Targeting regulated cell death pathways in lung cancer: mechanisms, therapeutic strategies, and clinical translation - PubMed
3 days ago
- #regulated cell death
- #targeted therapy
- #lung cancer
- Lung cancer is the leading cause of global cancer mortality, with treatment challenges due to heterogeneity, drug resistance, and immunosuppressive tumor microenvironment.
- Eight key regulated cell death (RCD) pathways in NSCLC include apoptosis, autophagy, necroptosis, ferroptosis, cuproptosis, pyroptosis, immunogenic cell death (ICD), and lysosome-dependent cell death (LDCD).
- Mechanistic insights reveal complex crosstalk among RCD pathways, such as apoptosis escape via EGFR/PI3K/Akt/mTOR signaling and autophagy's dual role regulated by RBBP4 and AURKA-CXCL5 axis.
- RCD pathways exhibit immunomodulatory functions: necroptosis activates T cells via DAMPs, while ferroptosis enhances NK cell cytotoxicity through GPX4 inactivation.
- Therapeutic advances include synergistic strategies like berberine with EGFR-TKIs inducing apoptosis and (-)-Guaiol triggering ICD to enhance PD-1/PD-L1 inhibitor efficacy.
- Novel inducers such as Auranofin (ferroptosis), TMEM100 agonists (necroptosis), and cuproptosis nanomedicines (e.g., DE-Cu4O3 NPs) show preclinical promise.
- Prognostic models based on RCD-related genes (e.g., LDCD signatures) can predict immune features and response to immune checkpoint inhibitors (ICIs).
- Clinical translation faces challenges like pathway crosstalk, immunosuppressive niche remodeling, low ICI response in EGFR-mutant patients, and lack of standardized biomarkers.
- Future research should focus on coordinated targeting of multiple death pathways, computational tools for RCD network analysis, and interdisciplinary translational efforts.