We evaluated the management and outcomes of patients with unresectable melanoma with and without bone metastases treated with single-agent or combination immune checkpoint inhibitors. We performed a retrospective chart review of unresectable or metastatic melanoma patients treated with immunotherapy at Sunnybrook Health Sciences Centre between June 2012 and November 2025. Patients were stratified by bone metastases and treatment regimen. Single-agent ipilimumab recipients were excluded from survival analyses. Overall survival (OS) was analyzed using Kaplan–Meier methods, with multivariable Cox regression evaluating associations of bone metastases and treatment type. We identified 490 patients: median age 68.0 years, 38.6% female, and 36.3% BRAF V600E/K-mutant. Bone metastases occurred in 27.6%, of whom 3.7% received bisphosphonates. With combination immunotherapy, median OS was 17.8 months [95% confidence interval (CI) = 11.0–30.9] with bone metastases ( n = 33) and 31.2 months (95% CI = 24.3–35.3) without ( n = 110). With single-agent immunotherapy, median OS was 16.8 months (95% CI = 13.5–24.9) with bone metastases ( n = 75) and 28.7 months (95% CI = 24.8–37.8) without ( n = 208). Toxicity-related discontinuation occurred in 47.6% with combination and 28.0% with single-agent immunotherapy. OS differed significantly across groups (log-rank P = 0.0048). On multivariable analysis, bone metastases independently predicted worse OS (hazard ratio = 1.58, 95% CI = 1.25–2.00, P < 0.001), while immunotherapy regimen did not (hazard ratio = 0.92, 95% CI = 0.71–1.19, P = 0.521). Bone metastases were independently associated with poor OS in metastatic melanoma, with no difference between combination and single-agent immunotherapy. Given the higher toxicity of combination therapy and limited bisphosphonate use, further evaluation of treatment strategies is warranted.
Immune-cold melanomas respond poorly to immune checkpoint blockade (ICB). We assessed whether RNA-seq-based immune subtyping and connectivity mapping could nominate repurposable compounds to shift immune-depleted melanoma toward an immune-enriched phenotype. Using RNA-seq from 432 The Cancer Genome Atlas Skin Cutaneous Melanoma cases, we assigned published molecular functional portrait subtypes and compared depleted (D, n = 169) with combined immune-enriched (IE + IE/F, n = 184) subtypes using limma-voom. The resulting 300-up/300-down signature underwent Library of Integrated Network-based Cellular Signatures L1000 connectivity mapping, with compound-level aggregation and mechanism-of-action annotation. The pipeline was rerun on two stratified split-half folds. Canonical cytotoxic and antigen-presentation genes ( CD8A , PDCD1 , CXCL9 , CXCL10 , CD3D , GZMB , PRF1 ) were depleted in D, validating the contrast. Raw connectivity-mapping hits were dominated by generic cytotoxic-stress compounds. After aggregation and filtering, DNA methyltransferase (DNMT) inhibitors showed the most consistent positive pattern; fdcyd, azacitidine, and RG-108, but not decitabine, were robust to sample-type sensitivity analysis. Class enrichment was not significant after correction [false discovery rate (FDR) q = 0.126]. Indoleamine 2,3-dioxygenase inhibitors trended negative (FDR q = 0.095), and mitogen-activated protein kinase kinase inhibitors showed no class-level pattern (FDR q = 0.698). Across both folds, all seven canonical genes replicated and all four DNMT inhibitors retained above-median ranks, but the cold-elevated signature module was markedly less stable than the hot-elevated module (25.7 vs. 88.7% overlap). This suggestive pattern converges with a phase II trial of azacitidine/carboplatin priming before anti-programmed death-ligand 1 rechallenge in ICB-resistant melanoma, supporting prospective evaluation.
