Integrating bulk, single-cell, and spatial transcriptomics to identify and functionally validate novel targets to enhance immunotherapy in NSCLC

作者：Kui Cao, Shenshui Wei, Tianjiao Ma, Xinxin Yang, Yuning Wang, Xiangrong He, Mengdi Lu, Yuwen Bai, Cuicui Qi, Luquan Zhang, Lijuan Li, Hongxue Meng, Jianqun Ma, Jinhong Zhu · 发表于：npj Precision Oncology · 年份：2025 · DOI：10.1038/s41698-025-00893-x · 被引用次数：8 · 研究领域：Cancer Immunotherapy and Biomarkers、Immunotherapy and Immune Responses、Immune cells in cancer

Programmed cell deaths (PCDs) are crucial for tumor progression. By analyzing 18 PCDs, we generated a robust multigene signature, Combined Cell Death Index (CCDI), comprising necroptosis and autophagy genes for non-small cell lung cancer (NSCLC). The CCDI accurately stratified patients by survival prognosis and predicted immunotherapy responses. We validated CCDI and prioritized CCDI genes using five single-cell RNA sequencing and two spatial transcriptomics datasets. CCDI positively correlates with tumor malignancy, invasiveness, and immunotherapy resistance. Four necroptosis genes (PTGES3, MYO6, CCT6A, and CTSH) may affect cancer cell evolution. In vitro, CTSH overexpression or PTGES3 knockdown inhibited NSCLC cell proliferation and migration while inducing necroptosis with necrosome formation. Moreover, we observed diminished CTSH, heightened PTGES3, and low necroptosis activity in 12 pairs of NSCLC tumors and normal tissues. CTSH overexpression or PTGES3 knockdown induced necroptosis and improved anti-PD1 therapy efficiency in syngeneic cancer mouse models. These findings indicate necroptosis genes as potential therapeutic targets in cancer treatments.