Deciphering Treatment Resistance in NSCLC with Single-Cell Sequencing Technology

Acquired resistance to targeted and immune therapies severely limits the success of non-small cell lung cancer (NSCLC) treatment. Single-cell sequencing technologies now empower researchers to dissect this resistance at unprecedented resolution, moving beyond the averaging limitations of bulk genomics. This review highlights how single-cell and spatial multiomics approaches reveal key mechanisms of NSCLC resistance, from rare drug-tolerant subpopulations and cellular plasticity to immunosuppressive niches and metabolic adaptation within the TME. We also discuss emerging strategies-such as liquid biopsy and AI-driven data integration-that hold promise for translating these insights into more effective therapeutic interventions.