Integrating bulk, single-cell, and spatial transcriptomics to identify and functionally validate novel targets to...

Area of Science:

• Oncology
• Molecular Biology
• Immunotherapy

Background:

• Programmed cell deaths (PCDs) play a critical role in tumor progression.
• Understanding the molecular mechanisms of PCD is essential for developing novel cancer therapies.

Purpose of the Study:

• To develop a multigene signature, the Combined Cell Death Index (CCDI), for non-small cell lung cancer (NSCLC).
• To assess the prognostic and predictive value of CCDI for patient survival and immunotherapy response.
• To identify specific necroptosis genes as potential therapeutic targets in NSCLC.

Main Methods:

• Analysis of 18 programmed cell death pathways to generate the CCDI.
• Validation of CCDI using single-cell RNA sequencing and spatial transcriptomics data.
• In vitro experiments and syngeneic cancer mouse models to investigate the role of specific necroptosis genes (PTGES3, CTSH) and their impact on necroptosis and anti-PD1 therapy.

Main Results:

• The CCDI, comprising necroptosis and autophagy genes, accurately stratified NSCLC patients by survival prognosis and predicted immunotherapy responses.
• CCDI positively correlated with tumor malignancy, invasiveness, and immunotherapy resistance.
• CTSH overexpression or PTGES3 knockdown inhibited NSCLC cell proliferation and migration, induced necroptosis, and improved anti-PD1 therapy efficacy in mouse models.

Conclusions:

• The CCDI serves as a robust biomarker for NSCLC prognosis and immunotherapy prediction.
• Specific necroptosis genes, particularly CTSH and PTGES3, are implicated in NSCLC progression and evolution.
• Targeting necroptosis pathways, such as through CTSH modulation, represents a promising therapeutic strategy for NSCLC.