. Two-tailed P values were reported and statistical significance was defined as P < 0.05.

The results of univariate and multifactorial Cox regression analysis for progression-free survival (PFS) revealed that only CD8+ T lymphocytes demonstrated a significant association with PFS (P = 0.034, P = 0.020). Additionally, the multifactorial Cox regression analysis results for overall survival (OS) revealed a significant association between natural killer (NK) cells and OS (P=0.049). Further, a systematic analysis was conducted on the CD8+ T cell biomarker. The KM survival curves indicated that the group with low CD8+ T cell levels experienced a significantly greater PFS benefit compared to the high CD8+ T cell group (P = 0.030).

The present study reveals that the reduction of both CD8+ T lymphocytes and NK cells in peripheral blood lymphocyte subsets after immunotherapy can serve as superior predictors for the effectiveness of ICIs in patients diagnosed with EC.

Liver cancer is a serious malignancy worldwide, and long noncoding RNAs (lncRNAs) have been implicated in its prognosis.It remains unclear how lncRNAs related to endoplasmic reticulum stress (ERS) influence liver cancer prognosis. Here, we analyzed RNA and clinical data from the Cancer Genome Atlas and sourced ERS-related genes from the Molecular Signatures Database. Co-expression analysis identified ERS-related lncRNAs, and Cox regression analysis as well as least absolute shrinkage and selection operator regression highlighted three lncRNAs for a prognostic model. Based on median risk scores, we classified patients into two risk groups. The high-risk group displayed poor prognosis, and this finding was validated in the test set. According to consistency clustering, the patients were assigned to two clusters, and tumor microenvironment scores were computed. Patients with a high mutation burden had worse outcomes. Furthermore, immune infiltration analysis indicated more immune cells and mutations in checkpoint molecules among high-risk individuals. Drug sensitivity varied between the risk groups. LINC01011 was selected for functional assays. Colony formation assay and CCK-8 assay revealed that silencing LINC01011 suppressed liver cancer cell proliferation. Transwell and scratch assays indicated that silencing LINC01011 inhibited liver cancer cell migration. Western blotting assay revealed that inhibiting LINC01011 induced apoptosis and simultaneously inhibited epithelial-mesenchymal transition. These findings confirm the validity of the prognostic model and indicate that LINC01011 could serve as a potential research target.

The tumor microenvironment (TME) is a complex, dynamic ecosystem where tumor cells interact with diverse immune and stromal cell types. This review provides an overview of the TME's evolving composition, emphasizing its transition from an early pro-inflammatory, immune-promoting state to a later immunosuppressive milieu characterized by metabolic reprogramming and hypoxia. It highlights the dual roles of key immunocytes-including T lymphocytes, natural killer cells, macrophages, dendritic cells, and myeloid-derived suppressor cells-which can either inhibit or support tumor progression based on their phenotypic polarization and local metabolic conditions. The article further elucidates mechanisms of immune cell plasticity, such as the M1/M2 macrophage switch and the balance between effector T cells and regulatory T cells, underscoring their impact on tumor growth and metastasis. Additionally, emerging therapeutic strategies, including checkpoint inhibitors and chimeric antigen receptor (CAR) T and NK cell therapies, as well as approaches targeting metabolic pathways, are discussed as promising avenues to reinvigorate antitumor immunity. By integrating recent molecular insights and clinical advancements, the review underscores the importance of deciphering the interplay between immunocytes and the TME to develop more effective cancer immunotherapies.

The adenoids and tonsils are important immune organs of the nasopharynx that often become hypertrophic in childhood because of recurrent pathogen infection. However, the differences in the immune microenvironment of adenoid hypertrophy (AH) and tonsil hypertrophy (TH) are unclear. Here, we show the epidemiological characteristics and peripheral blood cell indices of 1209 pediatric patients (1-15 years old) diagnosed with AH, and find that AH is often accompanied by TH and characterized by specific changes in immune cell types. Single-cell RNA sequencing analysis show that 12 paired AH and TH samples contain large numbers of B, T cells and some exhausted effector memory CD4+ T cells. Compared with matched TH, AH have more naïve B cells and regulatory CD4+ T cells and less plasma B cells. Weaker antigen presentation and more significant immunosuppression are also observed in AH. In contrast, the number and cytotoxicity of cytotoxic CD8+ T cells decrease with AH grade. These findings will help our understanding of the immune response to nasopharyngeal infection.

This study aimed to evaluate the effects of caudal block anesthesia with hydromorphone-ropivacaine compared to ropivacaine alone on postoperative immune function and pain management in children undergoing hypospadias surgery.

A total of 100 pediatric patients were randomly assigned to two groups: the Hydromorphone-Ropivacaine (HR) group and the Ropivacaine (R) group for caudal block anesthesia, with 50 patients in each group. The R group received 0.25% ropivacaine at a dose of 1 ml/kg, while the HR group received 0.25% ropivacaine (1 ml/kg) combined with hydromorphone (10 µg/kg). The maximum dose for both groups was capped at 30 ml (1 ml/kg). Anesthesia induction included intravenous administration of pentobarbital (0.01 mg/kg) and dexamethasone (0.15 mg/kg), followed by sevoflurane inhalation. All patients underwent ultrasound-guided caudal block anesthesia administered by the same anesthetist. Primary outcomes included the distribution of T lymphocyte subsets (CD3+, CD4+, CD8+, and CD4+/CD8 + ratios) measured at five time points: pre-anesthesia (T0), end of surgery (T1), 24 h postoperatively (T2), 48 h postoperatively (T3), and 72 h postoperatively (T4). Secondary outcomes included postoperative pain scores assessed using the Modified Children's Hospital of Eastern Ontario Pain Scale (M-CHEOPS) at 1, 6, 12, 18, and 24 h postoperatively, sedation levels evaluated using the Ramsay sedation scale at the same time points, and the incidence of postoperative adverse events.

The HR group exhibited significant reductions in CD3+, CD4+, and CD4+/CD8+ ratios at T1, T2, and T3 compared to baseline (T0) (p < 0.001). At all postoperative time points (T1, T2, T3, T4), the HR group demonstrated significantly higher levels of CD3+, CD4+, and CD4+/CD8+ ratios compared to the R group (p < 0.001). By T4 (72 h postoperatively), immune markers in the HR group had largely normalized to baseline levels, whereas those in the R group remained significantly lower (p < 0.001). Postoperative pain, assessed using the Modified Children's Hospital of Eastern Ontario Pain Scale (M-CHEOPS), was significantly lower in the HR group at 6, 12, and 18 h postoperatively compared to the R group (p < 0.001). The HR group also exhibited a longer duration of analgesia and required fewer doses of rescue analgesia within the first 24 h postoperatively (p = 0.046). Sedation levels, evaluated using the Ramsay sedation scale, showed significant differences between the groups at 1 h (p = 0.0087) and 6 h (p < 0.0001) postoperatively, with higher sedation scores observed in the HR group. There were no significant differences in heart rate, systolic blood pressure, diastolic blood pressure, mean arterial pressure, or oxygen saturation between the groups at any time point (p > 0.05). No significant differences were observed between the two groups in terms of postoperative adverse reactions (all p > 0.05).

Caudal block anesthesia with hydromorphone-ropivacaine offers enhanced postoperative pain relief and a lesser impact on immune function compared to ropivacaine alone in children undergoing hypospadias surgery. Further studies are warranted to explore the long-term effects on immune function.

The concurrent presence of COVID-19 infection in advanced cancer patients has increased the mortality since the compromised immunity was inevitably worsen. The role and clinical impact of autologous adoptive T cell immunotherapy (ACT) designed for anti-cancer treatment were not known in such circumstances. The safety and potential immune reconstitution of concurrent ACT in advanced cancer patients with active COVID-19 infection have yet unknown as well. The effect of infused ACT on the symptom severity manifestation should be summarized.

In this respectively clinical observation study, patients were non-randomized enrolled from the two centers according to the regular therapeutic plans including stage IV cancer patients for scheduled ACT, chemotherapy, cancer patients with symptomatic COVID-19 but without ACT, neither cancer or non-ACT but symptomatic cases of COVID-19 infection. We have incorporated the age-adjusted Charlson comorbidity index (aCCI) for each patient to compare the prognosis of the three groups. All patients were planned for the scheduled standard anti-cancer therapeutic considerations, chemotherapy plus ACT as planned as well as the supportive care.The clinical efficacy and impact of ACT on cancer patients within the 3 months from the peripheral blood apheresis, dendritic cell (DC) and cytokine induced killer T cell (CIK-T ) infusion and subsequent co-existence of COVID-19 infection were recorded as the primary objective. During the same period, the cancer cases without ACT and others were collected to compare the occurrence of both severe and death rate respectively.

There were 123 patients (35 of ACT, 23 of non-ACT, 65 of non-cancer) with similar aCCI. There were similar cohort-level COVID-19 in-hospital case fatality rates consistent with previously reported data for non-cancer (26.2%, 17/65) and non-ACT cancer (52.2%, 12/23) among those admitted severe cases after the adjustment.There were little overlapped adverse reactions during the ACT therapeutic period even in the presence of active COVID-19 infection. No death case was occurred (0/35) when those exposed to ACT regimen. Cancer patients receiving ACT had a shorter mean time to alleviation of symptoms compared with non-ACT and non-cancer (4.46 versus 16.88 and 17.90 days respectively) as well as the lowered severity incidence of symptoms (P = 0.0010). The infused ACT has not significant impact on peripheral blood count whereas the amount of CD3-CD16+CD56+ NK cells increased (P = 0.0017). The quantity of infused ACT was favorable for augmentation of possibility of severe to mild symptom shift.

These data demonstrate the clinical safety profiles while ACT infusions with active COVID-19 infection.The intervention of ACT for cancer patients could generate the benefit for symptom alleviation with improved recovery time. The concurrent ACT for advanced cancer patients during such infectious pandemic might simultaneously leverage and reduce the risk of immune compromised situation for subsequent chemotherapy complications.

Dendritic cells (DCs) are versatile professional antigen-presenting cells and play an instrumental role in the generation of antigen-specific T-cell responses. Modulation of DC function holds promise as an effective strategy to improve anti-tumor immunotherapy efficacy and enhance self-antigen tolerance in autoimmune diseases.

Wild-type (WT) and TLR2 knockout (KO) mice at 2 weeks of age were injected intraperitoneally (i.p.) with a single dose of diethylnitrosamine (DEN) to induce hepatocellular carcinoma (HCC). Four weeks later, WT and KO mice were randomly divided into control and treatment groups and treated once every two days for 30 weeks with phosphate buffered saline (PBS) and a mix of 4 TLR2-activating lactic acid-producing probiotics (LAP), respectively. Mice were euthanized after 30 weeks of LAP treatment and their liver tissues were collected for gene expression, histological, flow cytometric and single-cell RNA sequencing analyses.

We demonstrate here that oral administration of a mix of TLR2-activating LAP triggers a marked accumulation of regulatory DCs (rDCs) in the liver of mice. LAP-treated mice are protected from DEN-induced liver injury, fibrosis and HCC in a TLR2-dependent manner. Single-cell transcriptome profiling revealed that LAP treatment determines an immunosuppressive hepatic T-cell program that is characterized by a significantly reduced cytotoxic activity. The observed functional changes of T cells correlated well with the presence of a hepatic DC subset displaying a regulatory or tolerogenic transcriptional signature.

Overall, these data suggest that stimulation of regulatory dendritic cells (rDCs) in the liver by LAP suppresses cytotoxic T-cell function and alleviates DEN-induced liver damage, fibrosis and tumorigenesis.

The risk of secondary primary malignancies (SPMs) associated with bispecific antibody (BsAb)-a promising alternative to chimeric antigen receptor (CAR)-T therapy-remains insufficiently explored.

Using large-scale, real-world data from the US Food and Drug Administration's Adverse Event Reporting System, we identified the relative frequency and characteristics of SPMs following BsAbs therapy and conducted a comprehensive comparison of treatment-related SPM profiles between BsAbs and CAR-T therapies.

We identified 108 cases among 10,280 BsAb-treated patients. The incidence risk of SPMs was stable over the past 8 years, accounting for 1-2% of all adverse events, with a case fatality rate of 29.63% among the SPM cases. Myeloid leukemias and non-Hodgkin's lymphoma were more frequent in blinatumomab recipients, while solid malignancies predominated in those treated with teclistamab. Time-to-onset (TTO) was significantly shorter in BsAb recipients compared with non-recipients, with weight and treatment duration influencing TTO, while no significant differences in TTO were observed across different BsAb products, ages, and genders. Our findings highlight the first year of BsAbs as a critical window for early detection and intervention. Although the overall risk of SPMs was lower with BsAbs than with CAR-T, the outcomes of SPMs were comparable in both groups. TTO and SPM patterns were statistically similar between the two therapies.

Our study provides the first detailed characterization of SPMs post-BsAb, underscoring the need for continued pharmacovigilance and individualized risk management to mitigate SPM risks in patients undergoing BsAb therapy.

The abundant cell components of the adaptive immune system called T lymphocytes (T cells) play important roles in mediating immune responses to eliminate the invaders and create the memory of the germs to form a new immunity for the next encounter. Among them, cytotoxic T cells expressing cell-surface CD8 are the most critical effector cells that directly eradicate the target infected cells by recognizing antigens presented by major histocompatibility complex class I molecules to protect our body from pathological threats. In the continuous evolution of immunotherapy, various CD8+ T cell-based therapeutic strategies have been developed based on the role and molecular concept of CD8+ T cells. The emergence of such remarkable therapies provides promising hope for multiple human disease treatments such as autoimmunity, infectious disease, cancer, and other non-infectious diseases. In this review, we aim to discuss the current knowledge on the utilization of CD8+ T cell-based immunotherapy for the treatment of various diseases, the molecular basis involved, and its limitations. Additionally, we summarize the recent advances in the use of CD8+ T cell-based immunotherapy and provide a comprehensive overview of CD8+ T cells, including their structure, underlying mechanism of function, and markers associated with CD8+ T cell exhaustion. Building upon these foundations, we delineate the advancement of CD8+ T cell-based immunotherapies with fundamental operating principles followed by research studies, and challenges, as well as illustrate human diseases involved in this development.

Enhanced macrophage M2 polarization and CD8+ T cell dysfunction contribute to the pathophysiology of non-small cell lung cancer (NSCLC). Motor neuron and pancreatic homeobox 1 (MNX1) has emerged as a potential tumor-promoting player. Here, we clarified the activity of MNX1 in NSCLC. PMA-induced THP-1 M0-like macrophages or CD8+ T cells were co-cultured with NSCLC cells. Cell colony formation, migration, proliferation, apoptosis, and invasiveness were assessed by colony formation, wound healing, CCK-8, flow cytometry, and transwell assays, respectively. The ratio of CD206+ macrophages was analyzed by flow cytometry. Ki-67 expression was tested by immunofluorescence. ChIP and luciferase assays were used to evaluate the relationship between MYCN and MNX1. MNX1 was highly expressed in NSCLC, and its loss-of-function suppressed cell growth, motility, and invasiveness in NSCLC cells. MNX1 depletion also diminished macrophage M2 polarization and CD8+ T cell apoptosis. Mechanistically, MYCN increased MNX1 expression at the transcriptional level. MNX1 increase reversed the impact of MYCN depletion on NSCLC cell malignant behaviors, macrophage M2 polarization, and CD8+ T cell viability. MYCN depletion diminished the in vivo growth of A549 subcutaneous xenografts. Additionally, MNX1 increase counteracted the impact of MYCN depletion on the Wnt/β-catenin pathway. Our findings elucidate the oncogenic role of the MYCN/MNX1/Wnt/β-catenin pathway in NSCLC by driving macrophage M2 polarization and diminishing CD8+ T cell viability. Our study thus uncovers a novel mechanism underlying NSCLC development and highlights potential targets for combating NSCLC.

Virus-specific CD8+ T cells play a major role in the natural control of HIV infection, linked to memory-like features such as high survival capacity and polyfunctionality. However, virus-specific CD8+ T cells from HIV non-controllers exhibit an effector-like and exhausted profile, with limited antiviral potential. Metabolic reprogramming of cells from non-controllers could reinvigorate their functional capacities. Considering the implication of the cholesterol pathway in the induction of T cell exhaustion, here we evaluated the impact of rosuvastatin, an inhibitor of cholesterol synthesis, on the functionality and memory profile of HIV-specific CD8+ T cells from people on antiretroviral treatment.

We analysed samples from 10 individuals with HIV-1 on ART who participated in the IMEA 043-CESAR trial and received rosuvastatin for 12 weeks. We explored whether rosuvastatin treatment was accompanied by changes in the memory potential of CD8+ T cells. We evaluated the phenotype and functionality of total and HIV-specific CD8+ T cells before, during, and after treatment with rosuvastatin. A mixed effects model was used for repeated measures and corrected for multiple comparisons.

Total and HIV-specific CD8+ T cell survival and functionality were enhanced in individuals who received a 12-week course of rosuvastatin, with a consistent increase in polyfunctional IFN-γ+ TNF-α+ cells. The superior CD8+ T cell functionality after rosuvastatin treatment was associated with intrinsic metabolic changes, including the decrease of fatty acid uptake, as well as a reduction in effector/exhaustion markers. Changes in the characteristics of CD8+ T cells coincided with the duration of rosuvastatin administration, and most effects waned after the cessation of the treatment.

CD8+ T cell metabolic reprogramming by targeting the cholesterol pathway, combined with other available immunotherapies, might represent a promising strategy in the search for the cure of HIV or other chronic viral infections.

The CESAR trial was sponsored by IMEA. This work was supported by the NIH (grants UM1AI164562 and R01DK131476).

Rationale: Programmed cell death protein 1 (PD-1)-expressing CD8+ T cells are typically associated with exhaustion in cancer and infections, but their role in autoimmune diseases, particularly lupus nephritis (LN), remains less understood. Understanding the characteristics and functions of PD-1+CD8+ T cells in LN could help identify novel therapeutic strategies. Methods: We analyzed the abundance and phenotypes of PD-1+CD8+ T cells in LN patients and NZB/W F1 mice. Single-cell RNA sequencing (scRNA-seq) was used to delineate subsets and TCR clonal diversity in PD-1+CD8+ T cells in NZB/W F1 mice. The therapeutic efficacy of a PD-L1 Fc fusion protein on kidney pathology and proteinuria in NZB/W F1 mice was evaluated. In addition, the inhibitory mechanism of PD-1 in CD8+ T cells were further explored using RNA-seq, q-PCR, flow cytometry, and Western blot. Results: PD-1+CD8+ T cells were enriched in LN patients and NZB/W F1 mice, exhibiting elevated activation markers and cytotoxic molecules compared to PD-1- cells. scRNA-seq identified seven distinct subsets with diverse effector functions and robust TCR clonal expansion in the kidney of NZB/W F1 mice with severe disease. PD-L1 Fc treatment reduced kidney damage and proteinuria in NZB/W F1 mice, which correlated with decreased frequencies of PD-1+CD8+ and IFN-γ+CD8+ T cells. Mechanistically, PD-L1 Fc inhibited Stat1 phosphorylation, T-bet expression, and IFN-γ production in CD8+ T cells. Conclusion: These findings show that PD-1+CD8+ T cells in LN are hyperactive, clonally expanded, and contribute to disease progression. Targeting the PD-1/PD-L1 pathway with PD-L1 Fc effectively reduced kidney pathology in a murine model of LN, underscoring the potential of modulating PD-1 signaling as a treatment strategy for LN.

Significant sex disparities have been observed in cancer incidence, treatment response to immunotherapy, and susceptibility to adverse effects, affecting both reproductive and non-reproductive organ cancers. While lifestyle factors, carcinogenic exposure, and healthcare access contribute to these disparities, they do not fully explain the observed male-female variation in anti-tumor immunity. Despite the preferential expression of sex hormone receptors in immune cells, X chromosome also contains numerous genes involved in immune function, and its incomplete inactivation may enhance anti-tumor immune responses in females. In contrast, loss or downregulation of Y-linked genes in males has been associated with an increased cancer risk. Additionally, estrogen, progesterone and androgen signaling pathways influence both innate and adaptive immune responses, contributing to sex-specific outcomes in cancer progression and therapy. Sex-biased differences are also evident in the epigenetic regulation of gene expression, cellular senescence, microbiota composition, metabolism, and DNA damage response, all of which impact anti-tumor immunity and immunotherapy treatment efficacy. In general, the combination of sex chromosomes, sex hormones, and hormone receptors orchestrates the phenotype and function of various immune cells involved in tumor immunity. However, sex disparity in each specific immune cell are context and environment dependent, considering the preferential expression of hormone receptor in immune cell and sex hormone levels fluctuate significantly across different life stages. This review aims to outline the molecular, cellular, and epigenetic changes in T cells, B cells, NK cells, DCs, neutrophils, and macrophages driven by sex chromosomes and sex hormone signaling. These insights may inform the design of sex-specific targeted therapies and leading to more individualized cancer treatment strategies.

Chimeric antigen receptor (CAR) T cell therapies have revolutionized B cell malignancy treatment, but subsets of patients with large B cell lymphoma (LBCL) experience primary resistance or relapse after CAR T cell treatment. To uncover tumor microenvironment (TME)-induced resistance mechanisms, we examined patients' intratumoral immune infiltrates and observed that elevated levels of immunoregulatory macrophages in pre-infusion tumor biopsies are correlated with poor clinical responses. CAR T cell-produced interferon-gamma (IFN-γ) promotes the expression of inducible nitric oxide synthase (iNOS, NOS2) in immunoregulatory macrophages, impairing CAR T cell function. Mechanistically, iNOS-expressing macrophages upregulated the p53 pathway, mediating apoptosis and cell cycle arrest in CAR T cells, while downregulating the MYC pathway involved in ribosome biogenesis and protein synthesis. Furthermore, CAR T cell metabolism is compromised by depletion of glycolytic intermediates and rewiring of the TCA cycle. Pharmacological inhibition of iNOS enhances the CAR T cell treatment efficacy in B cell tumor-bearing mice. Notably, elevated levels of iNOS+CD14+ monocytes were observed in leukaphereses of patients with non-durable response to CAR T cell therapy. These findings suggest that mitigating iNOS in tumor-associated macrophages (TAMs) by blocking IFN-γ secretion from CAR T cells will improve outcomes for LBCL patients.

The occurrence of pediatric diarrhea is frequently associated with inflammatory responses, compromised barrier function, and dysbiosis in the gut. These conditions are commonly triggered by stressors, similar to postweaning diarrhea observed in piglets. Garlic-derived exosome-like nanoparticles (GELNs) hold the potential for ameliorating stress-induced diarrhea, yet supporting evidence remains scarce. Following the successful isolation of GELNs, this study employed weaned piglets as a model to evaluate the regulatory effects of GELNs on intestinal barrier integrity, mucosal inflammation, and the gut microbiota and its metabolites. Weaned Bama miniature piglets were orally administered phosphate buffer saline (PBS) or GELNs, and 1 week later, samples were collected following slaughter. Histological and molecular biological techniques were performed to examine intestinal structure, tight junction protein expression, mucin secretion, T lymphocyte infiltration, and the levels of pro-inflammatory cytokines. The composition of the gut microbiota was analyzed using 16S rRNA sequencing, while its derived metabolites were profiled via untargeted metabolomics. Subsequently, correlation analyses were performed to evaluate the associations between the microbiota and its derived metabolites, as well as between the microbiota and the key indicators of intestinal barrier function and cytokine levels in response to GELNs. The isolated GELNs exhibit typical exosome characteristics in size and morphology, alongside a rich content of proteins and RNAs. The incidence of diarrhea in weaned piglets was reduced with supplementation of GELNs at a dosage of 50 mg/kg body weight, compared to the control group. In addition, piglets receiving GELNs displayed an increase in mucin content within the tissues of the jejunum, ileum, and colon, a decrease in CD8+ T lymphocyte counts in the colon, and suppression of pro-inflammatory cytokines (IL-8 and TNF-α) levels in the mucosal layers of both the jejunum and ileum. Furthermore, 16S rRNA sequencing unveiled that GELNs reshaped the colonic microbiota in weaned piglets by augmenting beneficial bacteria, notably Lactobacillus and Lactobacillus reuteri, correlating strongly with diminished TNF-α protein levels and heightened mucin expression. Metabolite analysis demonstrated a significant increase in indole-3-propionic acid, derived from the gut microbiota, in piglets supplemented with GELNs. This increase was positively correlated with the abundance of Lactobacillus and Lactobacillus reuteri and negatively linked with the protein levels of IL-8 and TNF-α in the gut. In summary, our study demonstrates that GELNs mitigate stress-related intestinal mucosal inflammation and enhance mucin production in the gut of weaned piglets, which is potentially achieved through the optimization of gut microbiota composition, specifically by increasing the abundance of Lactobacillus and Lactobacillus reuteri, as well as via the induction of the anti-inflammatory microbial metabolite indole-3-propionic acid. The findings presented here provide essential groundwork for the future development of GELNs as a therapeutic strategy aimed at enhancing gut homeostasis disruption caused by stress in both weaned piglets and children.

Myasthenia Gravis (MG) is a heterogeneous autoimmune disorder characterized by fluctuating muscle weakness caused by autoantibodies targeting neuromuscular junction components. While the role of CD4 + T cells in MG is well established, the contribution of CD8 + T cells remains poorly understood. In this study, we analyze CD8 + T cells in 36 MG patients and 38 age- and gender-matched controls using flow cytometry to evaluate subset distribution, granzyme expression, and cytokine production. MG patients exhibit an altered CD4 + /CD8 + T cell ratio and significant changes in CD8 + T cell subsets, including increased central memory CD8 + T cell (Tcm) proportions and decreased effector memory CD8 + T cell (Tem) proportions. Granzyme B expression in Tcm cells is significantly elevated in MG patients, whereas no significant changes are observed in other subsets or GZMK expression. Cytokine analysis reveals increased IL-21, GM-CSF, and IL-17A production by CD8 + T cells in MG patients. These phenotypic and functional alterations of CD8 + T cells persist during the acute phase of the disease, regardless of immunotherapy usage, and vary between ocular and generalized MG. Subgroup and correlation analyses further identify age-dependent and age-independent dysregulations of CD8 + T cells, indicating complex and subtype-specific roles of CD8 + T cells in the immunopathological processes underlying MG. Our findings provide novel insights into the involvement of CD8 + T cells in MG pathogenesis, laying a foundation for future research and potential therapeutic strategies targeting CD8 + T cells.

Melanoma is a highly invasive malignancy with poor prognoses in advanced stages. Developing a risk model that can accurately assess prognosis and guide personalized treatment is crucial for improving the clinical management of melanoma. This study aims to develop and validate an immune-based prognostic risk model for melanoma through comprehensive bioinformatics analysis. We collected transcriptomic data from multiple public databases and identified 9 immune features significantly associated with prognosis using single-sample Gene Set Enrichment Analysis (ssGSEA) and Cox regression. These features were utilized to construct the risk model, which was subsequently validated using relevant bulk transcriptomic datasets and single-cell transcriptomic datasets from the GEO database, encompassing diverse patient populations and sample types. The model effectively stratified patients into high-risk and low-risk groups with distinct survival outcomes. Further analysis revealed significant associations between the risk model and genomic heterogeneity indicators, such as tumor mutational burden (TMB), loss of heterozygosity (LOH), and immune checkpoint gene expression. The model robustness was confirmed using single-cell transcriptomic data, highlighting key genes with potential therapeutic relevance. Our findings provide a reliable prognostic tool and novel insights for personalized melanoma treatment, emphasizing the need for further clinical validation.