e21531 Background: Melanoma immunotherapy faces challenges due to heterogeneous patient responses. Current predictive biomarkers are not available in clinical practice. Serum lipids, crucial in tumor biology, show prognostic potential but lack consistent validation. To develop and validate a machine learning (ML) prognostic model integrating systemic lipid metabolism factors for predicting overall survival in melanoma patients receiving immunotherapy. Methods: A retrospective study of 381 melanoma patients was conducted. LASSO and Cox regression analyses identified prognostic features. Eight ML algorithms were trained and validated on a 7:3 split dataset to build the model. The best model was deployed as a publicly accessible application. We conducted SHAP analysis at 1-year, 3-year, and 5-year survival timepoints to generate variable importance rankings for each time node. To further investigate the key populations benefiting from the protective factor and explore whether this protection might be mediated through lipid regulation, we performed subgroup and interaction analyses using previously established thresholds. Results: The LASSO-Cox model demonstrated superior performance. Multivariable analysis identified mucosal subtype, advanced AJCC stage, high Lactate Dehydrogenase, and Ki67 index as risk factors, while high high-density lipoprotein cholesterol (HDL-C) was a protective factor. SHAP analysis ranked HDL-C as the most important predictive feature. Subgroup analysis revealed a more pronounced protective effect of high HDL-C in patients with hyperlipidemia. Finally, the model was deployed as a web (https://melanomaslnmodel.shinyapps.io/Shiny/) application to facilitate its potential clinical utility. Conclusions: HDL-C is a significant prognostic factor in melanoma immunotherapy. The web-based model provides an accurate risk prediction tool, highlighting the importance of monitoring lipid profiles in patient management.

Gasdermins have been traditionally recognized for their canonical pore-forming activity in pyroptosis and generally considered as a tumor suppressor due to their low endogenous expression in various types of cancers. However, the pyroptosis-independent role of gasdermins in cellular biological processes remains poorly understood, sparking debates on their actual contribution to cancer pathogenesis. Here, we demonstrate a novel facet of GSDME as an epigenetic modifier that promotes melanoma development through the regulation of the centriole biogenesis regulator PLK4. Unexpectedly, GSDME expression is significantly up-regulated in melanoma, induced by prominent hypo-methylation at its promoter. The deficiency of GSDME prominently suppresses tumor growth and metastasis of melanoma, independent of CD8+ T cell-dependent anti-tumor immunity. Mechanistically, GSDME forms a complex with SMARCA5 and NCL in the nucleus, functioning as an epigenetic regulator, particularly facilitating the transcription of centriole biogenesis regulator PLK4 by increasing its promoter chromatin accessibility. The regulation of PLK4 is greatly implicated in the oncogenic role of GSDME in melanoma. Ultimately, this GSDME-SMARCA5/NCL-PLK4 axis is validated in patients with melanoma and has been proved of promising prognostic potential. Altogether, these results demonstrate that GSDME could be a critical oncogene through its pyroptosis-independent epigenetic regulatory function.

The prognosis of advanced melanoma remains poor, and immune checkpoint inhibitor monotherapy often shows limited efficacy, especially in acral and mucosal subtypes. This challenge is particularly relevant for Chinese patients. We conducted this retrospective cohort study to evaluate outcomes associated with the addition of anlotinib to anti-PD-1 plus IFN-α1b as first-line treatment for advanced melanoma. A total of 211 patients with stage Ⅲ-IV unresectable melanoma treated between June 2020 and June 2024 were included, of whom 179 received the doublet and 32 received the triplet therapy. Propensity score overlap weighting was applied to substantially improve the balance of measured baseline characteristics between the two groups. After weighting, triplet therapy was associated with longer overall survival than doublet therapy, with a median overall survival of 35.8 versus 16.2 months, respectively (HR, 0.42; 95

Vitiligo is a skin disease characterized by the destruction of epidermal melanocytes due to oxidative stress. Keratinocytes are the main responder to oxidative stress and facilitate melanocyte loss by inducing melanocyte death and recruiting antigen-specific CD8+ T cell to skin to destroy melanocytes. It has been proved that keratinocytes secrete functional exosomes, but the role of exosomes secreted from keratinocytes under oxidative stress in vitiligo pathogenesis is unknown. The present study investigated the role of exosomes from H2O2-treated human keratinocytes in the vitiligo progression in vitro. and in vivo. The results demonstrated that oxidative stress enhanced the secretion of exosomes from keratinocytes. These exosomes (OS-Exos) suppressed the survival of melanocytes while promoting the proliferation and activation of CD8+ T cells in vitro. Then, we confirmed that OS-Exos administration aggravated melanocyte loss and CD8+ T cell infiltration in the epidermis in the vitiligo mouse model, thereby driving vitiligo progression. Further, we performed Small RNAs-seq to screen miRNAs enriched in OS-Exos. The subsequent results revealed that miR-31-3p, which was enriched in OS-Exos, facilitated melanocyte death and decreased the expression of melanogenesis-related genes through MITF signaling. Meanwhile, it was found that miR-31-3p promoted the activation of CD8+ T cells, which could depend on impaired immunosuppression and activated T-cell growth. Taken together, these data suggest that OS-Exos enriched with miR-31-3p facilitated vitiligo progression through the destruction of melanocytes and activation of CD8+ T cells. Keratinocytes-derived exosomes under oxidative stress could serve as an important mediator for oxidative stress-induced killing of melanocytes in vitiligo.

Resistance to targeted therapies poses a significant challenge in advanced melanoma with BRAF mutations. Even with a BRAF + MEK inhibitor combination, about 70% of patients experience disease progression within two years, highlighting the need for novel strategies beyond MAPK signaling inhibition. This study investigates whether mitochondrial dysfunction induced by the copper ionophore disulfiram (DSF) can effectively counteract resistance to BRAF inhibitors. We established two BRAF inhibitor (BRAFi)-resistant melanoma cell lines using BRAF mutant 451Lu and UACC62. In vivo experiments were conducted using subcutaneous implantation in nude mice. Cell viability and colony formation assays assessed treatment efficacy, while mitochondrial morphology was evaluated via transmission electron microscopy. Mitochondrial respiration was measured using a Seahorse metabolic analyzer, and oxidative stress was assessed through flow cytometry and confocal microscopy. RNA sequencing identified downstream factors regulated by intracellular copper levels, and the CRISPR-Cas9 system was used to knock out candidate genes in BRAFi-resistant cells for mechanistic validation. We provided evidence that DSF induced cell death in BRAFi-resistant melanoma in a copper-dependent manner, severely impairing mitochondrial structure and function through increased oxidative stress. RNA-seq and immunoblotting revealed that thioredoxin-interacting protein (TXNIP) expression significantly increased in response to DSF. TXNIP knockout reduced DSF-induced cytotoxicity by mitigating oxidative stress. These findings were supported by in vivo experiments. Furthermore, we demonstrated that the oxidative damage mediated by TXNIP involved its interaction with thioredoxin 2 (TRX2). In conclusion, targeting mitochondrial function with disulfiram effectively inhibits BRAFi-resistant melanoma cells, independent of MAPK signaling blockage. These results point to the potential of combining disulfiram with BRAF inhibitors as a promising strategy to overcome BRAFi resistance.

Enhanced cholesterol biosynthesis is a hallmark metabolic characteristic of cancer, exerting an oncogenic role by supplying intermediate metabolites that regulate intracellular signaling pathways. The pharmacological blockade of cholesterol biosynthesis has been well documented as a promising therapeutic approach in cancer. Particularly, cholesterol biosynthesis is linked to macroautophagy/autophagy and lysosome metabolism, with the engagement of the critical autophagy regulators like MTOR to be fully activated by lysosomal cholesterol trafficking and accumulation. Previous studies have primarily focused on the role of cholesterol biosynthesis in tumor cell-intrinsic biological processes, whereas its involvement in tumor immune evasion and the underlying mechanisms related to autophagy or lysosome metabolism remain elusive. Herein, through bioinformatics analysis we discovered a negative correlation between cholesterol biosynthesis and the score of tumor-infiltrating lymphocytes in cancers. Inhibition of tumor cell cholesterol biosynthesis leads to increased infiltration and activation of CD8+ T cells in the tumor microenvironment, which is largely responsible for the impairment of tumor growth. Mechanistically, cholesterol biosynthesis inhibition impairs the activation of MTOR at lysosomes, thereby promoting the nuclear translocation of TFEB and downstream lysosome biosynthesis, facilitating the degradation of CD274/PD-L1 within lysosomes in tumor cells. Ultimately, the HMGCR-MTOR-LAMP1 axis that connects cholesterol, lysosome and tumor immunology, predicts poor response to immunotherapy and worse prognosis of patients with melanoma. These findings unveil an immunomodulatory role of tumorous cholesterol biosynthesis via the regulation of CD274 lysosomal degradation. Targeting cholesterol biosynthesis holds promise as a potential therapeutic strategy in cancer, particularly when combined with immune checkpoint blockade.Abbreviations: ATG5, autophagy related 5; CD274/PD-L1, CD274 molecule; CQ, chloroquine; CTLA4, cytotoxic T-lymphocyte associated protein 4; CHX, cycloheximide; EIF4EBP1, eukaryotic translation initiation factor 4E binding protein 1; GSVA, gene set variation analysis; GZMB, granzyme B; HMGCR, 3-hydroxy-3-methylglutaryl-CoA reductase; IFNG/IFN-γ, Interferon gamma; IHC, Immunohistochemistry; LAMP1, lysosomal associated membrane protein 1; MITF, melanocyte inducing transcription factor; MTOR, mechanistic target of rapamycin kinase; NK, natural killer; NSCLC, non-small cell lung cancer; PBMC, peripheral blood mononuclear cell; PDCD1/PD-1, programmed cell death 1; qRT-PCR, quantitative real-time polymerase chain reaction; SKCM, skin cutaneous melanoma; TCGA, The Cancer Genome Atlas; TFE3, transcription factor binding to IGHM enhancer 3; TFEB, transcription factor EB; TIL, tumor infiltrated lymphocyte; TME, tumor microenvironment; Treg, regulatory T.

Melanoma is the most life-threatening skin cancer with increasing incidence around the world. Although recent advances in targeted therapy and immunotherapy have brought revolutionary progress of the treatment outcome, the survival of patients with advanced melanoma remains unoptimistic, and metastatic melanoma is still an incurable disease. Therefore, to further understand the mechanism underlying melanoma pathogenesis could be helpful for developing novel therapeutic strategy. A20 is a crucial ubiquitin-editing enzyme implicated immunity regulation, inflammatory responses and cancer pathogenesis. Herein, we report that A20 played an oncogenic role in melanoma. We first found that the expression of A20 was significantly up-regulated in melanoma cell lines. Then, we showed that knockdown of A20 suppressed melanoma cell proliferation in vitro and melanoma growth in vivo through the regulation of cell-cycle progression. Moreover, A20 could potentiate the invasive and migratory capacities of melanoma cell in vitro and melanoma metastasis in vivo by promoting epithelial-mesenchymal transition (EMT). Mechanistically, we found that Akt activation mediated the oncogenic effect of A20 on melanoma development, with the involvement of glycolysis. What's more, the up-regulation of A20 conferred the acquired resistance to Vemurafenib in BRAF-mutant melanoma. Taken together, we demonstrated that up-regulated A20 promoted melanoma progression via the activation of Akt pathway, and that A20 could be exploited as a potential therapeutic target for melanoma treatment.

Background: Risk factors for sentinel lymph node (SLN) metastasis in melanoma have been studied. However, there remains a lack of widely applicable models with considerable predictive potential for clinical use. Objective: To developed a well-performing machine learning-based model for predicting SLN metastasis in melanoma patients. Methods: This study collected data on 351 melanoma patients with sentinel lymph node biopsy from our center. Univariate and multivariate logistic regression was used for recognizing key features. The optimal model was selected from 10 machine learning algorithms based on the F1 score. SHapley Additive exPlanations was employed to interpret the outcome of the predictive model. R package Shiny was used to develop a web tool. Results: The neural network model was chosen with the highest F1-score (0.73), indicating considerable predictive accuracy and calibration. SHapley Additive exPlanations results indicate the related factors for SLN metastasis in melanoma patients were Breslow thickness, microsatellites, Ki67 index, and subtype. Ultimately, we developed a web-based tool to promote the clinical application of the model. Limitations: Retrospective study, single institution. Conclusions: This study established a robust and interpretable machine learning approach for melanoma SLN metastasis prediction. With high sensitivity and accuracy, this approach could reduce misdiagnosis rates and alleviate patient suffering.

Introduction: Vitiligo is a hypopigmentation disorder characterized by epidermal melanocyte loss. Endogenous and exogenous oxidative stress causes the regulated cell death (RCD) of melanocytes in vitiligo. Recent studies have indicated that ferroptosis participates in vitiligo pathogenesis. Nevertheless, the underlying regulatory mechanisms remain elusive. Sirtuins (SIRT1-7) are nicotinamide adenine dinucleotide (NAD)+-dependent histone deacetylases, which are involved in a diverse array of cellular and physiological processes, including the inhibition of stress-induced ferroptosis. Objective: To investigate the potential regulatory mechanisms of SIRT7 in ferroptosis of vitiligo melanocytes. Methods: The protein levels of ferroptosis-related molecules were detected in perilesional skin from vitiligo patients and healthy donors. Genetic intervention targeting SIRT7 and biochemical assays were utilized to study the critical role and regulatory mechanisms of SIRT7 against oxidative stress-induced ferroptosis in melanocytes. The establishment of a vitiligo mouse model with melanocyte-specific Sirt7 knockout mice (Sirt7 MCKO) was engaged to verify the role of SIRT7 in vitiligo. Results: We found that anti-ferroptosis molecule expressions were significantly downregulated in melanocytes localized in vitiligo perilesional skin. Vitiligo melanocytes exhibited increased susceptibility to ferroptosis induced by oxidative stress compared to normal melanocytes. Furthermore, the expression and activity of SIRT7 were severely impaired in vitiligo melanocytes, as verified by publicly-available single-cell RNA sequencing (scRNA-seq) data. Mechanistically, SIRT7 promoted the expression of glutathione peroxidase 4 (GPX4) to protect melanocytes against ferroptosis via drosophila mothers against decapentaplegic protein 3 (SMAD3)-activating transcription factor 3 (ATF3) signaling pathway. What’s more important, the melanocyte-specific Sirt7 knockout could exacerbate the progression of vitiligo in mice, accompanied by reduced expression of GPX4 and increased levels of ATF3. Conclusion: Our study demonstrates that SIRT7 deficiency exacerbated ferroptosis of melanocytes induced by oxidative stress and contributed to vitiligo pathogenesis. The activation of SIRT7 could serve as a potential therapeutic strategy for preserving melanocyte survival in vitiligo.

White patchy skin lesions have always been difficult to distinguish, yet precise identification of specific types can enable targeted treatment and alleviate patient anxiety. Deep convolutional neural networks (DCNNs) show great potential in this regard. However, DCNNs still exhibit limitations such as incapacity to capture global correlations, inability to discern invisible data distributions, and difficulty in handling imbalanced datasets. To address these challenges, we propose a feature enhancement and interaction transformer module for accurately identifying common white patches. Our approach begins with the development of a dual-position encoding attention and convolution hybrid submodule, which aims to model the global information of the feature domain and enhance feature representation. Subsequently, we construct a feature interaction submodule on the batch dimension to enable the DCNN to explore sample relationships, learn about invisible distribution from the dataset, and reduce the imbalance problem. Based on the dataset comprising four types of white patchy skin lesions, the proposed approach achieved an accuracy, precision, recall, F1 score, and AUC of 92.65 %, 92.83 %, 92.65 %, 92.74 %, and 0.98, respectively. These results demonstrate the superior performance of our approach compared to other state-of-the-art models, underscoring its potential to enhance the classification of white patchy skin lesions and expand their clinical applications without compromising the integrity of the DCNN structure.

Vitiligo is a common dermatological disease featuring hypopigmentation. Accurate staging of vitiligo is crucial for enhancing treatment efficacy. However, traditional diagnostic methods, which rely on physicians' subjective judgments, are time-consuming, labor-intensive, and prone to misdiagnosis. Recently, AI-powered multimodal dermatological classification models have demonstrated significant potential in this area. But the credibility of these models at the decision-making stage is an area that requires further refinement. This study proposes a multimodal disease staging diagnostic model with uncertainty calibration to analyze multimodal samples from three stages of vitiligo. The model innovatively extracts feature information from various modalities and transforms it into a Dirichlet distribution to assess sample uncertainty. Then, the Dempster—Shafer theory is used to fuse evidence from different modalities, generating a final diagnostic result and an uncertainty score. Additionally, an uncertainty—based loss function is designed. And by using an uncertainty threshold method, the model can detect high—uncertainty samples that require additional judgment, effectively reducing the risk of misdiagnosis and missed diagnosis. Experimental results show that this model outperforms existing methods in terms of accuracy, precision, recall, and F1—score. Anomaly detection and noise—resistance experiments verify the model's robustness in handling unknown and noisy data. This model offers a new approach for AI-assisted vitiligo diagnosis, which can assist doctors in making more accurate diagnostic decisions, contribute to improving treatment efficiency.

Although dendritic cell (DC)- and CD8+ T cell-mediated autoimmunity is critical for destroying melanocytes in vitiligo, treatment options remain limited by the absence of therapies that cotarget both cell types. We first evaluated the association between the immunoregulatory metabolite itaconate and disease development, by determining human vitiligo serum itaconate levels and monitoring depigmentation progression in Acod1 knockout (KO) mice with endogenous itaconate deficiency. We further evaluated the therapeutic efficacy of the itaconate derivative, dimethyl itaconate (DI) in mice and assessed its effects on cutaneous infiltration and the functional properties of DCs and CD8+ T cells in vivo and ex vivo. The gene signatures and signaling pathways involved in DI-treated CD8+ T cells were also assessed. We observed an elevation of circulating itaconate in vitiligo patients, whereas itaconate deficiency accelerated depigmentation in Acod1 KO mice after vitiligo induction. The administration of DI halted vitiligo development and promoted repigmentation, with elevated circulating itaconate levels, increased melanocyte counts, and decreased cutaneous CD8+ T cell densities. Mechanistically, DI dampened CD8+ T cell activation (CD69), effector function (Interferon-γ, IFN-γ), cytotoxicity (Gzmb), proliferation, and proinflammatory gene expression (Csf1, Ifitm1, CD49a, NKG2D, and NKG2A), partly by suppressing the Janus kinase (JAK)‒STAT pathway. Moreover, DI-treated mice exhibited reduced cutaneous DC infiltration, as well as fewer DCs with mature and migratory phenotypes. Our findings identify DI as a metabolite-derived small molecule that protects against autoimmune injury by cotargeting DC and CD8+ T cell responses, thereby demonstrating a promising therapeutic strategy and providing a foundation for treating vitiligo and other cell-specific autoimmune diseases.

Vitiligo, a prevalent skin condition characterized by depigmentation, presents challenges in staging due to its inherent complexity. Multimodal skin images can provide complementary information, and in this study, the integration of clinical images of vitiligo and those obtained under Wood's lamp is conducive to the classification of vitiligo stages. However, difficulties in annotating multimodal data and the scarcity of multimodal data limit the performance of deep learning models in related classification tasks. To address these issues, a Multimodal Masked Autoencoder (Multi-MAE) based on adaptive masking is proposed in annotating multimodal data and the problem of multimodal data scarcity, and enhances the model's ability to extract characteristics from multimodal data. Specifically, an image reconstruction task is constructed to diminish reliance on annotated multimodal data, and a pre-training strategy is employed to alleviate the scarcity of multimodal data. Experimental results demonstrate that the proposed model achieves a vitiligo stage classification accuracy of 95.48% on a dataset of unlabeled dermatological images, an improvement of 5.16%, 4.51%, 3.87%, 2.58%, 4.51%, 4.51%, 3.87%, and 2.58% over that of MobileNet, DenseNet, VGG, ResNet-50, BEIT, MaskFeat, SimMIM, and MAE, respectively. These results verify the effectiveness of the proposed Multi-MAE model in assessing the stable and active vitiligo stages, making it a suitable clinical aid for evaluating the severity of vitiligo lesions.

BACKGROUND:Mitochondria play a pivotal role in oxidative stress-induced melanocyte destruction in vitiligo. FUN14 domain containing 1 (FUNDC1), a mitochondrial outer-membrane protein, has an important role in mitochondrial function by regulating mitophagy and mitochondria-associated endoplasmic reticulum membranes (MAM). However, the role of FUNDC1 in melanocyte damage under oxidative remains unclear. OBJECTIVES:To determine the contribution of FUNDC1 to oxidative stress-triggered melanocyte damage in vitiligo. METHODS:We treated human melanocyte cell line PIG1 with H2O2 to establish an oxidative stress model. Cell viability, mitochondrial function and dynamics as well as mitophagy were detected. The transmission electron microscopy was used to assess MAM structure. FUNDC1 was then knocked down to examine its effects on MAM structure and mitochondrial function under H2O2 treatment. Additionally, we compared FUNDC1 expression, MAM structure and mitochondrial function between PIG1 cells and human vitiligo melanocyte cell line PIG3V. Finally, FUNDC1 expression and MAM structure were analyzed in vitiligo lesions and healthy control skin. RESULTS:H2O2 treatment significantly increased intracellular H2O2 level, mitochondrial superoxide and lipid peroxide (LPO), while decreased glutathione (GSH) level in PIG1 cells. Impaired cell viability and mitochondrial function as well as excessive mitochondrial fission in PIG1 cells were observed after H2O2 incubation. However, H2O2 treatment didn't induce mitophagy but enhanced FUNDC1 expression and altered MAM structure. FUNDC1 knockdown inhibited H2O2-induced changes of MAM structure, mitochondrial calcium overloading, mitochondrial dysfunction, and recovered cell viability under oxidative stress. Interestingly, persistent H2O2 exposure reduced FUNDC1 expression, leading to MAM formation deficiency, excessive mitochondrial fusion and compromised mitochondrial function in the human vitiligo melanocyte cell line PIG3V. Finally, the decreased FUNDC1 expression and dysregulated MAM formation were confirmed in vitiligo lesions. CONCLUSIONS:FUNDC1-dependent MAM structure mediates oxidative stress-induced mitochondrial dysfunction and melanocytes damage in vitiligo, suggesting that FUNDC1 and its associated MAM structure are potential targets for vitiligo treatment.

The pathogenesis of cancer is complicated, with metabolic reprogramming and angiogenesis as the hallmark characteristics. Recent reports have unveiled that the glycolytic metabolite lactate could modify histone lactylation to epigenetically regulate gene expressions and biological processes in cancer, while the effect on tumor angiogenesis remains elusive. By taking advantage of melanoma as the model, we first proved that lactate and histone lactylation facilitated melanoma angiogenesis both in vitro and in vivo. Then, through RNA-sequencing and a series of biochemical assays, we found that lactate promoted the transcription of suppression of tumorigenicity 2 (ST2) in tumor-associated endothelial cells via the enhancement of histone lactylation at its promoter, so that to increase the response of endothelial cells to pro-angiogenic interleukin-33 (IL-33) stimulation. In addition, lactate could also suppress high endothelial venules transition of endothelial cells, which was critical for tumor development. Ultimately, the effect of anti-angiogenic drug synergized with lactate dehydrogenase (LDH) inhibition/ST2 inhibition on melanoma growth was proved in vivo. Taken together, we demonstrated that lactate-mediated histone lactylation promotes melanoma angiogenesis via IL-33/ST2 axis, which delineated a novel regulatory relationship among lactate, histone lactylation and angiogenesis in cancer, and provided a promising combined therapeutic strategy to target angiogenesis from the perspective of cell metabolism and epigenetics in cancer.

Besides the important pathogenic mechanisms of melanoma, including BRAF-driven and immunosuppressive microenvironment, genomic instability and abnormal DNA double-strand breaks (DSB) repair are significant driving forces for its occurrence and development. This suggests investigating novel therapeutic strategies from the synthetic lethality perspective. Poly (ADP-ribose) polymerase 4 (PARP4) is known to be a member of the PARP protein family. The low expression of PARP4 is significantly associated with defective DSB repair markers and poor prognosis in melanoma. Further research revealed that PARP4 plays a role in DSB repair by regulating the non-homologous end joining (NHEJ) pathway through its involvement in Ku80 mono-ADP-ribosylation. Moreover, from a synthetic lethality perspective, PARP4 expression is associated with ATM inhibitor sensitivity. Overall, our study provides new and valuable insights into the function of PARP4 and melanoma pathogenesis and suggests that ATM inhibitor may be a promising therapeutic approach for treating melanoma with low PARP4 expression.

Acetyl coenzyme A (acetyl-CoA), a versatile central metabolite, plays a critical role in various metabolic processes and protein acetylation. While its impact on tumor cell properties is well established, the connection between acetyl-CoA metabolism and immune evasion in tumors remains unclear. Here, we uncover a mechanism by which nucleo-cytosolic acetyl-CoA contributes to immune evasion through regulation of programmed death ligand 1 (PD-L1). Specifically, bioinformatics analysis reveals a negative correlation between acetyl-CoA metabolism and anti-tumor immunity across multiple cancers. Inhibition of the acetyl-CoA-producing enzyme ATP-citrate lyase (ACLY) leads to a re-invigoration of cytotoxic T cells and enhances the efficacy of immunotherapy. Mechanistically, nucleo-cytosolic acetyl-CoA promotes PD-L1 transcription via P300-dependent histone H3K27 acetylation at the promoter region of CD274. The ACLY-H3K27ac-PD-L1 axis is verified in clinical specimens and predicts poor immunotherapy response. Our findings suggest that targeting acetyl-CoA metabolism may act as a promising strategy to overcome immune evasion and improve the outcomes of cancer immunotherapy.

AbstractBackgroundImmune‐checkpoint inhibitors are now used more commonly in combination than monotherapy as the first‐line choice in patients with unresectable advanced melanoma. Nevertheless, for cases that progressed after the initial combination therapy, the subsequent regimen option can be very difficult. Herein, we reported the efficacy and safety of a triple combination regimen in Chinese unresectable advanced melanoma patients who had poor responses to the first‐line immune therapy.MethodsWe reviewed the clinical profiles of patients diagnosed with stage IIIC‐IV melanoma between June 1, 2020, and September 30, 2023. The patients who failed the prior immune therapies and received anti‐PD‐1 mono antibody plus interferon(IFN)‐alpha 1b and anlotinib hydrochloride as the second‐line therapy were enrolled in the retrospective analysis. Additionally, we examined the exhaustion of T‐cells using mIHC staining in available tumor samples.ResultsFifty‐five patients were included in this study. The median follow‐up period was 13.6 months. The objective response rate evaluated by the investigators was 9.1%(1CR, 4PR). The disease control rate was 47.3%. The median overall survival was 17.6 months, and the median progression‐free survival was 2.8 months. The adverse events rate of any grade was 100%. Grade 3 or 4 irAEs were observed in 29.1% of cases. Multiplex immunohistochemical staining revealed an increased trend of TIM3 expression on tumor‐infiltrating T cells in patients without objective response.ConclusionPD‐1 monoclonal antibody plus interferon‐alpha 1b plus anlotinib showed acceptable tolerability and anticancer benefits in Chinese metastatic melanoma patients as a second‐line therapy.

Melanoma, arising from the malignant transformation of melanocytes, stands as the most lethal type of skin cancer. While significant strides have been made in targeted therapy and immunotherapy, substantially enhancing therapeutic efficacy, the prognosis for melanoma patients remains unoptimistic. SIRT7, a nuclear-localized deacetylase, plays a pivotal role in maintaining cellular homeostasis and adapting to external stressors in melanoma, with its activity closely tied to intracellular nicotinamide adenine dinucleotide (NAD+). However, its involvement in adaptive resistance to targeted therapy remains unclear. Herein, we unveil that up-regulated SIRT7 promotes mitochondrial biogenesis to render the adaptive resistance to MAPK inhibition in melanoma. Initially, we observed a significant increase of SIRT7 expression in publicly available datasets following targeted therapy within a short duration. In consistent, we found elevated SIRT7 expression in melanoma cells subjected to BRAF or MEK inhibitors in vitro. The up-regulation of SIRT7 expression was also confirmed in xenograft tumors in mice after targeted therapy in vivo. Furthermore, we proved that SIRT7 deficiency led to decreased cell viability upon prolonged exposure to BRAF or MEK inhibitors, accompanied by an increase in cell apoptosis. Mechanistically, SIRT7 deficiency restrained the upregulation of genes associated with mitochondrial biogenesis and intracellular ATP levels in response to targeted therapy treatment in melanoma cells. Ultimately, we proved that SIRT7 deficieny could sensitize BRAF-mutant melanoma cells to MAPK inhibition targeted therapy in vivo. In conclusion, our findings underscore the role of SIRT7 in fostering adaptive resistance to targeted therapy through the facilitation of mitochondrial biogenesis. Targeting SIRT7 emerges as a promising strategy to overcome MAPK inhibitor adaptive resistance in melanoma.

Objective To observe and analyze depression-like behavioral performances of mouse models of vitiligo.Methods Fifteen female C57BL/6 mice aged about 9 weeks were modeled for vitiligo.Whether the mouse models of vitiligo were successfully constructed or not was determined by macroscopy and full-thickness epidermal immunofluorescence staining of mouse tail tissues on day 23 after the start of the experiment;on day 8(pre-modeling stage)and day 21(early modeling stage),the elevated plus maze test and the open field test were used to evaluate the behavioral performances of the mice,including the number of entry into the open arms,percentages of time spent in the open arms,percentages of time spent in the central area and total distance traveled,aiming to assess whether depression-like behaviors were exhibited in the mouse models of vitiligo.To further clarify the degree of the impact of vitiligo modeling on the depression-like state in mice,20 female C57BU6 mice were equally divided into 2 groups:vitiligo modeling group and vitiligo modeling+chronic restraint stress group;the mice in the vitiligo modeling+chronic restraint stress group were subjected to chronic restraint stress on day 9,that is,these mice were placed in centrifuge tubes and restrained for about 6 hours every day for 28 consecutive days;on days 7,22,29 and 38 after the start of vitiligo modeling,the above-mentioned behavioral indicators were determined by the elevated plus maze test and open field test in the 2 groups.Repeated measurement data in a single group were compared before and after treatment by using paired t-test,and repeated measurement data at multiple time points were compared by using two-way repeated measures analysis of variance.Results By macroscopy,the mice gradually developed well-defined white patches on the tail skin during vitiligo modeling,which were similar to the clinical manifestations of vitiligo patients;on day 23,full-thickness epidermal immunofluorescence staining of the mouse tail tissues was conducted and showed obvious infiltration of CD8+T cells and a decrease in the number of Melan-A-positive epidermal melanocytes under a laser confocal microscope,which were consistent with typical pathological characteristics of vitiligo;based on the macroscopic results and immunofluorescence findings,a total of 12 mouse models of vitiligo were successfully constructed on day 23.The elevated plus maze test showed that the number of entry into the open arms and the percentages of time spent in the open arms were significantly lower in the 12 mouse models of vitiligo on day 21(2.33±1.78 times,5.01％±5.27％,respectively)than in those on day 8(10.75±2.30 times,29.20％±12.48％,t=9.63,6.36,respectively,both P＜0.001);the open field test showed that the percentages of time spent in the central area and total distance traveled were also significantly lower in the mouse models on day 21(2.31％±1.53％,2 518.31±528.38 cm,respectively)than in those on day 8(4.47％±2.65％,3 533.45±465.47 cm,t=2.40,5.47,P=0.036,＜0.001,respectively).In the chronic restraint stress test,a total of 14 mouse models of vitiligo were successfully constructed on day 23,including 5 in the vitiligo modeling group and 9 in the vitiligo modeling+chronic restraint stress group.There were no significant differences in the number of entry into the open arms,percentages of time spent in the open arms,percentages of time spent in the central area,and total distance traveled between the vitiligo modeling group and the vitiligo modeling+chronic restraint stress group on days 7,22,29,and 38(F=0.21,0.20,0.46,2.35,P=0.889,0.893,0.719,0.134,respectively);moreover,all the above indicators significantly changed over time(all P＜0.001),except for the total distance traveled(P=0.422).Conclusion The mouse models of vitiligo developed depression-like behavior at the early modeling stage,and the degree of depression could not be further deepened by chronic restraint stress on the basis of vitiligo modeling.