GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE303nnn/GSE303456/primary200OKTranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE303456GEOGSEfalseSequential Imatinib and Anti-PD-1 Therapy in KIT-Altered Melanoma: Mechanistic Insights and Clinical BenefitKIT is a key oncogenic driver in triple-wildtype melanoma and represents a rational therapeutic target for KIT inhibitors such as imatinib. However, the tumor immune microenvironment in KIT-altered melanoma and optimal strategies to integrate immunotherapy remain poorly defined. In this study, we found that melanomas harboring KIT mutations or amplifications exhibited reduced CD8⁺ T cell infiltration, indicative of an immune-cold phenotype. Imatinib treatment reversed this Immunosuppressive microenvironment by enhancing CD8⁺ T cell infiltration and cytotoxic activity. Furthermore, imatinib upregulated O-GlcNAc transferase (OGT), which functions as a protein lactyltransferase and increased PD-L1 expression through lysine lactylation, thereby sensitizing tumors to anti–PD-1 therapy. Based on these findings, we conducted an open-label, single-arm phase II clinical trial in patients with advanced or metastatic KIT-altered melanoma. Patients received imatinib monotherapy as induction for six weeks, followed by combination therapy with toripalimab, an anti–PD-1 antibody. The combiniation therapy was well-tolerated and demonstrated encouraging clinical activity, with an objective response rate (ORR) of 59.4% in the overall cohort, 73.9% in patients with exon 11/13 mutations, and 100% in those with exon 11 mutation plus amplification—markedly higher than the ORRs of 23.3% with imatinib monotherapy and 25.7% with anti–PD-1 monotherapy. Median progression-free survival and overall survival were 8.2 months (95% CI, 6.5–9.9) and 15.1 months (95% CI, 13.1–20.8), respectively. These results support the use of imatinib as an immune-sensitizing induction therapy prior to PD-1 blockade in KIT-altered melanoma and highlight the therapeutic relevance of OGT-mediated PD-L1 regulation.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 sapiens