黑色素瘤是皮肤肿瘤中最致命的一种，G蛋白偶联受体（GPCRs）在其癌变过程中起着至关重要的作用。此外，肿瘤微环境（TME）会影响整体生存率（OS）和免疫治疗的效果。基于GPCRs和TME的多组学视角的结合，可以帮助预测黑色素瘤患者的生存以及对免疫治疗的反应。我们从公共数据库下载了Bulk-seq、单细胞RNA测序（scRNA-seq）、基因突变、免疫治疗反应和临床病理特征数据，并利用多种机器学习算法筛选了预后相关的GPCRs和免疫细胞。我们使用实时定量聚合酶链反应（qPCR）检测了A375和HaCaT细胞株中GPCRs的表达水平。然后我们构建并验证了GPCR-TME分类器，使用不同的队列和多组学进行验证。利用基因集富集分析（GSEA）、加权基因共表达网络分析（WGCNA）和肿瘤免疫表型跟踪（TIP）来识别GPCR-TME亚组中的关键生物通路。接下来，我们比较了这些亚组之间的肿瘤突变负荷（TMB）、重要突变基因、抗原呈递基因和免疫检查点。最后，我们调查了GPCR-TME亚组之间的免疫治疗反应率的差异。 我们筛选了12种GPCRs和5种免疫细胞类型来建立GPCR-TME分类器。两种细胞株中的12种GPCRs的表达水平无显著差异。GPCR高分组或TME低分组的患者具有较差的OS，因此GPCR低/TME高亚组具有最有利的OS。单细胞RNA测序结果表明，免疫细胞的GPCR得分高于肿瘤细胞和基质细胞。GPCR-TME分类器作为黑色素瘤的独立预后因素。GSEA、WGCNA和TIP分析表明，GPCR低/TME高亚组与抗肿瘤免疫细胞的活化和招募以及免疫应答的正调节相关。从基因组角度看，GPCR低/TME高亚组具有更高的TMB和不同的突变基因。最后，在GPCR低/TME高亚组中观察到更高表达的抗原呈递基因和免疫检查点，而黑色素瘤免疫治疗队列得到证实，在GPCR低/TME高亚组中反应率最高。 我们基于多组学分析开发了一种GPCR-TME分类器，可以高效预测黑色素瘤患者的OS和免疫治疗反应。© 2023. BioMed Central有限公司，Springer Nature的一部分。

Melanoma is the deadliest form of skin tumor, and G protein-coupled receptors (GPCRs) play crucial roles in its carcinogenesis. Furthermore, the tumor microenvironment (TME) affects the overall survival (OS) and the response to immunotherapy. The combination of GPCRs and TME from a multi-omics perspective may help to predict the survival of the melanoma patients and their response to immunotherapy.Bulk-seq, single-cell RNA sequencing (scRNA-seq), gene mutations, immunotherapy responses, and clinicopathologic feature data were downloaded from public databases, and prognostic GPCRs and immune cells were screened using multiple machine learning algorithms. The expression levels of GPCRs were detected using real-time quantitative polymerase chain reaction (qPCR) in A375 and HaCaT cell lines. The GPCR-TME classifier was constructed and verified using different cohorts and multi-omics. Gene set enrichment analysis (GSEA), weighted gene co-expression network analysis (WGCNA), and tracking tumor immunophenotype (TIP) were used to identify the key biological pathways among the GPCR-TME subgroups. Then, tumor mutational burden (TMB), vital mutant genes, antigen presentation genes, and immune checkpoints were compared among the subgroups. Finally, the differences in immunotherapy response rates among the GPCR-TME subgroups were investigated.A total of 12 GPCRs and five immune cell types were screened to establish the GPCR-TME classifier. No significant differences in the expression levels of the 12 GPCRs were found in the two cell lines. Patients with high GPCR score or low TME score had a poor OS; thus, the GPCRlow/TMEhigh subgroup had the most favorable OS. The scRNA-seq result revealed that immune cells had a higher GPCR score than tumor and stromal cells. The GPCR-TME classifier acted as an independent prognostic factor for melanoma. GSEA, WGCNA, and TIP demonstrated that the GPCRlow/TMEhigh subgroup was related to the activation and recruitment of anti-tumor immune cells and the positive regulation of the immune response. From a genomic perspective, the GPCRlow/TMEhigh subgroup had higher TMB, and different mutant genes. Ultimately, higher expression levels of antigen presentation genes and immune checkpoints were observed in the GPCRlow/TMEhigh subgroup, and the melanoma immunotherapy cohorts confirmed that the response rate was highest in the GPCRlow/TMEhigh cohort.We have developed a GPCR-TME classifier that could predict the OS and immunotherapy response of patients with melanoma highly effectively based on multi-omics analysis.© 2023. BioMed Central Ltd., part of Springer Nature.