Melittin, a cytolytic peptide derived from honeybee venom, has demonstrated potent anticancer activity through mechanisms such as membrane disruption, apoptosis induction, and modulation of key signaling pathways. Melittin exerts its anticancer activity by interacting with key molecular targets, including downregulation of the PI3K/Akt and NF-κB signaling pathways, and by inducing mitochondrial apoptosis through reactive oxygen species generation and cytochrome c release. However, its clinical application is hindered by its systemic and hemolytic toxicity, rapid degradation in plasma, poor pharmacokinetics, and immunogenicity, necessitating the development of targeted delivery strategies to enable safe and effective treatment. Nanoparticle-based delivery systems have emerged as a promising strategy for overcoming these challenges, offering improved tumor targeting, reduced off-target effects, and enhanced stability. This review provides a comprehensive overview of the mechanisms through which melittin exerts its anticancer effects and evaluates the development of various melittin-loaded nanocarriers, including liposomes, polymeric nanoparticles, dendrimers, micelles, and inorganic systems. It also summarizes the preclinical evidence for melittin nanotherapy across a wide range of cancer types, highlighting both its cytotoxic and immunomodulatory effects. The potential of melittin nanoparticles to overcome multidrug resistance and synergize with chemotherapy, immunotherapy, photothermal therapy, and radiotherapy is discussed. Despite promising in vitro and in vivo findings, its clinical translation remains limited. Key barriers include toxicity, manufacturing scalability, regulatory approval, and the need for more extensive in vivo validation. A key future direction is the application of computational tools, such as physiologically based pharmacokinetic modeling and artificial-intelligence-based modeling, to streamline development and guide its clinical translation. Addressing these challenges through focused research and interdisciplinary collaboration will be essential to realizing the full therapeutic potential of melittin-based nanomedicines in oncology. Overall, this review synthesizes the findings from over 100 peer-reviewed studies published between 2008 and 2025, providing an up-to-date assessment of melittin-based nanomedicine strategies across diverse cancer types.

Circulating tumor DNA (ctDNA) has gained increasing attention as a non-invasive biomarker with potential utility across multiple stages of melanoma. ctDNA reflects tumor-derived genetic alterations in real time and has shown value in detecting minimal residual disease, identifying early recurrence, estimating tumor burden, and monitoring response to systemic therapies. In early-stage melanoma, postoperative ctDNA positivity is strongly associated with higher recurrence risk and often precedes radiologic detection. In advanced disease, ctDNA correlates with tumor volume and can distinguish responders from non-responders during targeted therapy and immunotherapy, while also identifying emerging resistance mechanisms. Despite these advantages, clinical implementation remains limited by low shedding in early-stage disease, variation among detection platforms, and the absence of standardized clinical thresholds. Recent advances, including fragmentomics, methylation assays, and multi-target sequencing strategies, aim to improve sensitivity, particularly in low-tumor-burden settings. Integration of ctDNA with radiomics, artificial intelligence, and digital pathology represents an additional opportunity to enhance precision in risk stratification and treatment adaptation. This review summarizes current evidence on ctDNA biology, detection methods, and clinical applications in melanoma and outlines ongoing challenges and future directions required for translation into routine practice.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, but their association with thrombosis presents significant clinical challenges. Patients with cancer already exhibit elevated risks for venous thromboembolism and arterial thrombosis, with treatment modalities like chemotherapy further exacerbating this risk. Emerging evidence suggests that ICIs contribute to thrombotic events through multifactorial mechanisms, including immune dysregulation, T cell activation, endothelial dysfunction, elevated tissue factor expression, and impaired fibrinolysis. Additional risk factors such as obesity, smoking, prior thrombotic events, and combination ICI therapy further increase thrombosis susceptibility. The literature reports varying incidence rates of ICI-associated thrombosis, with some studies indicating comparable risks to chemotherapy, while others highlight higher rates, particularly during the initial treatment phase. Management aligns with standard protocols for cancer-associated thrombosis, using low-molecular-weight heparin or direct oral anticoagulants, though optimal treatment duration and the role of prophylactic anticoagulation require further investigation. This review provides a comprehensive overview of the mechanisms, incidence rates, and clinical management strategies of ICI-associated thrombosis, emphasizing the importance of proactive risk assessment to optimize patient outcomes.

SUMMARY: The interplay between the gut and skin microbiomes and their influence on skin cancer development has garnered significant attention. The gut and skin microbiomes, composed of bacteria, fungi, and viruses, play vital roles in immune modulation, inflammation regulation, and maintaining skin health. Dysbiosis in either microbiome may contribute to inflammatory skin conditions and cancer development through the gut-skin axis. The gut microbiota influences immune responses, skin barrier function, and carcinogenesis via microbial metabolites, such as short-chain fatty acids. These compounds impact systemic inflammation, immune cell activity, and response to immunotherapy, particularly in melanoma and non-melanoma skin cancers. Emerging evidence links distinct microbial profiles to skin cancer progression, with specific taxa associated with advanced stages. Conversely, certain skin commensals exhibit potential anti-tumor effects. In addition, microbial imbalances correlate with tumorigenesis via inflammatory and metabolic pathways. Advancements in microbiome profiling have further elucidated these associations, offering diagnostic and therapeutic opportunities. Potential interventions include probiotic therapies to restore microbial balance and enhance immunotherapy efficacy. However, the intricate dynamics of the gut-skin axis necessitate further investigation into causal mechanisms, microbial metabolite impacts, and personalized therapeutic strategies. This review highlights the dualistic role of the gut and skin microbiomes in skin cancer, emphasizing their diagnostic and therapeutic potential while proposing future research directions to unravel their complexities and clinical implications.

Background/Objectives: Acral melanoma (AM) is a rare and aggressive melanoma subtype that arises on sun-shielded, non-hair-bearing skin of the palms, soles, and nail beds. Although more common among individuals of non-European descent, AM remains underrecognized and understudied in the Middle East and North Africa (MENA). This study presents the first dedicated AM registry from Lebanon, aiming to characterize clinical, histopathological, and molecular features and evaluate diagnostic, referral, treatment approaches, and clinical outcomes over a 12-year period. Methods: This retrospective cohort study was conducted at the American University of Beirut Medical Center (AUBMC), a major tertiary referral center in the MENA region. All melanoma cases diagnosed between January 2012 and January 2024 were identified through electronic health records. From this cohort, all adult patients (≥18 years) with biopsy-confirmed AM or tumors located on the palms, soles, or under the nails were selected. Results: Our cohort consisted of 26 adult AM patients, identified from a total of 331 melanoma cases during the study period (8%). Median age at diagnosis was 58.5 years; 54% were female; and 96% of Middle Eastern origin. Most tumors were plantar (81%), and over half (53%) were diagnosed at early stages (Stage I–II). Surgery was performed in 92% of patients, yet 55% had positive margins. Sentinel lymph node biopsy was performed in 46%, and 35% received immunotherapy. Only 35% underwent molecular testing, identifying BRAF mutations in 11% of those tested; no patients received circulating tumor DNA analysis. At a median follow-up of 24.5 months, recurrence occurred in 27%, and metastasis developed in 23%. At the last follow-up, 92% were alive. Conclusions: Despite early-stage detection, high rates of positive margins and limited molecular testing reveal care gaps. This first national registry highlights the need to improve surgical management and expand access to precision oncology in the region.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment and prognosis of a variety of solid tumors. However, exaggerated immune activation can lead to immune-related adverse events (irAEs), among which hematologic irAEs remain poorly characterized. This study evaluated the frequency, spectrum, and risk factors of treatment-emergent cytopenia in patients with melanoma, renal cell carcinoma (RCC), and urothelial carcinoma (UCC) treated with ICIs. We retrospectively reviewed patients at the American University of Beirut Medical Center who received at least one dose of ICIs between January 2019 and January 2024. Clinical, treatment, and laboratory data were collected from electronic medical records. Binary logistic regressions assessed the relationships between potential predictors and development of treatment-emergent cytopenia. The primary outcome of interest was the incidence of at least one treatment-emergent cytopenia. We included 153 patients (median age 68.21 years, 64.7% male, mean BMI 27.6 ± 4.32 kg/m²) receiving ICIs for melanoma (27.45%), RCC (27.45%), or UCC (45.09%). Pembrolizumab (52.94%) and nivolumab (23.52%) were the most used ICIs, with 28.1% receiving combination therapy. Initially, 47.05% of patients had pre-treatment anemia (mostly grade 1), while thrombocytopenia was rare (5.9%, all grade 1), and no patients had neutropenia. Following initiation with ICIs, 61.43% (94/153) experienced at least one new-onset or worsening treatment-emergent cytopenia. Most common were anemia (46.4%), followed by thrombocytopenia (27.45%) and neutropenia (26.14%). Pancytopenia occurred in 15.6% and bicytopenia in 18.3%. Median time to first hematologic disturbance was 1.39 months (mean 4.71 months, IQR (Long et al., Ann Oncol, 35:1191-1199, 2024); (Motzer et al., N Engl J Med, 378:1277-1290, 2018); (Gupta et al., ESMO Open, 10:104506, 2025), ~ 5.8 cycles). Most treatment-emergent cytopenia were grade 1 (71.24%), fewer grade 2 (20.26%) and 3 (8.49%). There was no grade 4 or 5 events or hematology-related fatalities. Supportive treatment included transfusions in 22.22% and (granulocyte colony-stimulating factor (G-CSF) administration in 12.41%; no patient required steroids, IVIG, or treatment discontinuation due to hematologic irAEs. Univariate regression analysis evaluating the predictors of developing at least one treatment-emergent cytopenia showed that lower baseline hemoglobin and a history of anemia were significant factors (p < 0.001; OR = 0.56 and p < 0.002; OR = 6.50, respectively). Additionally, regression analysis showed that baseline hemoglobin (OR 0.42, p < 0.001) and eosinophil count (OR 1.42, p = 0.004) were significant predictors of anemia and thrombocytopenia, respectively. On multivariable analysis, hemoglobin emerged as a significant predictor, with HGB showing an OR of 0.91 (95% CI: 0.869-0.963, p = 0.001). Although usually rare in literature, we found treatment-emergent cytopenia to be common but mild and manageable with ICIs. Early monitoring and supportive care are key.