Non-small cell lung cancer research: advances and persistent challenges

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality, prompting significant advancements in therapeutic and precision medicine. Recent innovations include antibody-drug conjugates (ADCs) such as TROP-2-targeting agents and HER3-DXd, which show promising efficacy in refractory disease. Next-generation tyrosine kinase inhibitors (TKIs), including lorlatinib, tepotinib, and glecirasib, have shown improved outcomes for patients with oncogene-driven NSCLC. Immunotherapy continues to evolve, with novel therapeutic targets and metabolic modulation strategies expanding its potential. Emerging diagnostic tools, such as liquid biopsy and artificial intelligence (AI)-based histopathology, are enhancing prognostic accuracy and enabling more personalized treatment approaches. Despite these advancements, significant challenges persist. Acquired resistance mechanisms and bypass pathways continue to undermine long-term therapeutic efficacy. Limitations in biomarker utility, including the imperfect predictive value of PD-L1and the lack of validation for ctDNA, STK11, and KEAP1, complicate treatment decision-making. While comprehensive genomic profiling (CGP) has expanded the detection of actionable targets, barriers such as accessibility, reimbursement issues, and workflow integration remain, with only 11-34% of eligible patients receiving matched therapies. Additionally, critical data gaps exist for elderly patients and rare subtypes such as hepatoid adenocarcinoma. Future efforts must prioritize overcoming resistance through combination strategies and ADCs, validating biomarkers using AI and ctDNA, streamlining CGP implementation, and addressing the unique needs of special populations. Bridging these biological and systemic challenges is essential for improving survival outcomes and ensuring equitable benefits for all NSCLC patients.