{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T19:29:38Z","timestamp":1790882978106,"version":"4.1.0"},"reference-count":54,"publisher":"BMJ","issue":"3","license":[{"start":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T00:00:00Z","timestamp":1772755200000},"content-version":"unspecified","delay-in-days":5,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"AIRC","award":["22757"],"award-info":[{"award-number":["22757"]}]},{"name":"AIRC","award":["IG-23179"],"award-info":[{"award-number":["IG-23179"]}]},{"DOI":"10.13039\/501100005010","name":"Associazione Italiana per la Ricerca sul Cancro","doi-asserted-by":"publisher","award":["5 \u00d7 1000 grant n. 22757"],"award-info":[{"award-number":["5 \u00d7 1000 grant n. 22757"]}],"id":[{"id":"10.13039\/501100005010","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2026,1,18]]},"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Mucosal melanomas (MM) arise from mucosal melanocytes at various anatomical sites. These tumors are rare, highly aggressive, and often associated with poor outcomes. Current treatments, including immune checkpoint inhibitors, show limited efficacy in advanced disease. Compared with cutaneous melanomas, there is a lack of data on the immunogenicity and interferon (IFN)-\u03b3 sensitivity of MM. In this study, we examined these features in sino-nasal melanomas (SN-MM) cell lines and clinical samples using microscopy and functional genomics.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The immune contexture of SN-MM was analyzed by immunohistochemistry on 48 tumor biopsies. RNA sequencing and mass spectrometry-based proteomic approaches were used to study the IFN-\u03b3 receptor (IFNGR) pathways in five patient-derived SN-MM cell lines. Moreover, their IFN-\u03b3 sensitivity, in terms of cell viability, IFNGR\/JAK\/STAT signaling pathway and IFN-\u03b3 inducible proteins, was evaluated by flow cytometry and immunoblots. Neoantigen prediction was performed through integrated whole exome sequencing and RNA-sequencing analysis using pVAC-Seq. Immune effector functions were evaluated in co-culture in vitro assays.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>SN-MM tumors are mainly immune \u201cdesert\u201d with few tumor-infiltrating lymphocytes and contain immunosuppressive macrophages, features linked to poor prognosis; moreover, tumor cells are largely CD274\/programmed death-ligand 1 negative. SN-MM cell lines express transcripts for melanocytic and cancer testis antigens; moreover, sequencing analysis identified a repertoire of high-confidence neoantigens, including candidates derived from recurrently mutated oncogenic drivers. Functional assays revealed that SN-MM cells are susceptible to NK cell-mediated killing. In terms of IFN-\u03b3 sensitivity, SN-MM cells show normal surface expression of IFNGR and maintain the integrity of the IFNGR\/JAK\/STAT signaling pathway. Transcriptomic and proteomic analyses demonstrate that SN-MM cell lines, as a group, respond to IFN-\u03b3 by upregulating genes involved in immune recognition and antigen presentation. In 60% of SN-MM lines, IFN-\u03b3 also induces cytotoxic and anti-proliferative effects, the release of CXCL10 and upregulation of CD274\/PD-L1. The remaining SN-MM cell lines, characterized by poor differentiation, show refractoriness to these effects.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>SN-MM displays an immune-desert phenotype yet retains intrinsic immunogenicity. Most tumors preserve functional IFN-\u03b3 signaling, while poorly differentiated cells show resistance to IFN-\u03b3-mediated effects. These findings underscore heterogeneity in immune responsiveness and support functional immune profiling to refine immunotherapy strategies in MM.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2025-012222","type":"journal-article","created":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T14:35:33Z","timestamp":1772807733000},"page":"e012222","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":3,"title":["Integrating interferon gamma receptor pathways, antigenicity, and immune contexture as predictors of immunotherapeutic strategies for mucosal melanomas"],"prefix":"10.1136","volume":"14","author":[{"given":"Matilde","family":"Monti","sequence":"first","affiliation":[{"name":"Molecular and Translational Medicine, Universit\u00e0 degli Studi di Brescia, Brescia, 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