Figure (3). Opportunities for novel therapy development across lung cancer.

Key opportunities to extend precision oncology beyond oncogene-defined tumors and to foster durable therapeutic benefit across the full spectrum of lung cancer fall into three interconnected areas: (i) overcoming “undruggable” barriers by exploiting emerging chemistries, such as heterobifunctional protein degraders (proteolysis-targeting chimeras, PROTAC) and molecular glues, to eliminate oncogenic drivers and transcription factors previously considered intractable. This includes pursuing reactivation of mutant tumor-suppressors (e.g., p53), inhibition of oncogenes (e.g., c-MYC), and rational combination strategies targeting compensatory signaling networks; (ii) expanding targeted therapy options by investigating mechanisms in oncogene-negative lung cancers, refining drug delivery approaches such as ADCs to enhance the therapeutic index, and identifying novel surface receptors and payloads unique to lung tumors. Intervention in lung inflammatory pathways also represents a promising therapeutic approach. New molecular dependencies and precision targets may be uncovered by integrating innovative immunotherapies, including CAR T cells and T-cell engagers, with systematic functional genomic screening in preclinical models; (iii) addressing the needs of all lung cancer subtypes by increasing molecular profiling and developing subtype-specific therapeutic strategies. Additionally, mesothelioma-specific clinical trials and reverse translational studies are needed to better understand heterogeneity, plasticity, and other vulnerabilities and evaluate emerging therapeutic agents. (LUAD: lung adenocarcinoma; LUSC/SQCC: lung squamous cell carcinoma; LCLC/LCC: large-cell lung carcinoma; SCLC: small cell lung cancer; MESO: mesothelioma)