Resistance to immune checkpoint blockade in mucosal melanoma extends beyond low tumor mutational burden. Suppressive myeloid cells, stromal and vascular barriers, and candidate innate immune pathways may limit the effectiveness of antitumor immunity. Integrating spatial immune profiling with circulating biomarkers could support immune-state classification and guide rational combination trials.
ABSTRACT
Mucosal melanoma is a rare, aggressive melanoma subtype arising from melanocytes within mucosal surfaces of the head and neck, anorectal, gastrointestinal, and genitourinary tracts. Unlike ultraviolet-driven cutaneous melanoma, mucosal melanoma has lower tumor mutational burden, fewer BRAF V600 alterations, greater structural genomic complexity, and recurrent drivers including mutations in KIT, NRAS, NF1, SF3B1, and copy-number alterations. It is often diagnosed at advanced stages, recurs locally, disseminates early, and responds less favorably to immune checkpoint inhibition than cutaneous melanoma. Low neoantigen burden contributes to this resistance, but emerging evidence indicates that antitumor immunity is also shaped by spatially organized tumor-immune interactions, site-specific mucosal biology, suppressive myeloid and stromal programs, angiogenic signaling, and underexplored innate checkpoint pathways. Here, we review mucosal melanoma as a biologically distinct model of immune-excluded melanoma, summarizing its clinical behavior, genomic architecture, immunotherapy outcomes, and mechanisms of checkpoint resistance, with emphasis on restricted intratumoral CD8-positive T-cell infiltration, macrophage- and stroma-rich barriers, angiogenic remodeling, and candidate innate checkpoints including B7-H3, CD24–Siglec-10, CD47–SIRPα, and B7-H6/NKp30. We further discuss how spatial and circulating biomarkers may support response-adapted translational studies and define actionable immune states across mucosal melanoma sites.
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