Cellular senescence in lung cancer immune microenvironment and senotherapeutic opportunities.

Abstract

Cellular senescence (CS) shapes lung cancer biology by enforcing durable growth arrest while remodeling the tumor immune microenvironment (TIME) through the senescence-associated secretory phenotype (SASP). In non-small cell lung cancer (NSCLC), immune checkpoint inhibitors (ICIs) have improved outcomes, and senescence programs can influence antigen presentation, immune cell recruitment, and adaptive resistance. This review integrates evidence from cell and animal models, patient-derived datasets, and early clinical studies to map senescent cell states across cancer immunoediting and treatment contexts. We summarize senescence phenotypes in tumor and stromal compartments, highlight SASP-driven immune modulation, and discuss senescence-linked biomarkers that may inform prognosis and therapy selection. We also evaluate emerging senotherapeutic strategies-senolytics, prodrug approaches, and SASP-modulating senomorphics-designed to pair senescence induction with selective clearance or reprogramming. Together, these concepts frame a testable "induce, then edit or eliminate" paradigm to improve durability of lung cancer therapies.