Genomic classification and immune profiling define mucosal melanoma

Abstract

Mucosal melanoma is a rare, lethal melanoma subtype with distinct genetics and limited benefit from immunotherapy. To define features associated with mucosal melanoma clinical outcomes, we assembled a large, multimodally profiled cohort spanning primary and metastatic disease. Compared with cutaneous melanoma, primary mucosal melanoma showed greater genomic heterogeneity, ploidy and aneuploidy, and a more dedifferentiated, proliferative transcriptional state. Analysis of genomic sequencing of 339 patients with mucosal melanoma identified four mutually exclusive genomic subtypes: CDK4/MDM2/CCND1, SF3B1-mutated, TP53/ATRX, and mucosal melanoma Triple WT, associated with distinct anatomic sites but similar outcomes. In the tumor microenvironment, we observed reduced T cell infiltration and increased CD163+ tumor-associated macrophages in mucosal melanoma relative to cutaneous melanoma. In matched longitudinal samples, CD163+ tumor-associated macrophages increased with disease progression and immunotherapy resistance. CD163+ tumor-associated macrophages engaged non-regulatory T cells through GAL9-TIM-3 interactions, nominating TIM-3 blockade as a therapeutic strategy for mucosal melanoma. These findings define the distinct aggressive biology of mucosal melanoma and highlight potential therapeutic targets and mechanisms of immune resistance.

42 Integrated systemic and spatial profiling reveals vascular-immune determinants of response to dual PD-L1 and VEGF blockade in refractory melanoma
David Liu, Michael Manos, Rizwan Haq +10
Journal for ImmunoTherapy of Cancer6 Nov 2026Peer-reviewedCC BYFull textOncologyDOAJ
Integrated Genomic and Immune Profiling Reveals PIK3CA-Mutant HPV16-Positive Cervical Cancer as a Clinically Aggressive and Immunologically Distinct Subtype in Patients from Eastern India
A. Ghosh, A. Ghosh, A. Sinha +9
medRxiv27 Oct 2026PreprintAll rights reservedFull textOncologymedRxiv
Genomic and immune profiling characterizes immune heterogeneity and a TIGIT-associated subtype in intrahepatic cholangiocarcinoma.
Anastasiia Korosteleva, Josephine Sophie Reschke, Dawei Yi +14
Hepatology communications19 Oct 2026Peer-reviewedCC BY-NC-NDFull textSurgery & anaesthesiaEurope PMC
Epigenetic Priming with Oral Decitabine/Cedazuridine Combined with Nivolumab in Unresectable or Metastatic Mucosal Melanoma: Clinical and Correlative Findings from a Phase Ib/II Trial.
Jessica S W Borgers, Cheng-Chang Wu, Theresa M Medina +11
Cancers1 Oct 2026Peer-reviewedCC BYFull textOncologyEurope PMCCrossref
Integration of Immune checkpoint inhibitors within the definitive radiotherapy-based treatment continuum for locally advanced mucosal head and neck squamous cell carcinoma: a scoping review protocol
Ahmad Ameri, Shahrzad Ebrahimi, Mansour Bahardoust +4
BMJ Open6 Nov 2026Peer-reviewedLicence not statedGeneral medicineCrossref

Cite

BibTeX RIS

BibTeX

@misc{shi2026genomic,
  title = {{Genomic classification and immune profiling define mucosal melanoma}},
  author = {Y. Shi and P. Sharma and J.-r. Lin and A. Dedeilia and G. Taratino and R. Pelletier and M. L. Lopez and N. Aygun and M. P. Manos and A. R. Lawless and S. Cohen and Y. D. Lu and M. K. Roelofs and S. M. Pant and J. Chen and D. E. Fisher and R. Beroukhim and C. G. Lian and E. I. Buchbinder and P. K. Sorger and M. Insco and D. Liu and G. Boland},
  howpublished = {bioRxiv},
  year = {2026},
  month = oct,
  doi = {10.64898/2026.10.02.756347},
  url = {https://www.biorxiv.org/content/10.64898/2026.10.02.756347v1},
  note = {CC BY},
}

RIS

TY  - UNPB
TI  - Genomic classification and immune profiling define mucosal melanoma
AU  - Y. Shi
AU  - P. Sharma
AU  - J.-r. Lin
AU  - A. Dedeilia
AU  - G. Taratino
AU  - R. Pelletier
AU  - M. L. Lopez
AU  - N. Aygun
AU  - M. P. Manos
AU  - A. R. Lawless
AU  - S. Cohen
AU  - Y. D. Lu
AU  - M. K. Roelofs
AU  - S. M. Pant
AU  - J. Chen
AU  - D. E. Fisher
AU  - R. Beroukhim
AU  - C. G. Lian
AU  - E. I. Buchbinder
AU  - P. K. Sorger
AU  - M. Insco
AU  - D. Liu
AU  - G. Boland
PY  - 2026
DA  - 2026/10/02
PB  - bioRxiv
DO  - 10.64898/2026.10.02.756347
UR  - https://www.biorxiv.org/content/10.64898/2026.10.02.756347v1
AB  - Mucosal melanoma is a rare, lethal melanoma subtype with distinct genetics and limited benefit from immunotherapy. To define features associated with mucosal melanoma clinical outcomes, we assembled a large, multimodally profiled cohort spanning primary and metastatic disease. Compared with cutaneous melanoma, primary mucosal melanoma showed greater genomic heterogeneity, ploidy and aneuploidy, and a more dedifferentiated, proliferative transcriptional state. Analysis of genomic sequencing of 339 patients with mucosal melanoma identified four mutually exclusive genomic subtypes: CDK4/MDM2/CCND1, SF3B1-mutated, TP53/ATRX, and mucosal melanoma Triple WT, associated with distinct anatomic sites but similar outcomes. In the tumor microenvironment, we observed reduced T cell infiltration and increased CD163+ tumor-associated macrophages in mucosal melanoma relative to cutaneous melanoma. In matched longitudinal samples, CD163+ tumor-associated macrophages increased with disease progression and immunotherapy resistance. CD163+ tumor-associated macrophages engaged non-regulatory T cells through GAL9-TIM-3 interactions, nominating TIM-3 blockade as a therapeutic strategy for mucosal melanoma. These findings define the distinct aggressive biology of mucosal melanoma and highlight potential therapeutic targets and mechanisms of immune resistance.
ER  -

Abstract

Related

Cite