Enhancer of zeste homolog 2 (EZH2) is a methyltransferase that tri-methylates histone H3K27 as the catalytic subunit of the polycomb repressive complex 2. However, inhibition of EZH2 methyltransferase showed only variable anti-cancer efficacy, suggesting that this approach is insufficient. Here, we demonstrate a methyltransferase-independent mechanism of EZH2 wherein EZH2 interacts with inosine monophosphate dehydrogenase 2 (IMPDH2) in the cytoplasm to promote guanosine-5'-triphosphate (GTP) synthesis. Mass spectrometry identified methyltransferase-independent interactions between the EED-binding domain of EZH2 and the CBS domain of IMPDH2. EZH2 knockdown impeded IMPDH2 and reduced GTP levels, ribosome biogenesis, and cancer progression-effects reversed by guanosine. IMPDH2 knockout antagonized EZH2's tumor-promoting effects in vivo, and increased cytosolic EZH2 and IMPDH2 expression was observed in human melanomas and associated with nucleolar enlargement. EZH2-IMPDH2 complexes were also observed across multiple cancers, wherein Sappanone A (SA), which inhibits EZH2-IMPDH2 interactions, was anti-tumorigenic. These findings reveal a methyltransferase-independent oncogenic mechanism of EZH2.
To evaluate the clinical performance of ultra-widefield swept-source optical coherence tomography (UWF-OCT) in the assessment of choroidal tumors and to compare it with ultrasonography (US), spectral-domain (SD)-OCT, and magnetic resonance imaging (MRI). Retrospective diagnostic comparison. Thirty-nine eyes from 39 patients diagnosed with choroidal tumors at a single tertiary referral center. This retrospective diagnostic comparison evaluated patients diagnosed with choroidal tumors at a single tertiary referral center between January 2023 and August 2025. All patients underwent UWF-OCT imaging at diagnosis. Tumor measurements obtained with UWF-OCT were compared with US, SD-OCT, and MRI. Comparative analysis among imaging modalities and predictors affecting UWF-OCT applicability was performed. Tumor thickness (mm) and largest basal diameter (LBD, mm) measurements, and complete measurability rate across different tumor size categories. Thirty-nine eyes from 39 patients (mean age 59.2±16.9 years) were analyzed, including 27 choroidal melanomas (69.2%), 5 metastatic tumors (12.8%), 4 hemangiomas (10.3%), 2 osteomas (5.1%), and 1 (2.6%) indeterminate choroidal melanocytic lesion. UWF-OCT successfully measured both tumor thickness and largest basal diameter (LBD) in 100% (31/31) of small and medium choroidal tumors, substantially outperforming SD-OCT (complete measurement achieved in 63.6% of small tumors, and 0% of medium or large tumors). UWF-OCT measurements were systematically smaller than ultrasonography (thickness: -32.3%, P<0.01; LBD: -11.1%, P<0.01) and MRI (thickness: -29.2%, P<0.01). Mushroom-shaped tumor morphology was the strongest negative predictor of UWF-OCT quality (OR=0.015, 95% CI 0.001-0.196, P<0.01). UWF-OCT's complete measurability was limited in large tumors (12.5%, 1/8). UWF-OCT provides precise, noninvasive, single-scan assessment of small-to-medium choroidal tumors with detailed structural visualization. It may be particularly useful for dome-shaped tumors, while multimodal imaging with US and MRI remains optimal for complex morphologies. Overall, UWF-OCT represents a valuable tool for diagnosis and treatment planning, with potential utility for longitudinal follow-up in choroidal tumor management.
Mitochondria play a crucial role in cancer occurrence and progression, and the electron transport chain (ETC) is the core junction of mitochondrial energy metabolism. Interference ETC can induce mitochondrial dysfunction, but the efficacy is limited based on a single ETC complex. In this study, a multifunctional MOF@TK nanoplatform with intrinsic activity was innovatively synthesized by Zinc (Zn2+) and Fenofibric acid (FFa), which was modified through tumor cell membranes transfected with PD-1 (CMP-MOF@TK) to efficaciously induce mitochondrial dysfunction with ETC inactivation and amplified anti-tumor response. Significantly, the CMP-MOF@TK nano-biohybrid platform was effectively taken up following mitochondriotropic movement, and ROS-responsive decomposition releases Zn2+ and FFa. More importantly, the activities of ETC complex I and IV were synchronously inhibited through FFa and Zn2+, blocking electron transport and promoting the generation of ROS associated with increased oxidative stress and mitochondrial depolarisation, which systematacially induces mitochondrial metabolic dysfunction, down-regulating the production of ATP. In addition, the mitochondrial damage-mediated ICD of tumor cells promoted the increased HMGB1 and CRT in the cytomatrix, and tumor cell membrane transfection of PD-1 effectively down-regulated T cell-mediated immune tolerance, effectively activating anti-tumor immune response. In a word, this work offers a potent strategy for developing anti-tumor platforms with multiple functionalities, which provides translational promise for mitochondrial metabolism interference based on ETC dysfunction to strengthen the anti-tumor effect.
Combination treatment with anti-angiogenic agents and immune checkpoint inhibitors has demonstrated significant efficacy in advanced renal cell carcinoma (RCC). However, data on treatment-emergent renal injury during combination therapy and its prognostic implications remain limited. This study analyzed renal injury and its association with survival outcomes in patients with advanced RCC receiving first-line benmelstobart combined with anlotinib in the ETER100 trial. All randomized patients in the ETER100 (NCT04523272) trial treated with at least one dose of study treatment were included in this analysis. Baseline characteristics, laboratory test results, and information on objective responses, disease progression, and death events were collected. The primary outcomes of this study included renal function changes during therapy, risk factors for renal function abnormalities, clinical outcomes of patients with renal function abnormalities, and the association between renal function abnormalities and survival outcomes. Compared with sunitinib monotherapy, patients receiving benmelstobart combined with anlotinib showed no significant differences in the incidence of serum creatinine elevation (p = 0.0538), percentage decrease in creatinine clearance (p = 0.2546), absolute decrease in creatinine clearance (p = 0.7343), or proteinuria (p = 0.0728). Multivariate analysis identified a history of nephrectomy and estimated glomerular filtration rate <90 mL/min/1.73 m² as independent predictors of serum creatinine elevation in patients receiving combination therapy. As of January 2024, 64.00% of patients (64/100) who developed serum creatinine elevation during combination therapy had recovered to normal levels, and 6.00% (6/100) showed improvement. Besides, 45.56% of patients (77/169) who had proteinuria recovered to normal, and 22.49% (38/169) experienced improvement. Multivariate Cox regression analysis showed that both serum creatinine elevation (progression-free survival [PFS]: p = 0.3526; overall survival [OS]: p = 0.0521) and proteinuria (PFS: p = 0.5831; OS: p = 0.1224) were not independent risk factors for progression-free survival or overall survival in patients receiving combination therapy. For patients with advanced RCC in the ETER100 trial, combination therapy with anti-angiogenic agents and immune checkpoint inhibitors did not increase the risk of renal injury, and in this treatment context, renal function abnormalities occurring during treatment were not significantly associated with survival outcomes. ClinicalTrials.gov identifier: NCT04523272.
Artificial intelligence (AI) has moved from proof-of-concept studies in dermatology to selective, real-world clinical use, particularly in image-based triage, lesion assessment, and workflow augmentation. Dermatology is uniquely suited to AI because much of diagnostic reasoning depends on visual information (clinical photos, dermoscopy, reflectance confocal microscopy, optical coherence tomography) plus context (history, distribution, symptoms, treatments, and risk factors). Yet translation into routine care depends less on eye-catching benchmark accuracy and more on careful validation, robust reference standards, fairness across skin tones and devices, usability within clinical workflows, and continuous post-deployment monitoring for performance and safety. This review summarizes leading diagnostic applications of AI in dermatology, provides a practical framework for clinical validation, and highlights real-world deployment patterns including teledermatology triage, melanoma risk workflows, inflammatory dermatoses severity scoring, and AI-assisted dermatopathology. We emphasize that "AI performance" is not a single number: the intended use (screening vs. diagnosis vs. referral prioritization), operating thresholds, prevalence, human-AI interaction, and downstream clinical actions determine real impact. Finally, we outline implementation considerations (governance, privacy, regulatory expectations, and monitoring) and propose practical steps for clinics and health systems seeking safe adoption.
Melanoma is one of the most aggressive forms of skin cancer due to its high metastatic potential and mortality rate. Although understanding of metabolic reprogramming in melanoma has advanced, the connection between metabolic alterations and metastatic capacity remains incomplete. This study aimed to characterize the metabolic profiles of human melanoma cell lines with high (HT168-M1) and low (WM983B) metastatic potential, and to compare them with each other and also with the metabolic profile of normal human fibroblasts (MRC-5), in order to identify key metabolites and metabolic pathways associated with metastatic behavior. Non-targeted metabolomic profiling using ¹H-NMR spectroscopy was applied to hydrophilic extracts of the three cell lines. Multivariate statistical analyses (PCA and PLS-DA) were used to identify discriminating metabolites, and pathway analysis was performed to determine altered metabolic networks. Several metabolic pathways were significantly altered in melanoma cells compared to fibroblasts, including starch and sucrose metabolism, alanine, aspartate and glutamate metabolism, and glutathione metabolism. Metabolites showing more than two-fold differences included elevated UDP-glucose, ATP, glycerophosphocholine, GTP, creatine and glutathione in the melanoma cells, and reduced glucose, glutamine and 1-methylnicotinamide in fibroblasts. Comparison of the metabolites of melanoma cell lines with differing metastatic potential revealed changes in taurine and hypotaurine, β-alanine-, glutathione-, and amino acid metabolism. Metabolites showing the largest concentration changes were UDP-glucose, glutathione, NAD+, alanine and β-alanine. Metabolomic profiling revealed distinct metabolic reprogramming between melanoma and normal fibroblasts, characterized by enhanced glycolysis and glutathione-dependent antioxidant defense. Highly metastatic melanoma cells demonstrated stronger redox adaptation and altered amino acid utilization, with elevated glutathione and glutamate and reduced NAD⁺ and pyruvate, indicating a metabolic shift toward oxidative stress resistance.
To estimate the proportion of all healthcare expenses attributable to diagnosing and managing skin cancer in a large, population-based cohort, and identify characteristics of high users of skin cancer services. A prospective cohort study of 40,338 Queensland residents with linked healthcare data from the Medical Benefits Scheme (MBS), Pharmaceutical Benefits Scheme (PBS) and Queensland Hospital Admitted Patient Data Collection databases. We quantified the frequency of use and healthcare costs (out-of-pocket and government) for MBS services, PBS services and hospital admissions related to skin cancer. Over an average of 8.5 years follow-up, 71% (n=28,498) of participants used 245,919 skin cancer services, costing the government approximately $43.1 million (2.4% of all health service costs). In total, 51% (n=20,548) of participants had ≥1 skin biopsy, 36% (n=14,458) had ≥1 keratinocyte cancer excision and 8% (n=3,226) had hospital admissions. Out of the total government or out-of-pocket costs for skin cancer services, 44% and 41% were for keratinocyte cancer excisions, respectively. Services for diagnosing and treating skin cancer accounted for 2.4% of all direct health service costs in this Queensland cohort. As skin cancer is largely preventable, investing in enhanced primary prevention efforts may mitigate these significant burdens.
The complement system and natural killer (NK) cells play crucial roles in tumor growth and metastasis. The role of the complement system in affecting the phenotype and anti-tumor function of NK cells remains poorly understood. Using the B16F10 mouse melanoma model, we demonstrated that NK cells from C3-/- mice exhibit increased expression of activation receptors (NKG2D, NKp46, and Ly49H) and reduced inhibitory receptors (NKG2A, Ly49A, and KLRG1) and high cytotoxic activity compared to C3+/+ mice NK cells. C3-/- mice show reduced melanoma tumor growth and metastasis in an NK cell-dependent manner compared to C3+/+ mice. Intratumoral NK cells in C3-/- mice formed a unique phenotypic cluster characterized by higher expression of T-bet, CD69, GITR, CD62L, CCR7, and increased secretion of effector cytokines (IFN-γ, TNF-α, and GM-CSF) and granzyme B expression compared to C3+/+ mice. In C3-/- mice, NK cells from both the spleen and tumors exhibit markedly higher expression levels of C3aR and C5aR1 compared to those from wild-type mice. Activation of C3aR by C3a, leads to phosphorylation of AKT and STAT3 molecules, resulting in phenotypic changes to NK cells. Furthermore, antagonising complement anaphylatoxin receptors C3aR or C5aR1 in wild-type mice resulted in reduced tumor growth, accompanied by an increase in intratumoral effector NK cells. Together, we demonstrated that complement C3 regulates the effector and cytotoxic functions of NK cells, suggesting that targeting complement C3 and the anaphylatoxin receptor may be beneficial in controlling tumor growth in the clinic.
To evaluate the diagnostic performance of the CT-based Node-RADS score for assessing metastatic lymph node involvement in patients with cutaneous melanoma and to compare it with short axis and roundness index. This retrospective study included patients with histologically confirmed melanoma who underwent contrast-enhanced CT before sentinel lymph node biopsy. A control cohort of trauma patients free from any condition potentially affecting lymph nodes was included to represent physiological lymph nodes and to address class imbalance. Lymph nodes were independently assessed by two radiologists and re-evaluated after one month; inter- and intra-observer agreement were evaluated using Cohen's kappa. Diagnostic performance was assessed using ROC curve analysis, and AUCs were compared with the DeLong test. A total of 123 lymph nodes were analyzed, of which 55 (45%) were metastatic. Inter- and intra-observer agreement was excellent (κ = 0.84-0.97 and 0.85-0.98, respectively). All imaging features differed significantly between metastatic and non-metastatic lymph nodes (p < 0.001). Node-RADS yielded an AUC of 0.72 (95% CI 0.65-0.79), not superior to the short axis (AUC 0.80; p = 0.13) or long axis (AUC 0.71; p = 0.76), but outperforming the roundness index (AUC 0.60; p = 0.008). The short axis showed the highest discriminatory performance. Node-RADS showed high specificity (0.96) but low sensitivity (0.47), with 40% of low-risk nodes resulting metastatic. On multivariable analysis, only shape was independently associated with metastatic involvement (OR 6.69; p = 0.006). Node-RADS does not outperform short-axis measurement and shows limited sensitivity in subclinical nodal disease, highlighting the need for advanced detection approaches.
Skin cancer is highly prevalent in older adults; however, data on real-world sun-protective behaviors in this population are limited. Although patients with skin cancer are routinely educated about sun protection, whether these recommendations are reflected in daily practice remains unclear. This study aimed to evaluate real-world sun-protective behaviors by comparing geriatric patients with and without a history of skin cancer. Patients aged ≥65 years presenting to a tertiary-care dermatology outpatient clinic completed a structured questionnaire assessing sociodemographic factors and sun-protective behaviors. Histopathologically confirmed skin cancer type (basal cell carcinoma [BCC], squamous cell carcinoma [SCC], or malignant melanoma [MM]) was recorded. Sun-protective behaviors in the skin cancer group were assessed after diagnosis. A total of 903 patients were included (441 women, 462 men; mean age 73.58 ± 7.47 years), of whom 161 (17.8%) had skin cancer. Patients with skin cancer reported higher sunscreen use and lower outdoor exposure between 10:00 and 16:00 compared with those without skin cancer (both p < 0.001). Sunglasses use and spending less than two hours in direct sunlight were more common in the non-skin cancer group (p = 0.016 and p < 0.001). Among patients with MM, sunscreen use was highest and outdoor exposure was lowest compared to other skin cancer types (p = 0.016 and p = 0.022, respectively). Patients with skin cancer, particularly those with MM, reported greater use of sun-protective measures. However, these findings may reflect post-diagnosis behavioral changes and clinical counseling. Further research is needed to understand these behaviors and inform strategies for improving sun protection in older adults.
MDM2 is transcriptionally activated by the ST-MYCL-Tip60 complex in virus-positive Merkel cell carcinoma (MCC). MDM2 suppresses p53 and is a rational therapeutic target. MDM2 inhibitors face an intrinsic limitation: p53 activation induces MDM2 transcription, creating a feedback loop that blunts inhibitor efficacy. We demonstrate that MDM2 degraders KTX-049 and KT-253 overcome this limitation by collapsing the p53/MDM2 negative feedback loop. KTX-049 was >100-fold more potent than the MDM2 inhibitor DS-3032 across WT p53 MCC cell lines, and this superior potency was quantitatively supported by mechanistic mathematical modeling. In vivo, KT-253 produced deep and durable tumor regressions, including complete responses in patient-derived xenograft models. Acquired resistance was strongly associated with acquisition of TP53 mutations, confirming on-target pathway pressure. These findings establish feedback architecture as a critical determinant of therapeutic response and position MDM2 degradation as a qualitatively distinct strategy that produces more durable pathway engagement than MDM2 inhibition, providing a preclinical rationale for prioritizing MDM2 degraders in WT TP53 MCC.
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Acral lentiginous melanoma (ALM) classically presents in glabrous skin. Some studies suggest an association between mechanical stress and ALM development. People working jobs with long periods of standing/walking may be exposed to near-daily mechanical stress. To investigate the relationship between occupation type and ALM development, we performed a retrospective cohort study using Optum's Clinformatics Database (2007-2023). We compared the risk of ALM in adults with occupational data (n = 9,270,935). Retired patients had the highest prevalence (0.081) and incidence per 1,000,000 person-years (0.514, 95% confidence interval = 0.487-0.542) of ALM. We performed multivariate logistic regression, adjusted for demographics and insurance, and stratified by age. In patient aged <65 years, homemaker patients had 55.2% increased risk of ALM (P < .001). In patients aged ≥65 years, retired patients had 17% increased risk of ALM (P < .001). Our findings suggest that homemaker and retired patients are at highest risk of ALM, possibly owing to increased mechanical stress on the palmoplantar surfaces associated with work around the home in homemakers. Occupation-related mechanical stress may play a role in the retired population as well, although the previous occupation of retired patients is unreported. Future directions include exploring prior occupations in the retired population.
More advanced stages at diagnosis and lower survival rates are seen in women diagnosed with cancer during pregnancy compared to non-pregnant women with similar cancers. This study aims to investigate diagnostic and treatment delays, cancer stage, and survival in Danish pregnant cancer patients. Patients from the Danish cancer in pregnancy database were included. Cancer diagnosis, treatment, and obstetrical data were collected from the database. Time to treatment was compared to national cancer patient pathways. Cancer stages at diagnosis were compared to epidemiological studies identified through a systematic literature search. Survival was compared to data from NORDCAN, a Nordic cancer statistics database. The study included 74 patients diagnosed with cancer in pregnancy. The median total delay was 43.5 days (IQR 27.75-94.75) with a patient delay of three days (IQR 0-31), a diagnostic delay of 15 days (IQR 8-35), and a treatment delay of 9.5 days (IQR 0-19). Time from cancer suspicion to start of treatment fell within recommended national cancer patient pathway intervals in 80.0% of cases. Breast cancer and melanoma in pregnancy tended to have more advanced stages at diagnosis compared to non-pregnant patients. The 1- and 5-year mortality rates were 5.4% and 17.6%, respectively. Our findings suggest that pregnant cancer patients presented with advanced stages at diagnosis and lower survival rates compared to non-pregnant patients with similar cancers. Our results indicate that the main contributor to the delay in cancer in pregnancy in Denmark is delayed suspicion of cancer.
Uveal melanoma (UM) is a genetically well-defined yet phenotypically diverse malignancy with a strong predilection for liver metastasis. To define phenotypic divergence during progression, we performed comprehensive gene expression profiling of primary UM (pUM) and metastatic UM (mUM) samples. Two principal molecular subtypes emerged in both entities. Matched pUM-mUM samples showed little transcriptional concordance, indicating extensive reprogramming during metastasis. Approximately half of the pUM samples exhibited a proliferative, MAPK/PI3K-driven phenotype, suggesting heterogeneous dependency on PKC signaling. Immune landscapes also diverged; pUM was dominated by adaptive responses, whereas mUM displayed innate signaling and macrophage-driven immunosuppression. The inflammatory pUM-A subtype was associated with poor survival, consistent with The Cancer Genome Atlas (TCGA) data linking chromosomal aberrations such as monosomy 3 to progression. Analysis of 53 UM samples demonstrated context-dependent phenotypes, supporting site-specific, phenotype-guided therapeutic strategies integrating pathway inhibition and immune modulation.
Immunotherapy with checkpoint inhibitor (ICI) has revolutionized the treatment of cancer including squamous cell carcinoma. Nevertheless, there is an unmet need to gain a better understanding of the effect of these therapies on pregnancy and fertility. Treatment with anti-PD-1 therapy decreases fetal-maternal tolerance and increases the risk of pregnancy loss in animal studies. However, few data are currently available in humans. We report the case of conception and pregnancy, with successful maternal and fetal outcomes, in a young woman with metastatic squamous cell carcinoma originated from the palatin tonsil. She was 17-year-old at the diagnosis. After surgical removal of the primary tumor, she received adjuvant radiotherapy. Four years later she underwent surgery for a lung relapse and adjuvant chemotherapy. Three years later the patient experienced a pulmonary and mediastinal relapse. Immunotherapy with nivolumab was promptly started with a slow reduction of the disease until a near radiological complete response with a unique residual lung subpleural nodulation. Surgical romoval confirmed the residual disease of squamous cell carcinoma. Patient re-started immunotherapy with nivolumab but after 2 months, she was found to be 4 weeks pregnant. Treatment was stopped and, since the patient expressed her desire to carry her pregnancy to term, she was referred to gynecological and psychological support. She had an uneventful pregnancy, followed by spontaneous vaginal delivery. The baby was healthy and exhibited normal development. Furthermore, the patient breastfed until the sixth month without any adverse effects on the child growth. In November 2025, after 32 months of disease-free survival, the patient developed a new lung recurrence, presenting as a single 4-cm diameter lesion in the right lower lobe. In January 2026, she underwent surgical resection of the lesion and histology was consistent with the diagnosis of metastatic disease. Currently, in the absence of detectable disease, the patient continues active follow-up. Our case provides evidence that pregnancy and normal fetal development may occur after early exposure to nivolumab, Nevertheless, the impact of treatment interruption and pregnancy on disease recurrence remains an unresolved question.
MiT/TFE family of transcription factors, including MiTF, TFE3, TFEB, and TFEC genes, control transcriptional programs for autophagy and lysosome biogenesis and regulate energy metabolism in many cancers. Chromosomal translocations and amplifications involving the MiT/TFE genes contribute to the etiology and pathophysiology of renal cell carcinoma, melanoma, sarcomas, and many other tumors. Understanding the roles of MiT/TFE factors in cellular homeostasis, oncogenic, and stress-adaptive regulation through transcriptionally regulated pathways may reveal new strategies for cancer diagnostics, prognostication, and treatment.
While sodium-glucose cotransporter-2 (SGLT2) inhibitors provide major benefits across multiple chronic diseases, clinician prescription and patient adherence rates remain low. To explore perspectives of clinician and patient stakeholders regarding barriers and facilitators for SGLT2 inhibitor use. Semi-structured interviews, conducted as part of a larger project examining the type 2 diabetes mellitus (T2DM) standard of care. Australia. Clinicians involved in the care of people with T2DM, including primary care clinicians, endocrinologists, nephrologists, cardiologists, diabetes educators, and pharmacists; and adults with T2DM. Barriers and facilitators of SGLT2 inhibitor implementation were explored through the Consolidated Framework for Implementation Research. Analysis of interview transcripts was conducted in duplicate using a combination of framework and thematic analysis. A total of 24 clinicians, and four people with T2DM, were interviewed between November 2021 and August 2023, including four primary care clinicians, four endocrinologists, four nephrologists, four cardiologists, four diabetes educators, and four pharmacists. Key findings included that clinicians miss opportunities to prescribe due to competing priorities and therapeutic inertia, and may find it difficult to educate and engage patients about SGLT2 inhibitor use. Patients require detailed education to understand benefits and adverse effect prevention, ideally with multimodal resources and staggered over time, and would benefit from general adherence coaching. Some clinicians were concerned about the risk of urinary tract infections despite reassuring safety data, and few provided genital hygiene advice to reduce SGLT2 inhibitor-associated genital mycotic infections. Better health system support could be achieved through additional cost reimbursement and support for multidisciplinary care access. Most participants were from a single Australian state, New South Wales, which may not fully reflect experiences across Australia. Participation bias may under-represent those less engaged in SGLT2 inhibitor use. Clinicians are convinced about SGLT2 inhibitor benefits but require support to deliver evidence-based care, including effective patient education and engagement. These insights can help inform the design of interventions to maximise societal benefit from these effective medications.
Melanoma remains a highly aggressive malignancy with limited response to current immunotherapies due to its immunosuppressive tumor microenvironment. To overcome this limitation, we developed a radiolabeled coordination polymer, 177Lu-GAMP, through the self-assembly of 177Lu3+ with adenosine monophosphate (AMP) and guanosine monophosphate, exhibiting coordination-feature resemblance to the endogenous STING agonist cGAMP, thereby enabling activation of the STING pathway. We further incorporated 177Lu-GAMP into a dissolvable microneedle patch (177Lu-GAMP@MN) for localized, minimally invasive delivery to melanoma lesions. Our results demonstrate that 177Lu-GAMP@MN effectively penetrated the skin and retained at the tumor site, leading to robust STING activation and Gasdermin E-mediated pyroptosis. This, in turn, promoted dendritic cell maturation and enhanced T cell infiltration. In vivo, 177Lu-GAMP@MN significantly suppressed subcutaneous melanoma growth, prolonged survival, and elicited strong antitumor immune responses. When combined with anti-PD-L1 monoclonal antibodies, the treatment achieved synergistic tumor regression, improved effector T cell function, and induced durable immunological memory, demonstrating significant inhibition of both primary and distant tumors in murine models. Collectively, this work presents a transdermal brachytherapeutic-immunomodulatory strategy for melanoma treatment, offering promising potential for enhanced antitumor immunotherapy.
Hypopigmentation disorders are characterized by impaired melanogenesis and remain challenging to manage due to limited efficacy of current interventions and insufficient mechanistic insights. Natural products represent a valuable source of bioactive phytoconstituents capable of regulating key pathways involved in melanin synthesis. Despite its extensive traditional use and diverse pharmacological activities, Tinospora cordifolia and its major bioactive constituent tinosporide remain unexplored for their role in melanogenesis. The present study aimed to evaluate the melanogenesis-promoting potential of bioactive phytoconstituents isolated from Tinospora cordifolia, and to elucidate their underlying molecular mechanisms. Four phytoconstituents-columbin, tinosporide, 8-hydroxy tinosporide and ecdysterone-were isolated and structurally characterized from T. cordifolia. Their melanogenic potential was evaluated in murine (B16F10) and human (SK-MEL-2) melanoma cells by assessing melanin content, tyrosinase activity, and expression of melanogenesis-associated genes. Intracellular cAMP levels and associated signalling pathways were further analysed to investigate the mechanism of action. Among the isolated compounds, tinosporide exhibited the most pronounced melanogenic activity, significantly increasing melanin synthesis and tyrosinase activity. Tinosporide promotes nuclear localization of the microphthalmia-associated transcription factor (MITF), leading to upregulation of MITF-target genes, including Trp1, Tyr, Dct, Pmel, and Mlana. Furthermore, mechanistic studies revealed that tinosporide elevated intracellular cAMP levels and induced the phosphorylation of PKA and CREB, thereby activating cAMP/PKA/CREB signalling pathway. Pharmacological inhibition of PKA and CREB markedly attenuated tinosporide-induced melanogenesis, confirming the essential role of the cAMP/PKA/CREB-MITF axis. Collectively, these findings identify tinosporide as a promising natural melanogenic agent derived from Tinospora cordifolia and highlight its potential relevance in the development of plant-based interventions for hypopigmentation disorders.