Oral mucosal melanoma (OMM) is a rare, aggressive malignancy biologically distinct from cutaneous melanoma. Given complex anatomy and limited chemotherapy efficacy, immune checkpoint inhibitors (ICIs) are increasingly used. This systematic review evaluated the clinical outcomes and safety of ICIs in primary OMM.

A comprehensive literature search was conducted in accordance with PRISMA guidelines via Ovid MEDLINE, Web of Science, and Scopus for English-language human studies from January 1, 1990, to May 13, 2026, focusing on OMM and ICIs (PD-1/PD-L1, CTLA-4). Study screening and data extraction were independently performed by two reviewers, and case-report bias was assessed via the JBI Checklist.

Fourteen case reports and two cohorts ( n = 124) met the inclusion criteria. The mean age in case reports was 65 years, with the maxilla as the predominant site. The majority of patients had advanced disease (IVa 57.1%). RECIST assessments indicated one complete response with pembrolizumab and topical imiquimod and partial responses in 9 of 14 patients (64.3%). Survival ranged from 3 to > 96 months (mean ∼25). Immune-related adverse events (irAEs) occurred in 57.1% of the patients. In the cohort studies, the mean age ranged from 53 to 57 years, with a male predominance (54%), and most patients had advanced OMM. The two-year overall survival (OS) and progression-free survival (PFS) rates were 71% and 53.6%, respectively, with adjuvant PD-1–based therapy. With pembrolizumab–anlotinib, the objective response rate was 41.5%, the median PFS was 7.7 months, and the median OS was 10.8 months; toxicity was frequent but mostly manageable.

Findings derived from case reports and two cohort studies suggest clinically meaningful responses and survival benefits of ICIs in a subset of patients with advanced OMM.