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Background Despite the transformative role of immune checkpoint inhibitors in advanced melanoma, anti-PD-(L)1-refractory patients face limited treatment options.Methods This investigator-initiated trial assessed a novel quadruplet regimen combining DNV3 (anti-LAG-3), toripalimab (anti-PD-1), and chemotherapy (nab-paclitaxel/cisplatin) in 27 Asian patients with unresectable/metastatic melanoma (77.8%[21/27] anti-PD-[L]1-pretreated and 22.2%[6/27] treatment-naïve mucosal melanoma; subtypes: 13 mucosal, 6 acral, 5 cutaneous, 3 unknown primary melanoma).Results The regimen achieved a 44.4% overall response rate (ORR), with robust activity in anti-PD-(L)1-resistant subgroups (42.9% ORR, 7.36-month median PFS). Notably, treatment-naïve mucosal melanoma showed a 50% ORR, while patients with liver metastases (11/27) achieved a 54.5% ORR. At data cutoff, median overall survival was not reached across all analyzed groups. While grade ≥3 treatment-related adverse events occurred in 55.6% of patients initially, dose reduction (nab-paclitaxel: 260 mg/m 2, later reduced to 200 mg/m2) improved tolerability (22.2% grade ≥3 events). Immune-related toxicities (grade 3-4, 22.2%) were manageable without fatal events.Conclusions These results demonstrate that LAG-3/PD-1 dual blockade with chemotherapy exhibits encouraging efficacy in refractory melanoma, particularly for anti-PD-(L)1-resistant and mucosal subtypes, while maintaining acceptable safety post-dose adjustment. This approach may address an urgent unmet need for this challenging patient population.