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Lung Cancer in Never-Smokers: Risk Factors, Driver Mutations, and Therapeutic Advances.

Po-Ming Chen1,2, Yu-Han Huang3, Chia-Ying Li3

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|January 28, 2026
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Summary

Lung cancer in never-smokers (LCINS) is linked to environmental factors and unique genetic mutations. Understanding these distinct molecular features is key for developing targeted therapies and improving patient outcomes.

Keywords:
PM2.5air pollutiondriver mutationsimmunotherapylung cancernever-smokerstargeted therapy

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Area of Science:

  • Oncology
  • Environmental Health
  • Genetics

Background:

  • Lung cancer in never-smokers (LCINS) is a significant global health issue, distinct from smoking-related lung cancer.
  • LCINS results from intricate interplay between environmental carcinogens and specific genomic alterations.
  • This review focuses on environmental risks, molecular profiles, and treatment advancements for LCINS.

Purpose of the Study:

  • To review environmental risk factors associated with lung cancer in non-smokers.
  • To identify and compare driver mutations in never-smokers versus smokers across major lung cancer subtypes.
  • To examine progress in targeted therapies for lung cancer based on molecular profiling.

Main Methods:

  • Conducted a narrative review of studies on lung cancer risk factors in non-smokers.
  • Analyzed studies on driver mutations in small-cell lung cancer, lung adenocarcinoma, squamous cell carcinoma, and large-cell carcinoma.
  • Performed a PubMed search for phase III trials and targeted therapy studies (2016-2025).

Main Results:

  • Environmental factors like cooking fumes, radon, asbestos, arsenic, and PM2.5 are linked to LCINS via oxidative stress and inflammation.
  • Never-smokers show characteristic mutations in EGFR, PIK3CA, OS9, MET, and STK11, unlike smokers' TP53 mutations.
  • Targeted therapies and immunotherapies show promise, highlighting the need for molecular profiling.

Conclusions:

  • LCINS is a distinct entity influenced by environmental exposures and genetic susceptibility.
  • Genetic alterations in LCINS contribute to tumor immune evasion, driving cancer progression.
  • Improving air quality, molecular diagnostics, and precision medicine are crucial for managing LCINS globally.