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Simple Summary: Deficiency and targeting of Stabilin-1, which is expressed by liver sinusoidal endothelial cells and subsets of macrophages, has been shown to improve anti-tumor immune responses in preclinical and early clinical studies. This study investigated whether targeting of Stab1 might also influence melanoma liver colonization, as hepatic metastasis of melanoma is a poor prognostic factor. In two models of hepatic melanoma metastasis, no direct influence of anti-Stab1 treatment was found. However, effects on the local microenvironment were observed. We suggest that the organ- and tumor-specific effects of anti-Stab1 therapies should be further considered and analyzed in future human studies. Background: This study analyzed the role of Stabilin-1 on hepatic melanoma metastasis in preclinical mouse models. Methods: In Stabilin-1−/− mice (Stab1 KO), liver colonization of B16F10 luc2 and Wt31 melanoma was investigated. The numbers, morphology, and vascularization of hepatic metastases and the hepatic microenvironment were analyzed by immunofluorescence. Results: While hepatic metastasis of B16F10 luc2 or Wt31 melanoma was unaltered between Stab1 KO and wildtype (Ctrl) mice, metastases of B16F10 luc2 tended to be smaller in Stab1 KO. The endothelial differentiation of both types of liver metastases was similar in Stab1 KO and Ctrl. No differences in initial tumor cell adhesion and retention to the liver vasculature were detected in the B16F10 luc2 model. Analysis of the immune microenvironment revealed a trend towards higher levels of CD45+Gr-1+ cells in Stab1 KO as compared to Ctrl in the B16F10 luc2 model. Interestingly, significantly higher levels of POSTN were found in the matrix of hepatic metastases of Wt31, while liver metastases of B16F10 luc2 showed a trend towards increased deposition of RELN. Conclusions: Hepatic melanoma metastases show resistance to Stabilin-1 targeting approaches. This suggests that anti-Stab1 therapies should be considered with respect to the tumor entity or target organs. [ABSTRACT FROM AUTHOR]

The current study investigates the therapeutic and optical properties of bismuth oxide (Bi2O3) particles for selective melanoma therapy and prevention. The Bi2O3 particles were prepared using a standard precipitation method. The Bi2O3 particles induced apoptosis in human A375 melanoma cells but not human HaCaT keratinocytes or CCD‐1090Sk fibroblast cells. This selective apoptosis appears to be associated with a combination of factors: increased particle internalization (2.29 ± 0.41, 1.16 ± 0.08 and 1.66 ± 0.22‐fold of control) and enhanced production of reactive oxygen species (ROS) (3.4 ± 0.1, 1.1 ± 0.1 and 2.05 ± 0.17‐fold of control) in A375 cells compared to HaCaT and CCD‐1090SK cells, respectively. As a high‐Z element, bismuth is also an excellent contrast agent for computer tomography, which renders Bi2O3 a theranostic material. Moreover, Bi2O3 displays high UV absorption and low photocatalytic activity compared to other semiconducting metal oxides, which opens further potential fields of application as a pigment or as an active ingredient in sunscreens. Overall, this study demonstrates the multifunctional properties of Bi2O3 particles surrounding the treatment and prevention of melanoma. [ABSTRACT FROM AUTHOR]

Background: This study analyzed the role of Stabilin-1 on hepatic melanoma metastasis in preclinical mouse models. Methods: In Stabilin-1−/− mice (Stab1 KO), liver colonization of B16F10 luc2 and Wt31 melanoma was investigated. The numbers, morphology, and vascularization of hepatic metastases and the hepatic microenvironment were analyzed by immunofluorescence. Results: While hepatic metastasis of B16F10 luc2 or Wt31 melanoma was unaltered between Stab1 KO and wildtype (Ctrl) mice, metastases of B16F10 luc2 tended to be smaller in Stab1 KO. The endothelial differentiation of both types of liver metastases was similar in Stab1 KO and Ctrl. No differences in initial tumor cell adhesion and retention to the liver vasculature were detected in the B16F10 luc2 model. Analysis of the immune microenvironment revealed a trend towards higher levels of CD45+Gr-1+ cells in Stab1 KO as compared to Ctrl in the B16F10 luc2 model. Interestingly, significantly higher levels of POSTN were found in the matrix of hepatic metastases of Wt31, while liver metastases of B16F10 luc2 showed a trend towards increased deposition of RELN. Conclusions: Hepatic melanoma metastases show resistance to Stabilin-1 targeting approaches. This suggests that anti-Stab1 therapies should be considered with respect to the tumor entity or target organs.

Nanomaterials with photothermal combined chemodynamic therapy (PTT‐CDT) have attracted the attention of researchers owing to their excellent synergistic therapeutic effects on tumors. Thus, the preparation of multifunctional materials with higher photothermal conversion efficiency and catalytic activity can achieve better synergistic therapeutic effects for melanoma. In this study, a Cu–Zn bimetallic single‐atom (Cu/PMCS) is constructed with augmented photothermal effect and catalytic activity due to the localized surface plasmon resonance (LSPR) effect. Density functional theory calculations confirmed that the enhanced photothermal effect of Cu/PMCS is due to the appearance of a new d‐orbital transition with strong spin‐orbit coupling and the induced LSPR. Additionally, Cu/PMCS exhibited increased catalytic activity in the Fenton‐like reaction and glutathione depletion capacity, further enhanced by increased temperature and LSPR. Consequently, Cu/PMCS induced better synergistic anti‐melanoma effects via PTT‐CDT than PMCS in vitro and in vivo. Furthermore, compared with PMCS, Cu/PMCS killed bacteria more quickly and effectively, thus facilitating wound healing owing to the enhanced photothermal effect and slow release of Cu2+. Cu/PMCS promoted cell migration and angiogenesis and upregulated the expression of related genes to accelerate wound healing. Cu/PMCS has potential applications in treating melanoma and repairing wounds with its antitumor, antibacterial, and wound‐healing properties. [ABSTRACT FROM AUTHOR]

Abstract Nanomaterials with photothermal combined chemodynamic therapy (PTT‐CDT) have attracted the attention of researchers owing to their excellent synergistic therapeutic effects on tumors. Thus, the preparation of multifunctional materials with higher photothermal conversion efficiency and catalytic activity can achieve better synergistic therapeutic effects for melanoma. In this study, a Cu–Zn bimetallic single‐atom (Cu/PMCS) is constructed with augmented photothermal effect and catalytic activity due to the localized surface plasmon resonance (LSPR) effect. Density functional theory calculations confirmed that the enhanced photothermal effect of Cu/PMCS is due to the appearance of a new d‐orbital transition with strong spin‐orbit coupling and the induced LSPR. Additionally, Cu/PMCS exhibited increased catalytic activity in the Fenton‐like reaction and glutathione depletion capacity, further enhanced by increased temperature and LSPR. Consequently, Cu/PMCS induced better synergistic anti‐melanoma effects via PTT‐CDT than PMCS in vitro and in vivo. Furthermore, compared with PMCS, Cu/PMCS killed bacteria more quickly and effectively, thus facilitating wound healing owing to the enhanced photothermal effect and slow release of Cu2+. Cu/PMCS promoted cell migration and angiogenesis and upregulated the expression of related genes to accelerate wound healing. Cu/PMCS has potential applications in treating melanoma and repairing wounds with its antitumor, antibacterial, and wound‐healing properties.

Transdermal administration of chemotherapeutics into tumor tissues may be an effective treatment to reduce toxic side effects and improve patient compliance for melanoma. Herein, we report a multistage transdermal drug delivery system for chemotherapy of melanoma. In this system, dendritic lipopeptide (DLP) modified multistage targeted liposomes (Mtlip) were incorporated into the hydrogel matrix to achieve localized and sustained drug release; Ultra-deformability of Mtlip can pass through dense stratum corneum to the epidermis where melanoma is located; Virus-mimicking Mtlip enhances the payload in tumor tissues by high permeability; The positive charged Mtlip can improve cell uptake efficiency and selectively accumulate into mitochondria to increases toxic. The efficacy of this type of multistage targeted liposomes loaded hydrogel in treating melanoma was systematically evaluated both in vitro and in vivo. [Display omitted] • Multistage transdermal drug delivery system • Dendritic lipopeptide modified multistage targeted liposomes • Excellent permeability of drugs in tumor tissues [ABSTRACT FROM AUTHOR]

Neoantigen-based immunotherapy is an attractive potential treatment for previously intractable tumors. To effectively broaden the application of this approach, stringent biomarkers are crucial to identify responsive patients. ARID1A, a frequently mutated subunit of SWI/SNF chromatin remodeling complex, has been reported to determine tumor immunogenicity in some cohorts; however, mutations and deletions of ARID1A are not always linked to clinical responses to immunotherapy. In this study, we investigated immunotherapeutic responses based on ARID1A status in targeted therapy-resistant cancers. Mouse and human BRAFV600E melanomas with or without ARID1A expression were transformed into resistant to vemurafenib, an FDA-approved specific BRAFV600E inhibitor. Anti-PD-1 antibody treatment enhanced antitumor immune responses in vemurafenib-resistant ARID1A-deficient tumors but not in ARID1A-intact tumors or vemurafenib-sensitive ARID1A-deficient tumors. Neoantigens derived from accumulated somatic mutations during vemurafenib resistance were highly expressed in ARID1A-deficient tumors and promoted tumor immunogenicity. Furthermore, the newly generated neoantigens could be utilized as immunotherapeutic targets by vaccines. Finally, targeted therapy resistance-specific neoantigen in experimental human melanoma cells lacking ARID1A were validated to elicit T-cell receptor responses. Collectively, the classification of ARID1A-mutated tumors based on vemurafenib resistance as an additional indicator of immunotherapy response will enable a more accurate prediction to guide cancer treatment. Furthermore, the neoantigens that emerge with therapy resistance can be promising therapeutic targets for refractory tumors. Significance: Chemotherapy resistance promotes the acquisition of immunogenic neoantigens in ARID1A-deficient tumors that confer sensitivity to immune checkpoint blockade and can be utilized for developing antitumor vaccines, providing strategies to improve immunotherapy efficacy., (©2024 American Association for Cancer Research.)

Despite rising melanoma incidence in recent decades, there is a trend towards overall decreased mortality, reflecting multiple factors including improved treatment options for metastatic disease. While local treatments are the mainstay for early-stage melanoma, metastatic disease necessitates systemic treatment, with oncolytic virotherapy emerging as a promising option. For this review, articles were retrieved from PubMed from 1964 through 2024. We conducted title, abstract and full-text screening in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to identify articles describing the use of coxsackievirus A21 (V937), either as monotherapy or as part of combination therapy for malignant melanoma. Fifteen articles met inclusion criteria, offering preclinical and clinical data on V937's efficacy in reducing tumour burden. In addition to reporting manageable safety profiles, clinical trial data examining intratumoral V937 combination therapy with pembrolizumab and ipilimumab also endorsed favourable objective response rates compared to immune checkpoint inhibitor monotherapy (47% vs. 38% and 21% vs. 10%, respectively). In contrast, intravenous V937 monotherapy failed to yield additional benefit in a cohort of patients with Stage IIIC/IV melanoma (n = 3) despite achieving detectable levels in tumour tissue (1 × 10 9 TCID 50 ). Although small subsets of patients experienced severe adverse effects and study design limitations imposed constraints on collected data, evidence for the efficacy of V937 remains encouraging. With few clinical trials evaluating V937 in melanoma, additional data is required before routine usage in standard treatment for metastatic lesions., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Combination therapy using chemo-photothermal therapy (chemo-PTT) shows great efficacy toward tumor ablation in preclinical studies. Besides, lipopolymersomes as a hybrid nanocarriers, integrate advantages of liposomes and polymersomes in a single platform in order to provide tremendous biocompatibility, biodegradability, noteworthy loading efficacy for both hydrophobic and hydrophilic drugs with adjustable drug release and high stability. In this study, a multipurpose lipopolymersome was fabricated for guided chemotherapy-PTT and NIR-imaging of melanoma. A lipopolymerosomal hybrid nanovesicle consisting of equal molar ratio of 1,2-dioleoyl-3-trimethylammonium propane (DOTAP) and poly (ethylene glycol)-poly (lactic acid) (PEG-PLA) diblock copolymer (molar ratio 1:1) was fabricated. The nanoparticulate system was prepared through film rehydration technique for encapsulation of doxorubicin (DOX) and indocyanine green (ICG) to form DOX-ICG-LP platform. At the next stage, AS1411 DNA aptamer was conjugated to the surface of lipopolymersome (Apt-DOX-ICG-LP) for selective delivery. The sizes of DOX-ICG-LP and Apt-DOX-ICG-LP were obtained through DLS analysis (61.0 ± 6 and 74 ± 5, respectively). Near Infrared-responsive release pattern of the prepared lipopolymersome was verified in vitro. The formulated platform showed efficient photothermal conversion, and superior stability with acceptable encapsulation efficiency. Consistent with the in vitro studies, NIR-responsive lipopolymersome exhibited significantly higher cellular toxicity for Chemo-PTT versus single anti-cancer treatment. Moreover, superlative tumor shrinkage with favorable survival profile were attained in B16F10 tumor-bearing mice received Apt-DOX-ICG-LP and irradiated with 808 nm laser compared to those treated with either DOX-ICG-LP or Apt-DOX-ICG-LP without laser irradiation. The diagnostic capability of Apt-DOX-ICG-LP was addressed using in vivo NIR imaging, 6 and 24 h post-intravenous administration. The results indicated desirable feature of an established targeted theranostic capability of Apt-DOX-ICG-LP for both diagnostics and dual chemo-PTT of melanoma., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Melanoma pathogenesis, conventionally perceived as a linear accumulation of molecular changes, discloses substantial heterogeneity driven by non-linear biological processes, including the direct transformation of melanocyte stem cells. This heterogeneity manifests in diverse biological phenotypes and developmental states, influencing variable responses to treatments. Unveiling the aberrant mechanisms steering melanoma initiation, progression, and metastasis is imperative. Beyond mutations in oncogenic and tumor suppressor genes, the involvement of distinct molecular pathways assumes a pivotal role in melanoma pathogenesis. Ultraviolet (UV) radiations, a principal factor in melanoma etiology, categorizes melanomas based on cumulative sun damage (CSD). The genomic landscape of lesions correlates with UV exposure, impacting mutational load and spectrum of mutations. The World Health Organization's 2018 classification underscores the interplay between sun exposure and genomic characteristics, distinguishing melanomas associated with CSD from those unrelated to CSD. The classification elucidates molecular features such as tumor mutational burden and copy number alterations associated with different melanoma subtypes. The significance of the mutated BRAF gene and its pathway, notably BRAFV600 variants, in melanoma is paramount. BRAF mutations, prevalent across diverse cancer types, present therapeutic avenues, with clinical trials validating the efficacy of targeted therapies and immunotherapy. Additional driver mutations in oncogenes further characterize specific melanoma pathways, impacting tumor behavior. While histopathological examination remains pivotal, challenges persist in molecularly classifying melanocytic tumors. In this review, we went through all molecular characterization that aid in discriminating common and ambiguous lesions. Integration of highly sensitive molecular diagnostic tests into the diagnostic workflow becomes indispensable, particularly in instances where histology alone fails to achieve a conclusive diagnosis. A diagnostic algorithm based on different molecular features inferred by the various studies is here proposed., Competing Interests: Declaration of Competing Interest Authors declare no potential conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background Aims: Vγ9Vδ2 T cells are under investigation as alternative effector cells for adoptive cell therapy (ACT) in cancer. Despite promising in vitro results, anti-tumor efficacies in early clinical studies have been lower than expected, which could be ascribed to the complex interplay of tumor and immune cell metabolism competing for the same nutrients in the tumor microenvironment., Methods: To contribute to the scarce knowledge regarding gamma delta T-cell metabolism, we investigated the metabolic phenotype of 25-day-expanded Vγ9Vδ2 T cells and how it is intertwined with functionality., Results: We found that Vγ9Vδ2 T cells displayed a quiescent metabolism, utilizing both glycolysis and oxidative phosphorylation (OXPHOS) for energy production, as measured in Seahorse assays. Upon T-cell receptor activation, both pathways were upregulated, and inhibition with metabolic inhibitors showed that Vγ9Vδ2 T cells were dependent on glycolysis and the pentose phosphate pathway for proliferation. The dependency on glucose for proliferation was confirmed in glucose-free conditions. Cytotoxicity against malignant melanoma was reduced by glycolysis inhibition but not OXPHOS inhibition., Conclusions: These findings lay the groundwork for further studies on manipulation of Vγ9Vδ2 T-cell metabolism for improved ACT outcome., Competing Interests: Declaration of competing interest The authors have no commercial, proprietary or financial interest in the products or companies described in this article., (Copyright © 2024 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Conflicts of interest None disclosed.

Immunotherapy has transformed the treatment of advanced melanoma. However, up to two-thirds of patients experience disease progression after initially achieving a response to immunotherapy. Furthermore, most research has focused on cutaneous melanoma rather than acral or mucosal melanoma, although the latter predominates in Asian populations. In this review, we examine and summarize current definitions of resistance to immunotherapy and the epidemiology of resistance to PD-1 inhibition. We also review the available literature on molecular mechanisms of resistance, including how the tumor mutational landscape and tumor microenvironments of immunotherapy-resistant acral and mucosal melanomas may influence resistance. Finally, we review strategies for overcoming resistance to PD-1 inhibition and summarize completed studies and ongoing clinical trials. Our review highlights that improving the understanding of resistance mechanisms, optimizing existing therapies and further studying high-risk populations would maximize the potential of immunotherapy and result in optimized treatment outcomes for patients with melanoma., Competing Interests: Declaration of Competing Interest Hongwei Fan and Li Zhang are employees of MSD China. The other authors have no conflicts of interest to declare., (Copyright © 2024. Published by Elsevier B.V.)

Aim: Oral malignant melanoma (OMM) is a rare and aggressive malignant tumour arising from the proliferation of melanocytes and accounts for only 0.5 % of all oral malignancies. It is invasive and tends to metastasise. The aim of this study is to determine the patient profile of OMM and to provide information about the clinical features and treatment plans of the disease., Materials and Methods: The Pubmed database was searched for OMM cases published as case reports in the last 10 years. The search was limited to English and open-access case reports. A total of 49 OMMs in 45 patients from 43 case reports were analyzed. In addition to the age, gender, smoking and alcohol consumption habits of the patients, data on the signs and symptoms of OMM, location of the lesion, imaging modalities used in diagnosis and treatment, lymph node involvement, presence of metastasis, survival time, and treatment modalities were recorded., Results: In OMM cases, 18 (40 %) of the patients were female, 27 (60 %) were male, and the mean age was 53.13 ± 16.09 years. The most common symptom was "swelling" (n = 23, 33.8 %) and the most common finding was "hyperpigmentation" (n = 40, 24.4 %). The most common site of OMM was the maxilla (n = 21, 46.7 %). According to the rate of use of imaging modalities in the cases, it was determined that "advanced imaging modalities" were mostly used (n = 24, 53.3 %). It was determined that 22.2 % (n = 10) of the patients died within the first 5 years. Combined treatment (n = 21, 46.5 %) were mostly applied to the patients., Conclusion: OMM is more common in the maxilla, in males and in the fifth decade of life, and advanced imaging modalities are most commonly used to detect the disease. Because of its poor prognosis, knowing the patient profile and common clinical features of OMM will increase the clinical awareness of physicians., Competing Interests: Declaration of competing interest There is no conflict of interest., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Aberrant glycosylation recently emerged as an unmissable hallmark of cancer progression in many cancers. In melanoma, there is growing evidence that the tumour 'glycocode' plays a major role in promoting cell proliferation, invasion, migration, but also dictates the nature of the immune infiltrate, which strongly affects immune cell function, and clinical outcome. Aberrant glycosylation patterns dismantle anti-tumour defence through interactions with lectins on immune cells, which are crucial to shape anti-tumour immunity but also to trigger immune evasion. The glycan/lectin axis represents a new immune subversion pathway that is exploited by melanoma to hijack immune cells and escape from immune control. In this review, we describe the glycosylation features of melanoma tumour cells, and further gather findings related to the role of glycosylation in melanoma tumour progression, deciphering in detail its impact on immunity. We also depict glycan-based strategies aiming at restoring a functional anti-tumour response in melanoma patients. Glycans/lectins emerge as key immune checkpoints with promising translational properties. Exploitation of these pathways could reshape potent anti-tumour immunity while impeding immunosuppressive circuits triggered by aberrant tumour glycosylation patterns, holding great promise for cancer therapy., (© 2024 The Authors. Immunology published by John Wiley & Sons Ltd.)

An optimum safety excision margin (EM) delineated by precise demarcation of field cancerization along with reliable biomarkers that enable predicting and timely evaluating patients' response to immunotherapy significantly impact effective management of melanoma. In this study, optimized biphasic "immunofluorescence staining integrated with fluorescence insitu hybridization" (iFISH) was conducted along the diagnosis-metastasis-treatment-cellular MRD axis to longitudinally co-detect a full spectrum of intact CD31 - aneuploid tumor cells (TCs), CD31 + aneuploid tumor endothelial cells (TECs), viable and necrotic circulating TCs (CTCs) and circulating TECs (CTECs) expressing PD-L1, Ki67, p16 and Vimentin in unsliced specimens of the resected primary tumor, EM, dissected sentinel lymph nodes (SLNs) and peripheral blood in an early-stage melanoma patient. Numerous PD-L1 + aneuploid TCs and TECs were detected at the conventional safety EM (2 cm), quantitatively indicating the existence of a field cancerized EM for the first time. Contrary to highly heterogeneous PD-L1 expression and degrees of Chr8 aneuploidy in TCs and TECs in the primary lesions as well as CTCs and CTECs in peripheral blood, almost all TCs and TECs in SLNs and EM were homogeneously PD-L1 + haploid cells. Dynamic monitoring and cellular MRD assessment revealed that, in contrast to PD-L1 + CTCs being responsive to the immune checkpoint inhibitor (ICI-anti-PD-1), multiploid (≥pentasomy 8) PD-L1 + and Ki67 + CTECs were respectively resistant to ICI-sensitized T cells. In therapeutically stressed lymphatic and hematogenous metastatic cascades, stratified phenotypic and karyotypic profiling of iFISH tissue and liquid biopsied TCs, TECs, CTCs and CTECs in future large-cohort studies will enable appropriate re-specification of the optimal safety EM and distribution mapping of in-depth characterized, subcategorized target cells to help illustrate their metastatic relevance, ultimately improving risk stratification and clinical intervention of tumor progression, metastases, therapy resistance and cancer relapse., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The lysine-specific histone demethylase 1 A (LSD1) is involved in antitumor immunity; however, its role in shaping CD8 + T cell (CTL) differentiation and function remains largely unexplored. Here, we show that pharmacological inhibition of LSD1 (LSD1i) in CTL in the context of adoptive T cell therapy (ACT) elicits phenotypic and functional alterations, resulting in a robust antitumor immunity in preclinical models in female mice. In addition, the combination of anti-PDL1 treatment with LSD1i-based ACT eradicates the tumor and leads to long-lasting tumor-free survival in a melanoma model, complementing the limited efficacy of the immune or epigenetic therapy alone. Collectively, these results demonstrate that LSD1 modulation improves antitumoral responses generated by ACT and anti-PDL1 therapy, providing the foundation for their clinical evaluation., (© 2024. The Author(s).)

Lower extremity nodular melanoma (NM) is a common malignant tumor with a poor prognosis. We aims to identify the prognostic factors and develop a nomogram model to predict overall survival (OS) in patients with lower extremity NM. A total of 746 patients with lower extremity NM were selected and randomly divided into a training set (522 cases) and a validation set (224 cases) from the Surveillance, Epidemiology, and End Results(SEER) database. The training set underwent univariate and multivariate Cox regression analyses to identify independent prognostic factors associated with patient outcomes, and to develop a nomogram model. The effectiveness of the nomogram was subsequently validated using the validation set. Multivariable Cox regression analysis of the training set indicated that age, ulceration, radiotherapy, chemotherapy, primary site of first malignant tumor, and Breslow thickness were independent variables associated with OS. In the training set, the area under the curve (AUC) of the nomogram for predicting 3-year and 5-year OS was 0.796 and 0.811, respectively. In the validation set, the AUC for predicting 3-year and 5-year OS was 0.694 and 0.702, respectively. The Harrell's C-index for the training set and validation set were 0.754 (95% CI: 0.721-0.787) and 0.670 (95% CI: 0.607-0.733), respectively. Calibration curves for both training and validation sets showed good agreement. In this study, we develop and validate a nomogram to predict OS in patients with lower extremity NM. The nomogram demonstrated reasonable reliability and clinical applicability. Nomograms are important tools assessing prognosis and aiding clinical decision-making., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Neoadjuvant therapy improves recurrence-free survival (RFS) in resectable stage III cutaneous melanoma. However, accurately predicting individual recurrence risk remains a significant challenge. We investigated circulating tumour DNA (ctDNA) as a biomarker for recurrence in measurable stage IIIB/C melanoma patients undergoing neoadjuvant immunotherapy., Methods: Plasma samples were collected pre-neoadjuvant treatment, pre-surgery and/or six weeks post-surgery from 40 patients enrolled in the OpACIN-neo and PRADO clinical trials. Patients received two cycles of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) before surgery. Cell free DNA (cfDNA) underwent unbiased pre-amplification followed by tumour-informed mutation detection using droplet digital polymerase chain reaction (ddPCR) with the Bio-Rad QX600 PCR system., Results: Pre-treatment ctDNA was detectable in 19/40 (48%) patients. Among these, 17/19 (89%) zero-converted within six weeks of surgery and none recurred. Positive ctDNA post-surgery (N = 4), irrespective of pre-treatment ctDNA status, was 100% predictive of recurrence (sensitivity 44%, specificity 100%). Furthermore, ctDNA cleared prior to surgery in 7/9 (78%) patients who did not recur, warranting further investigation into ctDNA-guided surgical management., Conclusion: Post-surgery ctDNA positivity and zero-conversion are highly predictive of recurrence, offering a window for personalised modification of adjuvant therapy., (© 2024. The Author(s).)

Photothermal therapy (PTT) is a method for eradicating tumor tissues through the use of photothermal materials and photosensitizing agents that absorb light energy from laser sources and convert it into heat, which selectively targets and destroys cancer cells while sparing healthy tissue. MXenes have been intensively investigated as photosensitizing agents for PTT. However, achieving the selectivity of MXenes to the tumor cells remains a challenge. Specific antibodies (Ab) against tumor antigens can achieve homing of the photosensitizing agents toward tumor cells, but their immobilization on MXene received little attention. Here, we offer a strategy for the selective ablation of melanoma cells using MXene-polydopamine-antiCEACAM1 Ab complexes. We coated Ti 3 C 2 T x MXene with polydopamine (PDA), a natural compound that attaches Ab to the MXene surface, followed by conjugation with an anti-CEACAM1 Ab. Our experiments confirm the biocompatibility of the Ti 3 C 2 T x -PDA and Ti 3 C 2 T x -PDA-antiCEACAM1 Ab complexes across various cell types. We also established a protocol for the selective ablation of CEACAM1-positive melanoma cells using near-infrared irradiation. The obtained complexes exhibit high selectivity and efficiency in targeting and eliminating CEACAM1-positive melanoma cells while sparing CEACAM1-negative cells. These results demonstrate the potential of MXene-PDA-Ab complexes for cancer therapy. They underline the critical role of targeted therapies in oncology, offering a promising avenue for the precise and safe treatment of melanoma and possibly other cancers characterized by specific biomarkers. Future research will aim to refine these complexes for clinical use, paving the way for new strategies for cancer treatment.

Selenium and selenoproteins are closely related to melanoma progression. However, it is unclear how SELENOK affects lipid metabolism, endoplasmic reticulum stress (ERS), immune cell infiltration, survival, and prognosis in melanoma patients. Transcriptome data from melanoma patients was used to investigate SELENOK levels and their effect on prognosis, followed by an investigation of SELENOK's effects on immune cell infiltration. Furthermore, a risk model based on ERS, lipid metabolism, and immune-related genes was constructed, and its utility in melanoma prognosis was evaluated. Finally, the drug sensitivity of the risk model was analyzed to provide a reference for melanoma therapy. The results showed that melanoma with a high SELENOK level had a greater degree of immune cell infiltration and a better prognosis. Additionally, SELENOK was found to regulate ERS, lipid metabolism, and immune cell infiltration in melanoma. The risk model based on SELENOK signature genes successfully predicted the prognosis of melanoma, and the low-risk group exhibited a favorable immunological microenvironment. Furthermore, high-risk patients with melanoma were candidates for chemotherapy with RAS pathway inhibitors, whereas low-risk patients were more susceptible to routinely used chemotherapy medicines. In summary, SELENOK was shown to regulate ERS, lipid metabolism, and immune cell infiltration in melanoma, and SELENOK was positively associated with the prognosis of melanoma. The risk model based on SELENOK signature genes was valuable for melanoma prognosis and therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Messenger RNA (mRNA) vaccines are promising platforms for cancer immunotherapy because of their potential to encode for a variety of tumor antigens, high tolerability, and capacity to induce strong antitumor immune responses. However, the clinical translation of mRNA cancer vaccines can be hindered by the inefficient delivery of mRNA in vivo . In this review, we provide an overview of mRNA cancer vaccines by discussing their utility in treating melanoma. Specifically, we begin our review by describing the barriers that can impede mRNA delivery to target cells. We then review native mRNA structure and discuss various modification methods shown to enhance mRNA stability and transfection. Next, we outline the advantages and challenges of three nonviral carrier platforms (lipid nanoparticles, polymeric nanoparticles, and lipopolyplexes) frequently used for mRNA delivery. Last, we summarize preclinical and clinical studies that have investigated nonviral mRNA vaccines for the treatment of melanoma. In writing this review, we aim to highlight innovative nonviral strategies designed to address mRNA delivery challenges while emphasizing the exciting potential of mRNA vaccines as next-generation therapies for the treatment of cancers.

Purpose: We aim to improve the prediction of response or resistance to immunotherapies in patients with melanoma. This goal is based on the hypothesis that current gene signatures predicting immunotherapy outcomes show only modest accuracy due to the lack of spatial information about cellular functions and molecular processes within tumors and their microenvironment., Experimental Design: We collected gene expression data spatially from three cellular compartments defined by CD68+ macrophages, CD45+ leukocytes, and S100B+ tumor cells in 55 immunotherapy-treated melanoma specimens using Digital Spatial Profiling-Whole Transcriptome Atlas. We developed a computational pipeline to discover compartment-specific gene signatures and determine if adding spatial information can improve patient stratification., Results: We achieved robust performance of compartment-specific signatures in predicting the outcome of immune checkpoint inhibitors in the discovery cohort. Of the three signatures, the S100B signature showed the best performance in the validation cohort (N = 45). We also compared our compartment-specific signatures with published bulk signatures and found the S100B tumor spatial signature outperformed previous signatures. Within the eight-gene S100B signature, five genes (PSMB8, TAX1BP3, NOTCH3, LCP2, and NQO1) with positive coefficients predict the response, and three genes (KMT2C, OVCA2, and MGRN1) with negative coefficients predict the resistance to treatment., Conclusions: We conclude that the spatially defined compartment signatures utilize tumor and tumor microenvironment-specific information, leading to more accurate prediction of treatment outcome, and thus merit prospective clinical assessment., (©2024 American Association for Cancer Research.)

Fecal microbiota transplants (FMTs) recently entered the cancer therapeutics field as a method to resensitize treatment-resistant melanoma patients to immune checkpoint inhibitors (ICIs). In this issue of Cell Host & Microbe, Kim and colleagues extend its utility to other solid tumors, including esophageal and hepatocellular carcinomas. 1 ., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024. Published by Elsevier Inc.)

The innate immune system, composed of neutrophils, basophils, eosinophils, myeloid-derived suppressor cells (MDSCs), macrophages, dendritic cells (DCs), mast cells (MCs), and innate lymphoid cells (ILCs), is the first line of defense. Growing evidence demonstrates the crucial role of innate immunity in tumor initiation and progression. Several studies support the idea that innate immunity, through the release of pro- and/or anti-inflammatory cytokines and tumor growth factors, plays a significant role in the pathogenesis, progression, and prognosis of cutaneous malignant melanoma (MM). Cutaneous melanoma is the most common skin cancer, with an incidence that rapidly increased in recent decades. Melanoma is a highly immunogenic tumor, due to its high mutational burden. The metastatic form retains a high mortality. The advent of immunotherapy revolutionized the therapeutic approach to this tumor and significantly ameliorated the patients' clinical outcome. In this review, we will recapitulate the multiple roles of innate immune cells in melanoma and the related implications for immunotherapy.

Opinion Statement: Melanoma is defined as the most aggressive and deadly form of skin cancer. The treatment of melanoma depends on the disease stage, tumor location, and extent of its spread from its point of origin. Melanoma treatment has made significant advances, notably in the context of targeted and immunotherapies. Surgical resection is the main therapeutic option for earlystage melanoma, and it provides favourable outcomes. With disease metastasis, systemic treatments such as immunotherapy and targeted therapy become increasingly important. The identification of mutations that lead to melanoma has influenced treatment strategies. Targeted therapies focusing on these mutations offer improved response rates and fewer toxicities than conventional chemotherapy. Furthermore, developing immunotherapies, including checkpoint inhibitors and tumor-infiltrating lymphocyte (TIL) therapies, has demonstrated encouraging outcomes in effectively combating cancer cells. These therapeutic agents demonstrate superior effectiveness and a more tolerable side-effect profile, improving the quality of life for patients receiving treatment. The future of melanoma treatment may involve a multimodal approach consisting of a combination of surgery, targeted therapy, and immunotherapy adapted to each patient's profile. This approach may improve survival rates and health outcomes., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose of Review: Congenital melanocytic nevi (CMN) and acquired nevi are prevalent in pediatric populations, with distinct characteristics and management considerations. This chapter aims to equip pediatricians with knowledge to discern between benign and high-risk nevi, facilitating appropriate referrals and management within primary care settings. Risk factors associated with malignant melanoma (MM) underscore the importance of vigilant monitoring and early referral to dermatology for suspicious lesions., Recent Findings: Recent findings highlight the variability in CMN presentation and the evolving diagnostic strategies, emphasizing the need for multidisciplinary approaches to optimize patient outcomes., Summary: Management of CMN involves tailored surveillance and intervention strategies, with an emphasis on early identification of high-risk features for MM and neurocutaneous melanosis (NCM). Pediatricians play a crucial role in advocating for sun protection practices and facilitating timely referrals, thereby contributing to the overall well being of pediatric patients with nevi., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Psychosocial care of cancer patients is an important aspect throughout the entire course of oncological treatment. Since 2015, psychosocial screening has been implemented in the outpatient clinics of the Skin Cancer Center in Freiburg. We present here a post hoc analysis in the context of a quality management program., Question: Acceptance, psychosocial distress and desire for counseling were evaluated. Exploratively, we investigated which patient and disease characteristics are related to increased subjective distress., Materials and Methods: In a full survey from 06/2015 to 12/2015, we evaluated acceptance, psychosocial distress by distress thermometer (DT), and desire for counseling., Results: Of 753 patients, 345 (45.8%) participated in psychosocial screening and data from 310 (174 men, 136 women; 89.7% melanoma patients, mean time since initial diagnosis 4.7 ± 3.9 years) could be analyzed. The mean burden on the DT was 2.97 ± 2.83 (median 2, range 0-10). High distress (DT ≥ 5) was reported by 84 patients (28.8%). Thirty-four patients (11%) indicated a desire for counseling, and 23 patients took up the counseling offer. The patient group with high distress was younger, more often under ongoing or recently completed systemic therapy, and had more often a desire for counseling., Conclusion: In addition to assessing psychosocial distress with validated screening instruments, the survey of the subjective desire for care represents an important parameter for the identification of patients in need of care. Young patients and patients with ongoing systemic therapy should be the focus of attention., (© 2024. The Author(s).)

Purpose: Melanoma is widely utilized as a prominent model for the development of immunotherapy, thought an inadequate immune response can occur. Moreover, the development of apoptosis-related therapies and combinations with other therapeutic strategies is impeded by the limited understanding of apoptosis's role within diverse tumor immune microenvironments (TMEs)., Methods: Here, we constructed an apoptosis-related tumor microenvironment signature (ATM) and employ multi-dimensional analysis to understand the roles of apoptosis in tumor microenvironment. We further assessed the clinical applications of ATM in nine independent cohorts, and anticipated the impact of ATM on cellular drug response in cultured cells., Results: Our ATM model exhibits robust performance in survival prediction in multiple melanoma cohorts. Different ATM groups exhibited distinct molecular signatures and biological processes. The low ATM group exhibited significant enrichment in B cell activation-related pathways. What's more, plasma cells showed the lowest ATM score, highlighting their role as pivotal contributors in the ATM model. Mechanistically, the analysis of the interplay between plasma cells and other immune cells elucidated their crucial role in orchestrating an effective anti-tumor immune response. Significantly, the ATM signature exhibited associations with therapeutic efficacy of immune checkpoint blockade and the drug sensitivity of various agents, including FDA-approved and clinically utilized drugs targeting the VEGF signaling pathway. Finally, ATM was associated with tertiary lymphoid structures (TLS), exhibiting stronger patient stratification ability compared to classical "hot tumors"., Conclusion: Our findings indicate that ATM is a prognostic factor and is associated with the immune response and drug sensitivity in melanoma., (© 2024. The Author(s).)

Purpose of Review: The management of cutaneous melanoma has rapidly progressed over the past decade following the introduction of effective systemic therapies. Given the large number of recent clinical trials which have dramatically altered the management of these patients, an updated review of the current evidence regarding the management of localized melanoma is needed., Recent Findings: The role of effective systemic therapies in earlier stages (I-III) melanoma, both in adjuvant and neoadjuvant settings is rapidly changing the role of surgery in the management cutaneous melanoma, particularly regarding surgical safety margins for wide local excision (WLE), the role of sentinel lymph node biopsy (SLNB) and the extent of lymph node dissections. The randomized phase 2 SWOG1801 trial has demonstrated superiority of neoadjuvant-adjuvant anti-PD1 therapy in improving event-free survival by 23% at 2-years over adjuvant anti-PD-1 therapy only. Furthermore, the PRADO trial has suggested a more tailored approach both the extent of surgery as well as adjuvant therapy can safely and effectively be done, depending on the response to initial neoadjuvant immunotherapy. These results await validation and it is expected that in 2024 the phase 3 Nadina trial (NCT04949113) will definitively establish neo-adjuvant combination immunotherapy as the novel standard. This will further redefine the management of localized melanoma. The use of effective systemic therapies will continue to evolve in the next decade and, together with new emerging diagnostic and surveillance techniques, will likely reduce the extent of routine surgery for stage I-III melanoma., (© 2024. The Author(s).)

Purpose: Uveal melanoma (UM) is the most common intraocular malignant tumor. Despite successful treatment of the primary tumor, about 50% of patients will recur with systemic diseases for which there are no effective treatment strategies. Here we investigated the preclinical efficacy of a chimeric antigen receptor (CAR) T-cell-based immunotherapy targeting B7-H3., Experimental Design: B7-H3 expression on primary and metastatic human UM samples and cell lines was assessed by RNA sequencing, flow cytometry, and immunohistochemistry. Antitumor activity of CAR T cells targeting B7-H3 was tested in vitro with UM cell lines, patient-derived organotypic tumor spheroids from patients with metastatic UM, and in immunodeficient and humanized murine models., Results: B7-H3 is expressed at high levels in >95% UM tumor cells in vitro and in vivo. We generated a B7-H3 CAR with an inducible caspase-9 (iCas9) suicide gene controlled by the chemical inducer of dimerization AP1903, which effectively kills UM cells in vitro and eradicates UM liver metastases in murine models. Delivery of iCas9.B7-H3 CAR T cells in experimental models of UM liver metastases demonstrates a durable antitumor response, even upon tumor rechallenge or in the presence of a significant metastatic disease burden. We demonstrate effective iCas9.B7-H3 CAR T-cell elimination in vitro and in vivo in response to AP1903. Our studies demonstrate more effective tumor suppression with iCas9.B7-H3 CAR T cells as compared to a B7-H3-targeted humanized monoclonal antibody., Conclusions: These studies support a phase I clinical trial with iCas9.B7-H3 CAR T cells to treat patients with metastatic UM., (©2024 American Association for Cancer Research.)

Conjunctival melanoma, a rare malignancy of the ocular surface, is increasing in incidence. When small, straightforward excision with "no touch" surgery and cryotherapy at an experienced centre can provide excellent outcomes. When advanced, management is more complex and highly individualized. The risk of metastatic disease from conjunctival melanoma is as high as 30% and depends on tumour origin, American Joint Committee on Cancer (AJCC) classification, biomarkers, and perhaps most important, management technique. Metastatic disease can result in melanoma-associated death. Therefore, early detection and prompt directed treatment at an experienced centre are important for protection from metastasis. In this review, we provide an update on conjunctival melanoma clinical features, diagnostic modalities, AJCC staging, genetic markers, and the most critical, controlled management with minimization of tumour seeding. We detail the new era of characterization of conjunctival melanoma with molecular biomarkers that predict melanoma prognosis. This could lead to precision medicine with targeted approaches to specific mutations that improve patient survival. As we work together, the field of conjunctival melanoma is moving forward., (Copyright © 2023 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.)

The mortality and therapeutic failure in cutaneous melanoma (CM) are mainly caused by wide metastasis and chemotherapy resistance. Meanwhile, immunotherapy is considered a crucial therapy strategy for CM patients. However, the efficiency of currently available methods and biomarkers in predicting the response of immunotherapy and prognosis of CM is limited. Programmed cell death (PCD) plays a significant role in the occurrence, development, and therapy of various malignant tumors. In this research, we integrated fourteen types of PCD, multi-omics data from TCGA-SKCM and other cohorts in GEO, and clinical CM patients to develop our analysis. Based on significant PCD patterns, two PCD-related CM clusters with different prognosis, tumor microenvironment (TME), and response to immunotherapy were identified. Subsequently, seven PCD-related features, especially CD28, CYP1B1, JAK3, LAMP3, SFN, STAT4, and TRAF1, were utilized to establish the prognostic signature, namely cell death index (CDI). CDI accurately predicted the response to immunotherapy in both CM and other cancers. A nomogram with potential superior predictive ability was constructed, and potential drugs targeting CM patients with specific CDI have also been identified. Given all the above, a novel CDI gene signature was indicated to predict the prognosis and exploit precision therapeutic strategies of CM patients, providing unique opportunities for clinical intelligence and new management methods for the therapy of CM., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The standard of care for patients with resectable stage III/IV melanoma classically included upfront resection with adjuvant therapy. However, in more recent years, the amount of systemic therapies available for neoadjuvant use for these patients has increased. This article reviewed clinical trials investigating neoadjuvant therapy for patients with resectable stage III/IV melanoma. The outcomes of these trials have identified optimal treatment regimens to maximise patient response and minimize toxicities. Additionally, the date demonstrate advantages to neoadjuvant treatment compared to adjuvant therapy alone. Further research is needed to utilize a patient's response to neoadjuvant treatment for prognostication and creation of an individualized treatment plan., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Objectives: This study aims to evaluate the correlation between risk factors and treatment methods affecting nodular melanoma (NM) in the head and neck, as well as cancer-specific survival (CSS), and provide personalized predictive tools for clinical physicians., Methods: The retrospective study data of 1848 patients were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. All variables were included in the correlation analysis using the Spearman method. Significant prognostic factors were extracted and integrated through Cox risk regression analysis to construct a nomogram. To assess the performance of the nomogram, Harrell's concordance index (C-index) and a receiver operating characteristic (ROC) curve analysis were employed., Results: Spearman's correlation analysis revealed a positive correlation between radiotherapy and lymph node metastasis, whereas chemotherapy showed a stronger association with distant metastasis. However, Cox risk regression analysis demonstrated that Mohs surgery and wide excision with margins exceeding 1 cm yielded substantial therapeutic advantages. Five independent risk prognostic factors (Breslow thickness, ulceration, N classification, M classification, and surgery type) were employed to construct a nomogram. The C-index for this nomogram was 0.713 for the training set and 0.720 for the validation set. In the training set, the 3-, 5-, and 8-year areas under the curve (AUCs) for CSS were 0.752, 0.723, and 0.720, whereas the validation set's AUCs were 0.754, 0.763, and 0.760, respectively. Calibration curves indicated the nomogram's strong discriminative ability for predicting CSS., Conclusion: In this study, we identified independent prognostic factors for patients with NM in head and neck and developed a relatively accurate model to predict the survival probability of them, which could contribute to the tumor assessment and clinical decision-making., Level of Evidence: 3 Laryngoscope, 134:3611-3619, 2024., (© 2024 The American Laryngological, Rhinological and Otological Society, Inc.)

Objective: The aim of this work is to comprehensively review and synthesize the literature related to sinonasal mucosal melanoma (SNMM) treatment with immunotherapy, including potentially targetable genetic mutations, survival outcomes, and adverse events., Data Sources: Embase, Cochrane, Scopus, and Web of Science., Review Methods: The study protocol was designed according to Preferred Reporting Items for Systematic Reviews and Meta-analysis statement. Databases were searched from inception through May 23, 2023., Results: A total of 42 studies met inclusion criteria. Twenty-four of the included studies reported genetic mutations for a combined 787 patients with SNMM. 8.1% (95% confidence interval, CI: 7.6-8.6), 18.9% (95% CI: 18.1-19.8), and 8.5% (95% CI: 8.1-9.0) of reported patients were positive for BRAF, NRAS, and KIT mutations, respectively. The presence of brisk tumor-infiltrating lymphocytes was associated with improved recurrence-free survival and overall survival (OS). Six studies reported a combined 5-year OS after adjuvant immunotherapy treatment of 42.6% (95% CI: 39.4-45.8). Thirteen studies encompassing 117 patients reported adjuvant or salvage immune checkpoint inhibitor (ICI) immunotherapy response rates: 40.2% (95% CI: 36.8-43.6) had a positive response (tumor volume reduction or resolution). Eleven studies reported direct comparisons between SNMM patients treated with or without immunotherapy; the majority (7/11) reported survival benefit for their entire cohort or select subgroups of SNMM patients. With the transition to modern ICIs, there is a stronger trend toward survival improvement with adjuvant ICI. Tumors with Ki67 <40% may respond better to ICI's., Conclusion: ICI therapy can be an effective in select SNMM patients, especially those with advanced/metastatic disease., (© 2024 American Academy of Otolaryngology–Head and Neck Surgery Foundation.)

In-transit metastasis (ITM) develop in approximately 1 in 10 patients with melanoma and the disease course can vary widely. Surgical resection is the gold-standard treatment; however, ITM are often surgically unresectable due to size, distribution, and/or anatomic involvement. Oncolytic viral therapies are one category of non-surgical treatment options available for ITM. They induce tumor cell lysis and systemic anti-tumor activity through selective infection of tumor cells by naturally occurring or genetically modified factors. While there are numerous oncolytic viral therapies in various stages of development for the treatment of ITM, this discussion focuses on the mechanism and available literature for the two most established herpes virus-based therapies., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Patients with cutaneous melanoma can develop in-transit metastases (ITM), most often localized to limbs. For patients with uveal melanoma that develop metastatic disease, the overall majority develop isolated liver metastases. For these types of metastases, regional cancer therapies have evolved as effective treatments. Isolated limb perfusion (ILP), isolated limb infusion (ILI), isolated hepatic perfusion (IHP) and percutaneous hepatic perfusion (PHP) achieve a high local concentration of chemotherapy with minimal systemic exposure. This review discusses the mechanism and available literature on locoregional treatment modalities in the era of modern immunotherapy., (© 2023. The Author(s).)

Introduction: Despite the success of immunotherapies for melanoma in recent years, there remains a significant proportion of patients who do not yet derive benefit from available treatments. Immunotherapies currently licensed for clinical use target the adaptive immune system, focussing on Tcell interactions and functions. However, the most prevalent immune cells within the tumor microenvironment (TME) of melanoma are macrophages, a diverse immune cell subset displaying high plasticity, to which no current therapies are yet directly targeted. Macrophages have been shown not only to activate the adaptive immune response, and enhance cancer cell killing, but, when influenced by factors within the TME of melanoma, these cells also promote melanoma tumorigenesis and metastasis., Areas Covered: We present a review of the most up-to-date literatureavailable on PubMed, focussing on studies from within the last 10 years. We also include data from ongoing and recent clinical trials targeting macrophages in melanoma listed on clinicaltrials.gov., Expert Opinion: Understanding the multifaceted role of macrophages in melanoma, including their interactions with immune and cancer cells, the influence of current therapies on macrophage phenotype and functions and how macrophages could be targeted with novel treatment approaches, are all critical for improving outcomes for patients with melanoma.

Purpose of Review: This review summarizes the current role of radiotherapy for the treatment of cutaneous melanoma in the definitive, adjuvant, and palliative settings, and combinations with immunotherapy and targeted therapies., Recent Findings: Definitive radiotherapy may be considered for lentigo maligna if surgery would be disfiguring. High risk, resected melanoma may be treated with adjuvant radiotherapy, but the role is poorly defined since the advent of effective systemic therapies. For patients with metastatic disease, immunotherapy and targeted therapies can be delivered safely in tandem with radiotherapy to improve outcomes. Radiotherapy and modern systemic therapies act in concert to improve outcomes, especially in the metastatic setting. Further prospective data is needed to guide the use of definitive radiotherapy for lentigo maligna and adjuvant radiotherapy for high-risk melanoma in the immunotherapy era. Current evidence does not support an abscopal response or at least identify the conditions necessary to reliably produce one with combinations of radiation and immunotherapy., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Locoregionally advanced melanoma represents a large group of high-risk melanoma patients at presentation and poses major challenges in relation to management and the risks of relapse and death., Areas Covered: Melanoma systemic therapy has undergone substantial advancements with the advent of immune checkpoint inhibitors and molecularly targeted therapies, which have been translated to the neoadjuvant setting for the management of locoregionally advanced disease. Notably, PD1 blockade as monotherapy, in combination with CTLA4 blockade or LAG3 inhibition, has demonstrated significant progress in reducing the risk of relapse and mortality, attributed to high pathologic response rates. Likewise, BRAF-MEK inhibition for BRAF mutant melanoma has yielded comparable outcomes, albeit with lower response durability than immunotherapy. Localized intralesional therapies such as Talimogene laherparepvec (T-VEC) and Tavokinogene Telseplasmid (TAVO) electro-gene-transfer combined with anti-PD1 have demonstrated favorable pathologic responses and increased immune activation. Most importantly, the S1801 randomized trial has demonstrated for the first time the advantage of the neoadjuvant approach over standard surgery followed by adjuvant therapy., Expert Opinion: Current evidence supports neoadjuvant therapy as a standard of care for locoregionally advanced melanoma. Ongoing research will define the optimal regimens and the biomarkers of therapeutic predictive and prognostic value.

Although the incidence of cutaneous melanoma (CM) has been increasing annually, the mortality rate has been decreasing, likely due to better prevention, earlier detection, improved surveillance, and the development of new therapies. Current clinical management guidelines by the National Comprehensive Cancer Network (NCCN) are based on patient risk assignment using staging criteria established by the American Joint Committee on Cancer (AJCC). However, some patients with localized disease (stage I-II), generally considered to have a good prognosis, will develop metastatic disease and die, whereas some patients with later stage disease (stage III-IV) will be cured by surgery, adjuvant therapy, and/or systemic therapy. These results emphasize the importance of identifying patients whose risk may be over or underestimated with standard staging. Gene expression profile (GEP) tests are noninvasive molecular tests that assess the expression levels of a panel of validated genes, providing information about tumor prognosis, including the risk of recurrence, metastasis, and cancer-specific death. GEP tests can provide prognostic information beyond standard staging that may aid clinicians and patients in treatment and surveillance management decisions. This review describes how combining clinicopathologic staging with a robust assessment of tumor biology may provide information that will allow more refined intervention and long-term management., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

For time-sensitive treatment of a patient with malignant melanoma, physicians must obtain a rapid overview of the patient's status. This study aimed to analyze context-specific features and processes at the point of care to derive requirements for a dashboard granting more straightforward access to information. The Think-Aloud method, contextual inquiries, and interviews were performed with physicians from the Department of Dermatology at the University Hospital Essen in Germany. The user statements and observations that were obtained were grouped and categorized using an affinity diagram. Based on the derived subjects, requirements were defined, confirmed, and prioritized. The resulting affinity diagram revealed four topics of importance at the point of care. These topics are "Identifying and Processing the Important", a comprehensive "Patient Record", tasks and challenges in the "Clinical Routine", and interactions and experiences with the available "Systems". All aspects have been reflected in 135 requirements for developing context- and indication-specific patient dashboards. Our work has elucidated the most important aspects to consider when designing a dashboard that improves patient care by enabling physicians to focus on the relevant information. Furthermore, it has been demonstrated that the aspects most often mentioned are not context-specific and can be generalized to other medical contexts., (© 2024. The Author(s).)

Background: Over the past decade, cancer immunotherapies have revolutionized the treatment of melanoma; however, responses vary across patient populations. Recently, baseline tumor size has been identified as an independent prognostic factor for overall survival in patients with melanoma receiving immune checkpoint inhibitors. MG1 is a novel oncolytic agent with broad tumor tropism that has recently entered early-phase clinical trials. The aim of this study was to characterize T-cell responses in human and mouse melanoma models following MG1 treatment and to establish if features of the tumor immune microenvironment (TIME) at two distinct tumor burdens would impact the efficacy of oncolytic virotherapy., Methods: Human three-dimensional in vitro priming assays were performed to measure antitumor and antiviral T-cell responses following MG1 infection. T-cell receptor (TCR) sequencing, T2 killing assay, and peptide recall assays were used to assess the evolution of the TCR repertoire, and measure specific T-cell responses, respectively. In vivo, subcutaneous 4434 melanomas were characterized using RNA sequencing, immunohistochemistry, and flow cytometry. The effectiveness of intratumoral MG1 was assessed in advancing 4434 tumors and the generation of antitumor and antiviral T cells measured by splenocyte recall assays. Finally, combination MG1 and programmed cell death protein-1 antibody (αPD-1) therapy was investigated in advanced 4434 tumors., Results: MG1 effectively supported priming of functional cytotoxic T cells (CTLs) against tumor-associated antigens as well as virus-derived peptides, as assessed using peptide recall and T2 killing assays, respectively. TCR sequencing revealed that MG1-primed CTL comprised larger clusters of similar CDR3 amino acid sequences compared with controls. In vivo testing of MG1 demonstrated that MG1 monotherapy was highly effective at treating early disease, resulting in 90% cures; however, the efficacy of MG1 reduced as the disease burden (local tumor size) increased, and the addition of αPD-1 was required to overcome resistance in more advanced disease. Differential gene expression profiles revealed that increased tumor burden was associated with an immunologically colder TIME. Furthermore, analysis of TCR signaling in advancing tumors demonstrated a different dynamic of TCR engagement compared with smaller tumors, in particular a shift in antigen recognition by CD4+ cells, from conventional to regulatory subsets., Conclusion: Addition of αPD-1 to MG1 is required to overcome viral therapy resistance in immunologically 'colder' more advanced melanoma, highlighting the importance of tumor burden to different types of immunotherapy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)