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.