Researchers reveal why lung cancer in people who never smoked is increasing and explore how genetics, environmental exposures, and new screening strategies may help detect disease earlier and improve outcomes.
Opinion: Lung cancer in never smokers: from early detection to prevention. Image Credit: Thx4Stock team / Shutterstock
In a recent opinion piece published in the journal Trends in Cancer, researchers examined the rising global burden of lung cancer in people with no history of smoking. This phenomenon requires its own research and clinical framework, as traditional lung cancer models based on smoking history are inadequate for this population.
An emerging burden and distinct biology
Lung cancer accounts for the highest proportion of cancer-linked death worldwide, and lung cancer in never smokers (LCINS) represents a growing percentage of cases, although absolute incidence remains lower than smoking-related lung cancer. Historically overshadowed by smoking-associated disease, LCINS is increasingly recognized as a distinct biological and clinical entity, including lower tumour mutational burden, a high prevalence of actionable driver mutations, and often reduced responsiveness to immune checkpoint inhibitors.
LCINS is more common in women and in Asian populations, especially among women who have never smoked, although the reasons for this sex difference remain uncertain and debated. Many patients present with advanced or metastatic disease, partly because they do not meet traditional criteria for lung cancer screening, leading to delayed diagnosis.
Genetic susceptibility and clonal hematopoiesis
Identifying never smokers at elevated risk is challenging because baseline incidence remains relatively low. However, inherited and acquired biological predispositions are emerging as important contributors.
Germline variants in certain genes, including EGFR, TP53, ATM, and members of the APOBEC3 family, have been linked to an increased risk of lung cancer. Certain mutations, such as EGFR p.Thr790Met (T790M), confer a particularly high lifetime risk and may lead to the development of multifocal lung lesions at younger ages.
Additionally, population-specific genetic factors, such as the APOBEC3A/B germline deletion, significantly increase the risk of certain lung cancers in some ethnic groups. These findings suggest that genetic screening, especially in high-prevalence populations, may eventually inform risk-adapted surveillance.
Clonal hematopoiesis of indeterminate potential (CHIP) represents another emerging risk factor. CHIP involves somatic mutations in hematopoietic stem cells, commonly affecting genes such as DNMT3A, TET2, and ASXL1. Individuals with high variant allele fractions may experience a higher risk of solid tumors, including lung cancer, independent of smoking status.
Mechanistically, CHIP may promote tumorigenesis through chronic inflammation, including elevated interleukin-1β (IL-1β) signaling. Although anti-IL-1β therapies have shown signals of reduced risk of lung cancer in some studies, evidence remains mixed. Currently, no formal guidelines exist for CHIP-based cancer screening, underscoring the need for further research before clinical implementation.
Environmental exposures and the exposome
Beyond inherited risk, the “exposome” (the cumulative measure of environmental exposures across the lifespan) plays a central role in the development of LCINS.
Radon exposure is a well-established carcinogen, particularly in poorly ventilated indoor settings and specific geographic regions. While early studies focused on miners who experienced high occupational exposure, residential radon remains an important public health concern. Mechanistic studies suggest that radiation induces genomic damage, although the precise pathways remain unclear. Medical diagnostic radiation exposure, including repeated computed tomography imaging, has also been proposed as a potential contributor in some studies, though causal links remain under investigation.
Second-hand smoke increases lung cancer risk in never smokers by approximately 20–25%. Interestingly, tumors in these individuals do not consistently display classic smoking-related mutational signatures, suggesting that indirect tobacco exposure may act synergistically with other biological processes, such as APOBEC-related mutagenesis.
Air pollution, particularly fine particulate matter (PM2.5), is a known carcinogen and is strongly associated with lung cancer incidence. High PM2.5 exposure correlates with a greater mutation burden, TP53 mutations, telomere shortening, and inflammatory activation within the lung microenvironment.
Similar to CHIP-related mechanisms, pollution-induced inflammation, especially IL-1β-mediated signaling, appears to promote tumorigenesis. However, risk assessment is complicated by variable outdoor and indoor exposures, especially in rapidly urbanizing or resource-limited regions. Indoor air pollution from solid fuels or poorly ventilated cooking environments remains understudied but may be important in certain regions.
Inflammatory conditions and certain chronic diseases have also been linked to increased lung cancer risk, although causality remains uncertain due to observational study limitations.
Screening, early detection, and prevention strategies
Early detection dramatically improves outcomes in lung cancer. A screening trial showed a 20% reduction in lung cancer mortality using low-dose computed tomography (LDCT) in heavy smokers. However, applying LDCT to never smokers remains controversial because defining high risk without smoking history is difficult, and concerns persist regarding false positives, overdiagnosis, and cost effectiveness, particularly given the comparatively lower baseline incidence in never smokers.
A clinical trial of people who had never smoked in Taiwan identified an elevated risk among never smokers who had a first-degree family history of lung cancer, prompting the expansion of national screening criteria. Preliminary data indicate that LDCT may be effective in selected high-risk never-smoker subgroups, such as Asian women with familial predisposition. Still, randomized trials assessing mortality benefit and cost-effectiveness in broader never-smoker populations are lacking. Emerging multi-cancer early-detection blood tests based on circulating tumour DNA are also under investigation, although their sensitivity for detecting very early lung cancer remains limited.
Prevention strategies are also evolving. Targeted therapies, immunotherapies, and cancer vaccines are under investigation for the treatment of premalignant or early-stage disease. Vaccines targeting clonal neoantigens, as well as peptide-based approaches such as CIMAvax-EGF, are being evaluated for their preventive potential. Because LCINS tumors frequently harbor actionable, immunogenic driver mutations, this population may be particularly suitable for vaccine-based interception strategies. However, the benefits must outweigh the risks of toxicity and economic costs, and clinical effectiveness remains to be established.
Conclusions
LCINS is an increasingly important global health problem requiring distinct diagnostic, screening, and therapeutic approaches. Integrating genetic susceptibility, clonal hematopoiesis, family history, and environmental exposures into comprehensive risk models may enable more precise screening and prevention. Advancing biological understanding of LCINS will be essential to developing tailored interception strategies capable of reducing mortality in this underrecognized and growing patient population.
Rising lung cancer in never smokers demands urgent research focus