默克尔细胞癌 (MCC) 是一种侵袭性神经内分泌皮肤癌，对免疫检查点阻断 (ICB) 疗法的缓解率约为 50%。为了识别预测生物​​标志物，我们将来自 116 名患者的 186 个样本队列的批量和单细胞 RNA 序列与空间转录组学相结合，其中包括来自 ICB 前后 14 个匹配对的批量 RNA 序列。在无反应者中，肿瘤显示出肿瘤增殖、神经元干细胞标记物和 IL-1 增加的证据。应答者增加了 I/II 型干扰素和预先存在的组织驻留 (Trm) CD8 或 Vd1 gd T 细胞，这些细胞在功能上与重叠的抗原特异性转录程序和公共 TCR 的克隆扩增相融合。空间转录组学证明 T 细胞与 B 细胞和树突状细胞共定位，提供趋化因子和共刺激。最后，ICB 显着增加了肿瘤中 Trm 和 Vd1 细胞的克隆扩增或募集，特别是在应答者中，强调了它们的治疗重要性。这些数据确定了 MCC 的潜在临床可操作生物标志物和治疗靶点。

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer with a ~50% response rate to immune checkpoint blockade (ICB) therapy. To identify predictive biomarkers, we integrated bulk and single-cell RNA-seq with spatial transcriptomics from a cohort of 186 samples from 116 patients, including bulk RNA-seq from 14 matched pairs pre- and post-ICB. In non-responders, tumors show evidence of increased tumor proliferation, neuronal stem cell markers, and IL-1. Responders have increased type I/II interferons and pre-existing tissue resident (Trm) CD8 or Vd1 gd T cells that functionally converge with overlapping antigen-specific transcriptional programs and clonal expansion of public TCRs. Spatial transcriptomics demonstrated co-localization of T cells with B and dendritic cells, which supply chemokines and co-stimulation. Lastly, ICB significantly increased clonal expansion or recruitment of Trm and Vd1 cells in tumors specifically in responders, underscoring their therapeutic importance. These data identify potential clinically actionable biomarkers and therapeutic targets for MCC.