Melanoma represents a significant public health challenge due to its increasing incidence and potential for metastasis. This review will explore the current clinical approaches to the management of melanoma, focusing on advancements in diagnosis, treatment, and prognosis. Methods for early detection and accurate staging have been enhanced by new diagnostic strategies. Treatment modalities have expanded beyond traditional surgical excision to include targeted therapy and immunotherapy. Prognostic assessment has benefited from the development of novel biomarkers and genetic profiling. This review will highlight the progress made in the multidisciplinary management of melanoma, underscoring the importance of continuous research to improve patient outcomes.

Background: The role of B cells in antitumor immunity remains controversial, with studies suggesting the protumor and antitumor activity. This controversy may be due to the heterogeneity in B cell populations, as the balance among the subtypes may impact tumor progression. The immunosuppressive regulatory B cells (Breg) release interleukin 10 (IL-10) but only represent a minor population. Additionally, tumor-specific antibodies (Abs) also exhibit antitumor and protumor functions dependent on the Ab isotype. Transcription factor c-Maf has been suggested to contribute to the regulation of IL-10 in Breg, but the role of B cell c-Maf signaling in antitumor immunity and regulating Ab responses remains unknown. Methods: Conditional B cell c-Maf knockout (KO) and control mice were used to establish a KPC pancreatic cancer model and B16.F10 melanoma model. Tumor progression was evaluated. B cell and T cell phenotypes were determined by flow cytometry, mass cytometry, and cytokine/chemokine profiling. Differentially expressed genes in B cells were examined by using RNA sequencing (RNA-seq). Peripheral blood samples were collected from healthy donors and patients with melanoma for B cell phenotyping. Results: Compared with B cells from the spleen and lymph nodes (LN), B cells in the pancreas exhibited significantly less follicular phenotype and higher IL-10 production in naïve mice. c-Maf deficiency resulted in a significant reduction of CD9⁺ IL-10-producing Breg in the pancreas. Pancreatic ductal adenocarcinoma (PDAC) progression resulted in the accumulation of circulating B cells with the follicular phenotype and less IL-10 production in the pancreas. Notably, B cell c-Maf deficiency delayed PDAC tumor progression and resulted in proinflammatory B cells. Further, tumor volume reduction and increased effective T cells in the tumor-draining LN were observed in B cell c-Maf KO mice in the B16.F10 melanoma model. RNA-seq analysis of isolated B cells revealed that B cell c-Maf signaling modulates immunoglobulin-associated genes and tumor-specific Ab production. We furthermore demonstrated c-Maf-positive B cell subsets and an increase of IL-10-producing B cells after incubation with IL-4 and CD40L in the peripheral blood of patients with melanoma. Conclusion: Our study highlights that B cell c-Maf signaling drives tumor progression through the modulation of Breg, inflammatory responses, and tumor-specific Ab responses.

Background/Objectives: Tumor-draining lymph nodes (TDLNs) play a critical role in shaping a pre-metastatic and immunosuppressive niche that facilitates tumor dissemination. However, a robust in vivo model that recapitulates regional lymph node and distant metastasis remains elusive. We sought to establish and characterize an animal model that reliably mimics spontaneous human melanoma progression from primary tumor to regional lymph node and distant organ metastasis. Methods: B16F10-Luc2 melanoma cells were subcutaneously implanted from the hock area into the lower medial thigh of C57BL/6J mice to establish a metastatic melanoma mouse model with reliable regional lymph node metastasis and distant metastasis. Tumor growth was monitored over time. ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) and bioluminescence imaging (BLI) were used to track lymph node and lung metastases in vivo. Immunocytochemistry (IHC) was performed to confirm the metastatic melanoma cells in tissues. The immune landscape of metastatic lymph nodes was characterized by Cytometry by Time-Of-Flight (CyTOF). Results: This implantation strategy resulted in consistent primary tumor growth accompanied by reproducible metastasis to ipsilateral inguinal lymph nodes (IILN) and subsequent lung metastasis. Multi-modal imaging (PET/CT and BLI) enabled non-invasive monitoring of metastatic progression in vivo. Histological analyses confirmed melanoma cell infiltration in lymph nodes and lung tissues. Notably, CyTOF profiling revealed a distinct immunological remodeling within the TDLN, characterized by immunosuppressive phenotypes in the tumor-draining ipsilateral inguinal lymph node (IILN) compared with naïve nodes, indicative of a potential immunotolerant environment in tumor-bearing mice associated with metastatic progression. Conclusions: We present a reproducible and clinically relevant syngeneic melanoma mouse model that recapitulates lymphatic dissemination to regional lymph nodes and distant lung metastasis, and mimics the immunosuppressive phenotypes in the tumor-draining lymph node microenvironment seen in human melanoma patients. This model provides a valuable platform for investigating the mechanisms of lymphatic metastasis and the immunological dynamics of TDLNs, with potential applications in evaluating therapeutic strategies targeting metastatic progression.