Small interfering RNA (siRNA) plays a crucial role in tumor therapy, especially for non-druggable targets with obvious advantages. Nevertheless, its molecular weight, negative charge, and susceptibility to degradation hinder effective delivery to tumor cells for therapeutic action. Lipid nanoparticles (LNPs) serve as an excellent delivery mechanism for siRNA but still face problems such as suboptimal tumor targeting and inefficient intracellular release. To enhance melanoma treatment, we designed lipid nanoparticles modified with phenylboronic acid (PBA) for efficient delivery of siRNA targeting "undruggable" microphthalmia-associated transcription factor (MITF). This nanocarrier successfully encapsulated siRNA and improved tumor targeting by allowing phenylboronic acid to interact with sialic acid residues overexpressed in tumor cells. Furthermore, PBA-modified lipid nanoparticles facilitated the ATP-responsive release of siRNA intracellular. These two aspects enhance gene silencing efficiency. The in vivo targeting and gene silencing capabilities of PBA-modified lipid nanoparticles significantly surpassed those of unmodified LNP. Additionally, PBA-modified nanoparticles exhibited considerable anti-tumor and anti-metastatic effects in animal models, offering an alternative approach for siRNA therapy.

The mechanisms behind UVB-initiated, neonatal-specific melanoma linked to BRAFV600E are not well understood, particularly regarding its role in growth arrest. We found that, beyond mutations, neonatal UV irradiation or Lkb1 loss promotes a cell-autonomous transcriptional reprogramming that prevents BRAFV600E-induced growth arrest, leading to melanoma development. Using UVB-dependent and independent mouse models, genomic analyses, clinical data, and single-cell transcriptomics, we identified a transcriptional program that bypasses growth arrest, promoting melanoma. In humans, many of these genes are linked to poor survival and are upregulated in melanoma progression and other RAS pathway-driven tumors. Reconstitution experiments showed these genes cooperate with BRAFV600E in melanocyte transformation, dedifferentiation, and drug resistance. Depleting gene products like UPP1 highlights their potential as therapeutic targets. Our findings reveal that BRAFV600E-mutated melanomas can develop independently of nevus progression and identify novel targets for treatment.

Melanoma is a devastating form of skin cancer characterized by a high mutational burden, limited treatment success, and dismal prognosis. Although immunotherapy and targeted therapies have significantly revolutionized melanoma treatment, the majority of patients fail to achieve durable responses, highlighting the urgent need for novel therapeutic strategies. Ferroptosis, an iron-dependent form of regulated cell death driven by the overwhelming accumulation of lipid peroxides, has emerged as a promising therapeutic approach in preclinical melanoma models. A deeper understanding of the ferroptosis landscape in melanoma based on its biology characteristics, including phenotypic plasticity, metabolic state, genomic alterations, and epigenetic changes, as well as the complex role and mechanisms of ferroptosis in immune cells could provide a foundation for developing effective treatments. In this review, we outline the molecular mechanisms of ferroptosis, decipher the role of melanoma biology in ferroptosis regulation, reveal the therapeutic potential of ferroptosis in melanoma, and discuss the pressing questions that should guide future investigations into ferroptosis in melanoma.

Cutaneous melanoma is characterized by malignant proliferation, high aggressiveness, high metastasis, rapid recurrence, and low survival rate; therefore, research on its treatment is vital. In this study, a novel nano system combining sonodynamics and immunotherapy for cutaneous melanoma treatment was designed and developed. Based on the use of phycocyanin for the biomineralization of manganese ions, smart and multifunctional manganese phycocyanin nanoparticles encapsulating the immune adjuvant levamisole (LMS) with melanoma B16-OVA cell membranes wrapped around its outer layer (Mn-PCNP-LMS@CM) were designed and prepared. The experimental results showed that Mn-PCNP-LMS@CM efficiently targeted cutaneous melanomas. Under ultrasonic excitation, it catalyzed oxygen production from hydrogen peroxide in the tumor environment, reduced high glutathione levels in tumor tissues, and significantly enhanced (reactive oxygen species) ROS generation, thus improving the outcome of sonodynamic therapy. In contrast, sonodynamic therapy induced immunogenic death of tumor cells, together with the loaded immune adjuvant levamisole, which promoted the maturation of dendritic cells (DCs), modulated the immunosuppressive microenvironment, enhanced the immunotherapeutic effect, and stimulated the function of long-term immune memory to prevent tumor growth and recurrence. This study is expected to provide new ideas for developing novel anti-tumor nano systems and achieving anti-tumor synergistic therapy.

Melanoma is the most dangerous skin cancer due to its difficulty in treatment, high recurrence rate and metastatic ability. As a vector for oncolytic viruses (OVs), vesicular stomatitis virus (VSV) has been shown to be effective against malignant melanoma. However, the glycoprotein G protein of VSV has potential neurotoxicity. It has been shown that replacing glycoprotein G with E3-E2-6K-E1 of chikungunya virus (CHIKV) reduces its neurotoxicity and targets gliomas. Therefore, the aim of this study was to investigate the oncolytic effect of recombinant VSV-CHIKV on melanoma and the underlying mechanism. In this study, we found that recombinant VSV-CHIKV triggered GSDMD-mediated melanoma cell pyroptosis. Importantly, the NLRP3/Caspase-1/GSDMD axis was activated after VSV-CHIKV infection in melanoma cell lines and in a xenograft mouse model. Inhibition of GSDMD blocked cell pyroptosis, antitumor immunity and the tumor response in response to VSV-CHIKV treatment, suggesting that VSV-CHIKV act through the GSDMD pathway. VSV-CHIKV-triggered GSDMD-mediated tumor pyroptosis recruited cytotoxic T lymphocytes (CTLs) into the tumor microenvironment, which was accompanied by the release of inflammatory mediators. This remodeled the tumor microenvironment and turned immunologically "cold" tumors into "hot" tumors, thereby sensitized these tumors to checkpoint blockade. Finally, the combination therapy of VSV-CHIKV and an immune checkpoint inhibitor (anti-PD-1) prolonged the survival of mice. In conclusion, the VSV-CHIKV strategy is an attractive biologic therapy against melanoma.

A new near-infrared fluorescence probe (PBA-BDP) was developed by coupling boron-10 (10B) to a phenylboronic acid (PBA)-functionalized BODIPY dye. This multifunctional probe not only delivers 10B for boron neutron capture therapy (BNCT) but also enhances tumor-specific targeting and provides dynamic insight into boron distribution during treatment.

Knowledge of cancer development and progression gained over the last few decades has enabled mapping of genetic and epigenetic changes unique to different phases of tumor evolution. Here we focus on epigenetic changes that drive melanoma development and progression. We highlight the importance of epigenetic mechanisms which encompass crosstalk with melanoma microenvironment that affect metastasis and therapy resistance. This review summarizes recent advances and describes potential strategies to leverage this knowledge to devise new therapies.

Great advances have been made in malignant melanoma treatments, whereas drug resistance still limits many drug applications. CRKL has been reported to be overexpressed in various tumors and showed poor prognosis. However, its specific function and mechanism in melanoma remain unclear. In the present study, we investigated the expression of CRKL and its clinical association by bioinformatics and clinical analysis, and then performed a series of in vitro and in vivo experiments to demonstrate its function and mechanism. Results showed that CRKL increased during melanoma progression and was strongly associated with poor prognosis. CRKL silencing effectively inhibited melanoma cell growth and invasion via ERK/MMP9 and PI3K/AKT signaling pathways both in vitro and in vivo. Moreover, CRKL silencing induced pyroptosis in melanoma cells by upregulating the levels of pyroptosis-associated proteins, such as NLRP3, cleaved Caspase-1, and GSDMD-N. Importantly, our study demonstrated that interfering with CRKL expression enhanced the chemotherapy sensitivity of melanoma cells to cisplatin by regulating PI3K/AKT and NLRP3/GSDMD signaling pathways. In conclusion, our study uncovers a novel molecular mechanism by which CRKL functions in melanoma and highlights potential therapeutic strategies for improving chemotherapy sensitivity in melanoma patients.

Bisindole alkaloids constitute a significant class of natural compounds distinguished by their characteristic bisindole structure and renowned for their anticancer properties. Over the last six decades, researchers have isolated 425 microorganism-derived bisindole alkaloids (MDBAs). Among them, 187 MDBAs have demonstrated anticancer properties against various in vitro cancer cell lines, primarily by impeding the cell cycle, restraining cell proliferation, and inducing apoptosis and autophagy. These effects are mediated by regulating key targets and signaling pathways such as hypoxia-inducible factor (HIF)-1, MAPK, and phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR. This review provides a comprehensive examination of the sources, chemical diversity, and anticancer properties of these compounds. Furthermore, it summarizes the structure-activity relationship (SAR), druggability, and the mechanisms underlying MDBAs' anticancer effects. Ultimately, this article aims to furnish a thorough overview of the advancements in the investigation of microorganism-derived bisindole alkaloids for their continued development and utilization.

Oral melanoma is an aggressive neoplasm arising from melanocytes in the mucosal epithelium, accounting for 0.2%-0.8% of all melanomas. Unlike cutaneous melanoma, it is not associated with UV exposure, and its pathogenesis involves complex genetic and molecular alterations. This neoplasm predominantly affects older adults (≥ 60 years). Clinically, lesions often present as macular or nodular with an exophytic growth pattern, sometimes ulcerated, and exhibit varied pigmentation. Diagnosis is further complicated by non-pigmented (amelanotic) variants that can resemble other oral pigmentations. Wide surgical excision remains the mainstay treatment, often combined with chemotherapy; however, recurrence and distant metastasis remain high. While immunotherapy has shown promise in other melanoma subtypes, its efficacy in oral melanoma remains uncertain. Treatment in older adults is particularly challenging due to comorbidities and treatment-related morbidity. This review summarizes the epidemiology, clinical features, and current treatment strategies for oral melanoma in older adults. Key advances in the molecular mechanisms underlying this neoplasm are also outlined. As a strategic approach, integrating oral melanoma screening into routine geriatric dental care, supported by diagnostic algorithms, may improve early detection, prognosis, and survival outcomes in this vulnerable population.

Cancer remains a global health challenge, and this challenge comes with a significant burden. Current treatment modalities, such as surgery, chemotherapy, and radiotherapy, have their limitations. The emergence of nanomedicines presents a new frontier in postoperative cancer treatment, offering potential to inhibit tumor recurrence and manage postoperative complications. This review deeply explores the application and potential of nanomedicines in the treatment of cancer after surgery. In particular, it focuses on local drug delivery systems (LDDS), which consist of in situ injection, implantation, and spraying. LDDS can provide targeted drug delivery and controlled release, which enhancing therapeutic efficacy. At the same time, it minimizes damage to healthy tissues and reduces systemic side effects. The nanostructures of these systems are unique. They facilitate the sustained release of drugs, prolong the effects of treatment, and decrease the frequency of dosing. This is especially beneficial in the postoperative period. Despite their potential, nanomedicines have limitations. These include high production costs, concerns regarding long-term toxicity, and complex regulatory approval processes. This paper aims to analyze several aspects. These include the advantages of nanomedicines, their drug delivery systems, how they combine with multiple treatment methods, and the associated challenges. Future research should focus on certain issues. These issues are stability, tumor specificity, and clinical translation. By addressing these, the delivery methods can be optimized and their therapeutic efficacy enhanced. With the advancements in materials science and biomedical engineering, the future design of LDDS is set to become more intelligent and personalized. It will cater to the diverse needs of clinical treatment and offer hope for better outcomes in cancer patients after surgery.

While cationic antimicrobial peptides (AMPs) are extensively studied for antitumor effects, anionic AMPs remain underexplored. Notably, no amphibian-derived anionic cathelicidins with antitumor activity have been reported. This study identifies Boma-CATH, a novel anionic cathelicidin (net charge-3) from Bombina maxima skin, which suppresses melanoma growth in mice and triggers pyroptosis-like morphological changes in A375 cells via the NLRP3/Caspase-1/GSDMD pathway. Further investigation revealed that ROS played a crucial role in promoting pyroptosis, as NAC (ROS scavenger) and Ac-YVAD-cmk (Caspase-1 inhibitor) reversed cell death and reduced LDH/IL-1β release in vitro and in vivo. GSDMD knockdown further validated its role. Additionally, Boma-CATH inhibited A375 cell proliferation, migration, and invasion, demonstrating dual antitumor mechanisms: pyroptosis induction and metastasis suppression. Importantly, Boma-CATH caused no adverse effects in mice, highlighting its therapeutic safety. These findings position Boma-CATH as a promising melanoma treatment and expand the mechanistic understanding of anionic AMPs in oncology.

Malignant melanoma (MM) is the most lethal skin cancer globally, with a high incidence of over 300,000 per year. Though constant efforts have been made to elucidate the mechanisms of MM, we are still away from a complete understanding. Recently, the essential role of zinc finger proteins in tumor development was covered, but none of these roles were explored in MM. Herein, we first identified a zinc finger protein ZNF280A that serves as the risk factor in MM prognosis and acted as a driver of MM development in vitro and in vivo. The level of ZNF280A was significantly higher in the 130 MM tissues than in 18 para-carcinoma tissues. Knockdown of ZNF280A contributed to the inhibition of cell proliferation, migration, and invasion in MM. Furthermore, the mechanism of increased apoptosis and stagnant cell cycle may be associated with p53 expression regulated by ZNF280A. In conclusion, our study first displayed that ZNF280A may promote the development of MM by regulating cell proliferation, migration, invasion, cell cycle, and apoptosis.

Cutaneous melanoma is a common cancer in Australia and New Zealand, Europe, and North America, and its incidence is still increasing in many regions. Ultraviolet (UV) radiation exposure (for example, through excessive sunlight exposure) remains the primary risk factor for melanoma; however, public awareness campaigns have led to a marked reduction in mortality. In addition to genetic damage from UV radiation, specific genetic alterations have been linked to melanoma. The stage of the tumour at the time of diagnosis is of greater importance for melanoma prognosis than in almost any other cancer. Context-dependent genetic mutations that attenuate tumour-suppressive mechanisms or activate growth-promoting signalling pathways are crucial factors in the development of cutaneous melanoma. In addition to external factors such as UV radiation, the tumour microenvironment can contribute to melanoma progression, invasion and metastasis. Cutaneous melanoma treatment has improved considerably over the past decade with the discovery and development of immune checkpoint inhibitors and therapy targeting BRAF and MEK. Over the next decade, several priorities are likely to influence melanoma research and management, including the continued advance of precision medicine methods to identify the most suitable patients for the most effective treatment, with the aim of improving clinical outcomes.

Antitumor photodynamic therapy (PDT) faces huge challenges as selectivity and phototoxic damage, requiring delivery photosensitizers (PSs) to specifically accumulate in tumors even in organelle, and avoid the phototoxic damage during delivery. Herein, a microneedle patch (AIE-mito-TPP@MN) containing mitochondria- and lysosomes- dual targeting prodrug-like PSs (AIE-mito-TPP/AlPcSNa4) that is self-assembled by mitochondria-targeted aggregation-induced-emission molecule (AIE-mito-TPP) and lysosome-targeted aluminum phthalocyanine tetrasulfonate (AlPcSNa4), is developed to achieve cancer-cell-organelle-specific targeting delivery for precise PDT with high selectivity and low phototoxic damage. AIE-mito-TPP/AlPcSNa4 displays prodrug-like activity via the regulated photoactivity to reduce the phototoxic damage caused by the "always on" PSs. Meanwhile, AIE-mito-TPP/AlPcSNa4@MN can insert into the epidermis to achieve rapid AIE-mito-TPP/AlPcSNa4 delivery in tumor lesion, and enhance selective accumulation in tumor cells. The higher lysosomal acidity in tumor cells facilitates AIE-mito-TPP/AlPcSNa4 disassembly and promotes targeting. Under light irradiation, AIE-mito-TPP/AlPcSNa4@MN impairs mitochondrial and lysosomal function to induce deeper tumor cells apoptosis at a low dose (≈6 µg), presenting greater therapeutic efficacy than AIE-mito-TPP@MN, AlPcSNa4@MN, or intravenous injection. Moreover, AIE-mito-TPP/AlPcSNa4@MN presents good biocompatibility as lower accumulation and targeting in normal cells, as well as the regulated photoactivity of prodrug-like PSs. Therefore, the dual organelle-targeting microneedle possesses great potential for precise PDT with high selectivity.

Peritumoral subcutaneous injection has been highly envisioned as an efficient yet low-risk administration of photothermal agents for superficial tumor photothermal therapy. However, obstructed by complex subcutaneous tissue, the delivery of injected photothermal agents to the specific tumor remains a critical issue. Herein, the study reports a polydopamine (PDA)-encapsulated spherical core/shell nanomotor with fluorescent indocyanine green (ICG) immobilized on its PDA shell. Upon the first near-infrared (NIR-I) irradiation, this motor can generate favorable photothermal heat, and meantime, emit a robust ICG fluorescence in the second near-infrared window (NIR-II). The heat turns the motor into an active photothermal agent able to perform thermophoretic propulsion along the irradiation direction in subcutaneous tissue, while the ICG fluorescence can direct the subcutaneous propulsion of motors toward specific tumor through real-time NIR-II imaging. These functions endow the motor with the ability of moving to tumor after being injected at peritumoral site, enabling an enhanced photothermal therapy (PTT). The results demonstrated herein suggest an integrated nanorobotic tool for the superficial PTT using peritumoral administration, highlighting an NIR-II imaging-directed subcutaneous propulsion.

Melanin pigmentation in oocytes is a critical feature for both the esthetic and developmental aspects of oocytes, influencing their polarity and overall development. Despite substantial knowledge of melanogenesis in melanocytes and retinal pigment epithelium cells, the molecular mechanisms underlying oocyte melanogenesis remain largely unknown.

Here, we compare the oocytes of wild-type, tyr-/- and mitf-/- Xenopus tropicalis and found that mitf-/- oocytes exhibit normal melanin deposition at the animal pole, whereas tyr-/- oocytes show no melanin deposition at this site. Transmission electron microscopy confirmed that melanogenesis in mitf-/- oocytes proceeds normally, similar to wild-type oocytes. Transcriptomic analysis revealed that mitf-/- oocytes still express melanogenesis-related genes, enabling them to complete melanogenesis. Additionally, in Xenopus tropicalis oocytes, the expression of the MiT subfamily factor tfe3 is relatively high, while tfeb, mitf, and tfec levels are extremely low. The expression pattern of tfe3 is similar to that of tyr and other melanogenesis-related genes. Thus, melanogenesis in Xenopus tropicalis oocytes is independent of Mitf and may be regulated by other MiT subfamily factors such as Tfe3, which control the expression of genes like tyr, dct, and tyrp1. Furthermore, transcriptomic data revealed that changes in the expression of genes related to mitochondrial cloud formation represent the most significant molecular changes during oocyte development.

Overall, these findings suggest that further elucidation of Tyr-dependent and Mitf-independent mechanisms of melanin deposition at the animal pole will enhance our understanding of melanogenesis and Oogenesis.

As a highly aggressive malignancy, the issue of curing melanoma at an advanced stage could suffer from severe metastasis and a lower 5-year survival rate. Therefore, the early diagnosis of melanoma with high accuracy is vital and contributes to a significantly improved 5-year survival rate. This work reports a dual-locked receptor, m-BA-Hcy, which releases the near-infrared (NIR) fluorophore Hcy-OH upon the dual activation of reactive oxygen species (ROS) and tyrosinase (TYR). The substitution of boric acid on the phenyl ring was studied, which influences the feasibility of the performance of the envisaged cascade reaction. The sensing behavior was discussed in terms of optical spectroscopy and reaction mechanism, and imaging was fully performed at the cellular and organism levels. Receptor m-BA-Hcy was hence clarified to possess supreme sensitivity and accuracy for melanoma detection.

Malignant melanoma, a rare and aggressive skin cancer, arises from the transformation of cutaneous melanocytes and is associated with a poor prognosis. Evodiamine (EVO), a bioactive compound derived from traditional Chinese herbal medicine, has demonstrated significant inhibitory effects on various tumor cells. In this study, we aimed to investigate the potential of EVO in regulating melanoma immunity and elucidate its underlying mechanisms. Experimental results revealed that the IC50 value of EVO in B16-F10 cells for 24, 48, and 72 h were 11.73, 5.083, and 4.604 µM, respectively. EVO inhibited the proliferation, invasion, and metastasis of B16-F10 cells by more than 50%, while promoting apoptosis of higher concentration of EVO. EVO also significantly suppressed tumor growth by more than 80% and reduced spleen damage in tumor-bearing mice. Treatment with EVO led to a marked increase in T-cell subsets in the spleen, bone marrow, and tumors, with immunohistochemical (IHC) staining in particular showing about 50% higher. Furthermore, EVO inhibited the expression of programmed cell death ligand 1 (PD-L1) and the PI3K/AKT signaling pathway-related proteins in both B16-F10 cells and tumors. These findings suggest that EVO exerts antitumor effects by enhancing the tumor immune microenvironment and indicates its potential as a therapeutic agent for melanoma.

With ever-increasing incidence and high metastatic potential, cutaneous melanoma is the deadliest skin cancer. Risk prediction based on the Tumor-Node-Metastasis (TNM) staging system has medium accuracy with intermediate IIB-IIIB stages, as roughly 25% of patients with low-medium-grade TNM, and hence a favorable prognostic, undergo an aggressive disease with short survival and around 15% of deaths arise from metastases of thin, low-risk lesions. Therefore, reliable prognostic biomarkers are required. We used genomic and clinical information of melanoma patients from the TCGA-SKCM cohort and two GEO studies for discovery and validation of potential biomarkers, respectively. Neither mutation nor overexpression of major melanoma driver genes provided significant prognostic information. Conversely, expression of MGRN1 and the melanocyte-specific genes MLANA, PMEL, and TYRP1 provided a simple 4-gene signature identifying with high-sensitivity (>80%), low-medium TNM patients with adverse outcomes. Transcriptomic analysis of tumors with this signature, or from low-medium-grade TNM patients with poor outcomes, revealed comparable dysregulation of an inflammatory response, cell cycle progression, and DNA damage/repair programs. A functional analysis of MGRN1-knockout cells confirmed these molecular features. Therefore, the simple MGRN1-MLANA-PMEL-TYRP1 combination of biomarkers complemented TNM staging prognostic accuracy and pointed to the dysregulation of immunological responses and genomic stability as determinants of a melanoma outcome.

Mucosal melanomas (MMs) are under-researched tumors with a poor prognosis that arise from melanocytes found in the mucous membranes at different anatomical locations throughout the body. MMs are an uncommon yet highly aggressive tumor that typically develops on mucosal surfaces, predominantly in the head and neck region. MM of the head and neck occurs in 8-10% of all head and neck melanomas. It most commonly affects the mucosa of the nasal cavity and paranasal sinuses (75%), followed by the oral cavity mucosa (25%). A family history and the presence of mucosal nevi are associated with the occurrence of MM. Inhaled and dietary carcinogens are also linked to the development of sinonasal melanoma, much like other malignancies of the nasal cavity. Overexpression of the C-KIT gene is found in more than 80% of all primary mucosal melanomas, with somatic mutations in 10-30% of cases. The presence of these genetic alterations is also reflected in recent clinical studies of specific gene inhibitors that have proven efficiency in the systemic therapy of melanoma. There are various treatment modalities for MM. Surgical therapy involves en bloc surgical resection with a macroscopically visible and palpable mucosal margin of 1.5-2 cm. Partial resection of the maxilla may be considered if it ensures adequate tumor-free margine. Because of its rarity, outcome data for locally advanced head and neck MM is limited and primarily derived from retrospective studies with small case numbers. This review aims to update and summarize findings from clinical trials, prospective observational studies, and retrospective studies, while also exploring future directions for multimodal treatment approaches in this area.

Metastatic melanoma remains a major clinical challenge. Large-scale genomic sequencing of melanoma has identified bona fide activating mutations in RAC1, which are associated with resistance to BRAF-targeting therapies. Targeting the RAC1-GTPase pathway, including the upstream activator PREX2 and the downstream effector PI3Kβ, could be a potential strategy for overcoming therapeutic resistance, limiting melanoma recurrence, and suppressing metastatic progression. Here, we used genetically engineered mouse models and patient-derived BRAFV600E-driven melanoma cell lines to dissect the role of PREX2 in melanomagenesis and response to therapy. Although PREX2 was dispensable for the initiation and progression of melanoma, its loss conferred sensitivity to clinically relevant therapeutics targeting the MAPK pathway. Importantly, genetic and pharmacologic targeting of PI3Kβ phenocopied PREX2 deficiency, sensitizing model systems to therapy. These data reveal a druggable PREX2/RAC1/PI3Kβ signaling axis in BRAF-mutant melanoma that could be exploited clinically. Significance: Cotargeting the MAPK and the PREX2/RAC1/PI3Kβ pathways has remarkable efficacy and outperforms monotherapy MAPK inhibition in BRAF-mutant melanoma, supporting the potential of this combination therapy for treating metastatic melanoma.

Melanoma is a highly aggressive skin cancer with a poor prognosis. The endocannabinoids 2-arachidonoylgylcerol (2-AG) and anandamide have been linked to melanoma progression, though their roles remain unclear. We hypothesized that the 2-AG-arachidonate-prostaglandin axis could drive aggressive melanoma progression.

The genetically engineered melanoma mouse model B6-Tyr::CreERT2; BRafCA; PtenloxP was characterized by targeted metabolomics. Functionally expressed serine hydrolases in the tumor tissue were identified by chemoproteomics. Pharmacological inhibition of carboxylesterase 1 (CES1) was achieved through chronic in vivo i.p. treatment with JZL184 (10 mg/kg daily), confirmed by activity-based protein profiling (ABPP) and targeted lipidomics. CES1-mediated 2-AG hydrolysis was further confirmed in radiotracer-based assays using CES1-transfected cell lines.

The diacylglycerol and protein kinase C activator 1-stearoyl-2-arachidonoyl-sn-glycerol (SAG) was significantly elevated in the nodular-like melanoma tissues, along with 2-AG and arachidonic acid (ARA), compared to normal skin. AEA and other N-acylethanolamines were decreased, while, notably, prostaglandin levels remained unchanged. Significant changes in the levels of neuromodulators and neurotransmitters, including serotonin and adenosine, were observed. Pronounced differences between serine hydrolase activity in normal skin and melanoma tissue were identified by ABPP. Intriguingly, CES1 was identified as the only 2-AG-hydrolyzing enzyme in this melanoma tissue, as MAGL and ABHD6/12 were not expressed. The MAGL inhibitor JZL184 also efficiently inhibited CES1 in vitro and in vivo, increasing glycerol esters and reducing tumor progression. Additionally, scRNA-seq data from previous studies revealed divergent MAGL/CES1 expression patterns across different human melanoma subtypes.

A role of CES1 expression in skin is demonstrated for the first time. Our study suggests that 2-AG degradation to arachidonate favors melanoma progression, either reflecting the carcinogenic role of ARA or that monoacylglycerols like 2-AG and/or other CES1 substrates may exert antitumor effects, indicating that CES1 could be a potential therapeutic target. CES1 expression and high SAG, 2-AG, and ARA levels may be a signature of specific BRAF-driven malignant melanoma subtypes which are associated with discrete metabolic adaptations.

To better understand the homeostatic mechanisms governing melanocytes, we performed deep phenotyping of clonal expansions of single melanocytes from human skin. In total, we interrogated the mutational landscapes, gene expression profiles, and morphological features of 297 melanocytes from 31 donors. To our surprise, a population of melanocytes with low mutation burden was maintained in sun damaged skin. These melanocytes were more stem-like, smaller, less dendritic and displayed distinct gene expression profiles compared to their counterparts with high mutation burdens. We used single-cell spatial transcriptomics (10X Xenium) to reveal the spatial distribution of melanocytes inferred to have low and high mutation burdens (LowMut and HighMut cells), based on their gene expression profiles. LowMut melanocytes were found in hair follicles as well as in the interfollicular epidermis, whereas HighMut melanocytes resided almost exclusively in the interfollicular epidermis. We propose that melanocytes in the hair follicle occupy a privileged niche, protected from UV radiation, but periodically migrate out of the hair follicle to replenish the interfollicular epidermis after waves of photodamage. More broadly, our study illustrates the advantages of a cell atlas that includes mutational information, as cells can change their cellular states and positional coordinates over time, but mutations are like scars, providing a historical record of the homeostatic processes that were operative on each cell.

Cancer is a group of diseases characterized by uncontrolled cell growth, invasive capacity, and metastatic potential. Despite the continual progress in cancer treatment, high toxicity and resistance to therapy remain recurring challenges. Croton grewioides Baill. is a plant from the brazilian semi-arid region with significant pharmacological potential due to its reported antidiarrheal, antioxidant, and antitumor properties. This study evaluated the antitumor activity of the essential oil from C. grewioides leaves (CgEO) by in vitro assays. CgEO showed higher cytotoxicity in human melanoma cells (SK-MEL-28), with a 50 % inhibitory concentration (IC50) of 70.0 μg/mL after 72 h, but with low toxicity in healthy keratinocytes (HaCaT). Additionally, it was suggested that the antitumor effect of CgEO is associated with the induction of apoptosis, cell cycle alterations, and combined antioxidant action mechanisms. In conclusion, CgEO exhibits antitumor activity with lower toxicity in non-tumor cells.

Tumour cells possess a multitude of chemoresistance mechanisms, which could plausibly contribute to the ineffectiveness of chemotherapy. O6-methylguanine-DNA methyltransferase (MGMT) is an important effector protein associated with Temozolomide (TMZ) resistance in various tumours. To some extent, the expression level of MGMT determines the sensitivity of cells to TMZ, but the mechanism of its expression regulation has not been fully elucidated. Cultured malignant melanoma cell lines A375 and Sk-MEL28 were employed. A luciferase assay was used to detect the transcriptional activity of the MGMT promoter. Western blotting was used to compare the expression levels of phosphorylated ERK1/2 (P-ERK1/2) after TMZ treatment. Immunofluorescent staining was used to detect TMZ-induced DNA damage protein levels. The sensitivity of melanoma cells to TMZ was detected by MTT assay and animal experiments. The expression of MGMT mRNA was tested by Quantitative real-time PCR (RT-qPCR). Flow cytometry was used to measure the apoptosis of TMZ-treated cells. TMZ enhanced the transcription of MGMT through activating the ERK pathway. ERK inhibitors U0126 and vemurafenib (vMF) inhibited the TMZ induced transcription of MGMT. The expression of MGMT and p-ERK1/2 was closely related in human MM tissues. vMF increased the sensitivity of melanoma (MM) to TMZ in vitro and in vivo through downregulating MGMT and promoting the TMZ induced DNA damage in MM. TMZ-promoted MGMT transcription contributed to instinctive chemoresistance by activating the ERK signalling pathway in malignant melanoma. Our study indicates that the use of the ERK inhibitor in combination with TMZ could potentially enhance the effectiveness of clinical treatment for malignant melanoma.

Dermal hyperpigmentation stands out among the various skin pigmentation phenotypes in chickens, where most other pigmentation variants affect feather color and patterning predominantly. Despite numerous black chicken breeds worldwide, only a select few exhibit comprehensive black pigmentation, which encompasses the skin, meat, flesh, and bones. The process of skin melanin pigmentation is intricate and develops successively. Historically, research has concentrated primarily on specific developmental points or stages, but fewer studies have examined the entire transcriptome across the timeline of the development of the embryo integument. In our investigation, we undertook the sequencing of chicken embryo skin samples from d 4 to d 13 of incubation. Our results showed that melanoblasts continued to migrate from E4 to the epidermis until E12. Beginning with E6, melanin was synthesized and transferred to epidermal cells and feather follicles in large quantities, and genes such as DCT, TYR, TYRP1, and MITF played a key role in this process, which is significantly different from that of white-skinned chickens. There were 854 differentially expressed genes between E7 and E8. At this stage, melanocytes formed dendritic forms and transferred melanin to keratinocytes, while the dorsal skin became visibly dark. In addition, CDH3, which is a core factor involved in a variety of biological processes, may have an important impact on skin melanin pigmentation. Collectively, our findings unveiled a phased relationship between the canonical pathway and the noncanonical pathway from E4 to E13. These analyses illuminated the gene regulatory mechanism and provided foundational data that pertained to pigmentation in chickens.

Melanoma, caused by malignant melanocytes, is known for its invasiveness and poor prognosis. Therapies are often ineffective due to their heterogeneity and resistance. Bacillus Calmette-Guérin (BCG), primarily a tuberculosis vaccine, shows potential in treating melanoma by activating immune responses. In this study, data from The Cancer Genome Atlas and the National Center for Biotechnology Information Gene Expression Omnibus database were utilized to determine pivotal DEGs such as DSC2, CXCR1, BOK, and CSTB, which are significantly upregulated in BCG-treated blood samples and are strongly associated with the prognosis of melanoma. We employ tools like edgeR and ggplot2 for functional and pathway analysis and develop a prognostic model using LASSO Cox regression analysis to predict patient survival. A notable finding is the correlation between BCG-related genes and immune cell infiltration in melanoma, highlighting the potential of these genes as both biomarkers and therapeutic targets. Additionally, the study examines genetic alterations in these genes and their impact on the disease. This study highlights the necessity of further exploring BCG-related genes for insights into melanoma pathogenesis and treatment enhancement, suggesting that BCG's role in immune activation could offer novel therapeutic avenues in cancer treatment.

The TGFβ signaling pathway is known for its pleiotropic functions in a plethora of biological processes. In melanoma, TGFβ signaling promotes invasiveness and metastasis formation. However, its involvement in the response to therapy is controversial. While several studies have linked TGFβ signaling to elevated resistance to targeted therapy in melanoma, separate findings have indicated a favorable treatment response through TGFβ-mediated increase of cell death. We now found that the outcome of TGFβ signaling in the context of targeted therapy is dose dependent. Unlike low doses, high levels of TGFβ signal activation induce apoptosis upon simultaneous MAPK pathway inhibition, even in targeted therapy resistant melanoma cell lines. Using transcriptomic analyses, combined with genomic target identification of the critical TGFβ signaling effector SMAD4, we demonstrate that parallel activation of TGFβ signaling and MAPK pathway inhibition causes a complete switch of TGFβ target genes from promoting pro-invasive processes to fueling pro-apoptotic pathways. Investigations of underlying mechanisms identified a novel apoptosis-inducing gene signature. Functional validation of signature members highlighted a central role of the pro-apoptotic BCL2 family member BCL2L11 (BIM) in mediating apoptosis in this condition. Using a modified, synthetic version of the TGFB1 mRNA for intra-tumoral injections, we additionally showcase a potential therapeutic application of this treatment combination.

Melanoma, the most prevalent form of skin cancer, is primarily treated with surgical intervention. However, complete tumor cell removal is challenging, and surgical wounds are prone to infection, complicating treatment and increasing costs. The successful treatment of melanoma generally requires multifunctional agents that are coordinated in tumor therapy and wound healing. In this study, we developed platinum (Pt)- and selenium (Se)-based nanozymes, Pt-Se@Chitosan (PS@CS), which exhibit synergistic antitumor and bactericidal efficacy attributed to their multienzyme activity and strong photothermal conversion efficiency. Furthermore, we engineered PS@CS hydrogels capable of inhibiting tumor regrowth postsurgery and accelerating healing of infected wounds. The PS@CS and PS@CS hydrogels presented herein incorporate characteristics including catalytic therapy, photothermal therapy, antibacterial properties, and skin damage healing, providing an innovative and comprehensive therapeutic approach for melanoma treatment.

A case report by Liu et al describes the characteristics of metastatic clear cell sarcoma (CCS) of the pancreas and provides valuable therapeutic insights for this rare malignancy. This case is interesting because of its rarity, suggesting that the pancreas may be a potential target organ for CCS, either primary or metastatic. At the same time, the authors also emphasize the importance of regular postoperative follow-up for timely detection of recurrent lesions, as CCS is characterized by a high degree of malignancy and a high rate of recurrent metastases. Considering that CCS of the gastrointestinal tract is easily confused with malignant melanoma (MM) of the gastrointestinal tract, here we compare the clinical features, histopathological and immunohistochemical characteristics, diagnosis, treatment, and prognosis of CCS and MM of the gastrointestinal tract, hoping to provide a reference for clinical work.

This study compares the effects of vitamins - including ascorbic acid, its derivative 3-O-ethyl-ascorbic acid (EAA), and tocopherol - as well as the main non-psychoactive phytocannabinoids on the viability of various skin cells, including healthy (keratinocytes/melanocytes/fibroblasts) and cancer cells (melanoma/SCC), under standard culture conditions and after the exposure to UVA radiation. All the conducted tests (MTT, SRB, and LDH) consistently indicate that the regenerative effect of EAA is stronger than that of ascorbic acid, while tocopherol acts selectively on healthy/cancer cells, inducing or inhibiting their proliferation, respectively. In the case of phytocannabinoids, only cannabidiol shows protective/regenerative properties for healthy cells. Moreover, the response of melanocytes to cannabigerol is divergent; however, only the LDH test indicates that cannabigerol strongly increases the membrane permeability of those cells. In summary it should be emphasized that various tests may give partially divergent results due to a variety of measured parameters. Nevertheless, despite the positive viability test results for the potential protective compound, caution should be taken as it may promote healthy skin cells but also protect cancer cells.

The immune checkpoint inhibitor therapy represented by blocking programmed cell death protein 1/ programmed cell death-ligand 1 (PD-1/PD-L1) has made significant progress in melanoma treatment. However, the response rate and therapeutic effect of immunotherapy alone are still not ideal for melanoma. In this study, we aimed to evaluate the defects of treating anti-PD-L1 alone and the therapeutic effect and molecular mechanism of combined therapy with anti-PD-L1 and MnCl2. We detected the changes of immune cell populations after anti-PD-L1 treatment in melanoma xenograft mouse model. Further, we evaluated the regulatory effect of MnCl2 on dendritic cells (DCs) maturation in vitro. Next, we tested the therapeutic effect and regulatory effect on the tumor microenvironment with anti-PD-L1 and MnCl2 via combining treatment with anti-PD-L1 and MnCl2. Anti-PD-L1 therapy has a certain tumor suppressive function, but the effect is not ideal. The results of flow cytometry showed that the number of CD4+ T cells and CD8+ T cells significantly increased after anti-PD-L1 treatment. However, the number of DCs remained basically unchanged after anti-PD-L1 treatment. In vitro, we confirmed that MnCl2 significantly promoted DCs maturation vis activating cGAS-STING signaling pathway. The combination of anti-PD-L1 and MnCl2 displayed the best tumor suppression effect in melanoma xenograft mouse model. In tumor microenvironment, the infiltration of T cells and the maturation of DCs were significantly promoted, demonstrating a strong anti-tumor immune response. In summary, we conclude that combining anti-PD-L1 with MnCl2 is a promising therapeutic strategy for melanoma.

Melanoma is one of the most malignant forms of skin cancer, characterised by the highest mortality rate among affected patients. This study aims to analyse and compare the effects of lipid extracts from the microalgae Nannochloropsis oceanica (N.o.) and Chlorococcum amblystomatis (C.a.) on the intra and extracellular proteome of UVA-irradiated melanoma cells using a three-dimensional model. Proteomic analysis revealed that UVA radiation significantly increases the levels of pro-inflammatory proteins in melanoma cells. Treatment with algae extracts reduced these protein levels in both non-irradiated and irradiated cells. Furthermore, untreated cells released proteins responsible for cell growth and proliferation into the medium, a process hindered by UVA radiation through the promotion of pro-inflammatory molecules secretion. The treatment with algae extracts effectively mitigated UVA-induced alterations. Notably, UVA radiation significantly induced the formation of 4-HNE and 15-PGJ2 protein adducts in both cells and the medium, while treatment with algae extracts stimulated the formation of 4-HNE-protein adducts and reduced the level of 15-PGJ2-protein adducts. However, both algae extracts successfully prevented these UVA-induced modifications. In conclusion, lipid extracts from N.o. and C.a. appear to be promising agents in supporting anti-melanoma therapy. However, their potent protective capacity may limit their applicability, particularly following cells exposure to UVA.

Cutaneous melanoma is an increasingly common and potentially lethal form of skin cancer. Current staging systems based on clinical and pathological features have limitations in accurately predicting outcomes, particularly for early-stage disease. The 31-gene expression profile (31-GEP) test has emerged as a promising tool for improving risk stratification in melanoma patients.

We conducted a systematic review and meta-analysis of studies evaluating the prognostic performance of the 31-GEP test in cutaneous melanoma. A comprehensive literature search was performed in multiple databases. Studies reporting survival outcomes stratified by 31-GEP class were included. Random-effects models were used to determine survival estimates across studies.

Thirteen studies comprising 14,760 patients were included in the meta-analysis. The 31-GEP test consistently stratified patients into risk groups with significantly different outcomes. The 5-year melanoma-specific survival rates were 99.8% (95% CI: 98-100%) for Class 1A, 97.6% (95% CI: 92.4-99.3%) for Class 1B/2A, and 83.4% (95% CI: 66.5-92.7%) for Class 2B. Similar trends were observed for recurrence-free and distant metastasis-free survival.

This meta-analysis supports the prognostic utility of the 31-GEP test in cutaneous melanoma prognostication. The test consistently stratified patients into clinically meaningful risk groups across multiple survival metrics. These findings support the potential clinical utility of the 31-GEP test in enhancing current staging systems and informing personalized management strategies for melanoma patients.