Targeted drug conjugates and molecular mechanisms in overcoming lung cancer drug resistance

Lung cancer, a leading cause of cancer-related mortality, is frequently characterized by late-stage diagnosis and the development of resistance to conventional therapies, including chemotherapy and tyrosine kinase inhibitors. While novel agents like antibody-drug conjugates (ADCs) have emerged, challenges such as off-target toxicity, limited tumor penetration, and acquired resistance persist, highlighting a critical gap in targeted therapeutic strategies with sustained efficacy and improved safety profiles. This review systematically delineates the molecular mechanisms underpinning drug resistance in lung cancer, focusing on key oncogenic drivers (EGFR, ALK, KRAS, MET) and their evasion pathways. Furthermore, we comprehensively evaluate the evolving landscape of drug conjugates-not only ADCs but also Peptide-drug conjugates (PDCs), radionuclide conjugates, and other novel modalities-as a strategic approach to overcome these resistance mechanisms by enhancing target specificity and drug delivery. Our analysis concludes that drug conjugates represent a paradigm shift in lung cancer treatment; however, their full potential is hampered by linker instability, payload-related toxicity, and complex resistance pathways. We recommend future research focus on the development of next-generation conjugates with optimized linker chemistry, novel payloads with bystander effects, and rational combination therapies to address the dynamic tumor microenvironment and prevent resistance.