Today, I review, link to, and excerpt from Trends In Cancer’s “Lung cancer in never smokers: from early detection to prevention”. [PubMed Abstract] [Full-Text HTML] [Full-Text PDF]. Trends Cancer. 2026 Apr;12(4):310-319. doi: 10.1016/j.trecan.2025.12.009. Epub 2026 Feb 11.
Lung cancer in never smokers (LCINS) now accounts for a growing proportion of lung cancer cases, with distinct demographics and biology.
Identifying risk factors for LCINS remains challenging. The most well-established factors—germline variants, clonal hematopoiesis, and environmental exposures—currently lack validated screening tests.
Abstract
Lung cancer in never smokers (LCINS) is a growing global health challenge. Unlike smoking-related lung cancer, LCINS is characterized by distinct epidemiological patterns and unique molecular pathogenesis and, consequently, requires different clinical management approaches. Unfortunately, for patients with lung cancer who have never smoked, symptoms are nonspecific and often dismissed due to these patients not fitting a high-risk profile (e.g., smoker), underscoring the need for improved detection and interception. Emerging risk factors, including germline variants, clonal hematopoiesis, and environmental exposures, offer new avenues for risk stratification and preventive strategies. While low-dose computed tomography screening shows promise in high-risk subgroups, challenges remain in optimizing cost-effectiveness. Novel prevention approaches, from interleukin (IL)-1β inhibition to cancer vaccines, are under investigation. This opinion article discusses why LCINS demands unique clinical and research paradigms to address its biological complexity.
Lung cancer is the leading cause of cancer-related deaths worldwide [1]. As smoking rates have decreased, lung cancer in never smokers (LCINS) (see Glossary) [2,3] accounts for an increasing proportion of patients [1]. Recent findings suggest that the absolute incidence of LCINS may be increasing [4,5]. Unfortunately, a higher proportion of LCINS cases goes undiagnosed for longer periods compared to those involving smoking-related lung cancer, and many patients are diagnosed with metastatic disease and therefore receive treatment with palliative intent [3,6]. In part, this relates to the lack of lung cancer screening programs for never smokers, as the background risk is low (incidence 5–20/100 000) [7], and there are no established risk algorithms other than age to stratify individuals for screening. LCINS often harbors mutations or fusions in epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK). Results from trials of adjuvant tyrosine kinase inhibitor (TKI) treatment following surgery in patients with EGFR and ALK mutation-positive lung cancer show a benefit even in the earliest stages of disease (stage IB and II), prior to detection of metastatic dissemination [8,9]. The recurrence patterns observed in patients across these studies indicate that adding adjuvant TKIs protects against extrathoracic and central nervous system metastases. These findings underscore the urgent need for earlier detection and interception strategies to increase the proportion of patients whose cancer is detected at the earliest possible stage and ultimately to reduce lung cancer mortality.
From a clinical point of view, never smokers are more likely to present with adenocarcinoma histology and oncogene-addicted tumors (especially for EGFR and ALK), making them candidates for targeted therapies [11]. Multiple studies have demonstrated that a high prevalence of actionable driver mutations (~80%) is found in LCINS, in contrast to LCS [1,12–15]. Pivotal immune checkpoint inhibitor (ICI) trials consistently show that patients with lung cancer who have never smoked, unlike those who have smoked, are significantly less responsive to ICI regimens, partly because LCINS tumors have a lower mutational burden [16]. These findings reinforce the concept that LCINS represents a distinct biological entity compared to patients with a smoking history.
Lung cancer prevention is an area still in its infancy. Studies testing therapies at the earliest stages of disease, even prior to transformation, are being carried out in both preclinical and clinical settings. These include targeted therapies, immunotherapies, and cancer vaccines. All these approaches could have major benefits for patients, but these benefits must outweigh the risk of toxicity, iatrogenic complications, and economic costs to health care systems. Targeted therapies, such as EGFR and ALK TKIs and KRAS G12C inhibitors, commonly cause dermatologic and gastrointestinal toxicities. These side effects are usually low grade but can significantly impact patient quality of life [17–19]. Immunotherapies can cause nausea, fatigue, and diarrhea, as well as immune-related adverse events such as pneumonitis, which can be life-threatening [20–23]. Cancer vaccines, in general, have a higher safety profile than both targeted therapies and immunotherapies, with some studies showing only mild to moderate adverse events [24,25]. For all these therapies, evidence of benefits that outweigh risks is needed in the relevant patient population—individuals at high risk of lung cancer or with preneoplastic lung lesions [24–26].
Risk factors for LCINS
Identifying those at risk of lung cancer in a never-smoker population is particularly challenging. Environmental and genetic factors have been implicated in the etiology of lung cancer in nonsmoking populations. These include germline variants in oncogenes and DNA damage response genes (e.g., EGFR, TP53, and ATM, among others) [27–29], clonal hematopoiesis [30], radon exposure [31], secondhand smoke [1,32–35], inflammatory diseases [36], and air pollution [37] (Figure 1). However, much of the supporting evidence is retrospective, and the relative risk associated with each of these exposures is modest, so justifying costly screening or therapy is difficult. Together, the global disease burden from each of these factors results in a significant number of deaths annually [38] (https://www.healthdata.org/research-analysis/library/transport-health-global-burden-disease-motorized-road-transport), supporting more work aimed at lung cancer prevention in a never-smoker population.
Figure 1Schematic of the innate and extrinsic risk factors for lung cancer in patients who have never smoked.
Inherited or acquired predisposition
Germline alterations
It is estimated that up to 4.5% of patients with lung adenocarcinoma have germline variants that correlate with increased lung cancer risk [39]. Specific germline mutations in known oncogenes, such as EGFR p.Thr790Met (T790M), have been associated with increased lung cancer risk (>50% diagnosed with lung cancer by age 60) [40,41]. Individuals with these mutations are at high risk of developing multifocal lung lesions consistent with adenocarcinoma spectrum diagnosis, even at a very early age, with a high risk of developing invasive EGFR-driven lung cancer [40,41]. In addition to canonical germline variants, early developmental mosaicism has recently been investigated as a distinct mechanism of genetic predisposition to EGFR-mutant lung cancer [42].
Germline alterations in the apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3 (APOBEC3) family of cytosine deaminases are also linked with elevated lung cancer risk [27–29]. APOBEC3 genes normally function as part of the body’s defense against viruses, attacking and mutating viral RNA and DNA [43]. Unfortunately, APOBEC3 genes can also mutate the host genome and are linked with DNA damage and mutational signatures in up to 70% of human cancer types [43]. The APOBEC3A/B germline deletion correlates with significantly increased non-small cell lung cancer (NSCLC) risk, with a 2.7-fold increase in risk in a southern Chinese population after adjusting for age, sex, and smoking history [29]. In another study based on a Norwegian population, the APOBEC3A/B germline deletion polymorphism was associated with a younger age at diagnosis of both lung and prostate cancer, with a 2.2-fold increase in risk [27]. The impact of this germline alteration is likely population-dependent. In an East Asian population (APOBEC3A/3B prevalence 37%), about 15% of NSCLC cases were attributable to the APOBEC3A/B germline deletion, while in Native American populations, where the APOBEC3A/B germline deletion is more prevalent (57.7%), the impact was greater, with about 30% of NSCLC cases potentially attributable to the APOBEC3A/B germline deletion [44]. Screening for the APOBEC3A/B germline deletion polymorphism is simple and low cost, as it uses polymerase chain reaction [27,44]. [Emphasis added]
Clonal hematopoiesis
Another potential at-risk population comprises individuals with an expansion of somatic alterations in the DNA of hematopoietic stem cells, called clonal hematopoiesis of indeterminate potential (CHIP). CHIP is associated with an elevated risk of developing several types of solid cancers [45,46]. Recent data demonstrate that CHIP carriers with a high variant allele fraction (≥ 0.1) have an increased risk of lung cancer, independent of smoking status [30,45,46]. CHIP alterations significantly associated with increased lung cancer include the most frequently mutated CHIP genes—DNMT3A, TET2, and ASXL1[30,45,46]. The mechanism behind the increased risk of lung cancer with CHIP is complex. Research points to the involvement of increased inflammatory processes [47,48]. Macrophages show elevated secretion of cytokines and chemokines, including CXCL1, CXCL2, CXCL3, CXCL4, IL-1β, and IL-16 [47–49]. In mouse models, inhibiting IL-1β reduces lung cancer [37], while decreased lung cancer incidence was observed in patients treated with a therapeutic monoclonal antibody targeting IL-1β [50,51]. However, recent evidence suggests that the effect may not be as significant as initially observed [52]. Despite these conflicting findings, anti-IL-1β therapy could be an approach for lung cancer prevention in individuals classified as high risk. Studies have also revealed that tumor-infiltrating clonal hematopoiesis increases the risk of lung cancer progression by driving tumor immune evasion and growth, underscoring how age-related clonal hematopoiesis fuels cancer evolution [45]. However, there are currently no standard guidelines for screening cancer patients or those at high risk of cancer for CHIP [53].
Highlights
Lung cancer in never smokers (LCINS) now accounts for a growing proportion of lung cancer cases, with distinct demographics and biology.
Identifying risk factors for LCINS remains challenging. The most well-established factors—germline variants, clonal hematopoiesis, and environmental exposures—currently lack validated screening tests.
Abstract
Lung cancer in never smokers (LCINS) is a growing global health challenge. Unlike smoking-related lung cancer, LCINS is characterized by distinct epidemiological patterns and unique molecular pathogenesis and, consequently, requires different clinical management approaches. Unfortunately, for patients with lung cancer who have never smoked, symptoms are nonspecific and often dismissed due to these patients not fitting a high-risk profile (e.g., smoker), underscoring the need for improved detection and interception. Emerging risk factors, including germline variants, clonal hematopoiesis, and environmental exposures, offer new avenues for risk stratification and preventive strategies. While low-dose computed tomography screening shows promise in high-risk subgroups, challenges remain in optimizing cost-effectiveness. Novel prevention approaches, from interleukin (IL)-1β inhibition to cancer vaccines, are under investigation. This opinion article discusses why LCINS demands unique clinical and research paradigms to address its biological complexity.
Lung cancer is the leading cause of cancer-related deaths worldwide [1]. As smoking rates have decreased, lung cancer in never smokers (LCINS) (see Glossary) [2,3] accounts for an increasing proportion of patients [1]. Recent findings suggest that the absolute incidence of LCINS may be increasing [4,5]. Unfortunately, a higher proportion of LCINS cases goes undiagnosed for longer periods compared to those involving smoking-related lung cancer, and many patients are diagnosed with metastatic disease and therefore receive treatment with palliative intent [3,6]. In part, this relates to the lack of lung cancer screening programs for never smokers, as the background risk is low (incidence 5–20/100 000) [7], and there are no established risk algorithms other than age to stratify individuals for screening. LCINS often harbors mutations or fusions in epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK). Results from trials of adjuvant tyrosine kinase inhibitor (TKI) treatment following surgery in patients with EGFR and ALK mutation-positive lung cancer show a benefit even in the earliest stages of disease (stage IB and II), prior to detection of metastatic dissemination [8,9]. The recurrence patterns observed in patients across these studies indicate that adding adjuvant TKIs protects against extrathoracic and central nervous system metastases. These findings underscore the urgent need for earlier detection and interception strategies to increase the proportion of patients whose cancer is detected at the earliest possible stage and ultimately to reduce lung cancer mortality.
The demographics of patients with lung cancer who have never smoked differ markedly from those of lung cancer in patients who have smoked (LCS). LCINS occurs more commonly in women and Asian populations, with women who have never smoked being more than twice as likely to get lung cancer as men who have never smoked [1,9,10]. However, this increased risk in women remains controversial and poorly understood [1,3]. A better understanding of the biological mechanisms driving LCINS is essential not only to inform cancer prevention strategies and improve patient outcomes but also to enable the identification of high-risk individuals who would benefit most from targeted screening approaches.
From a clinical point of view, never smokers are more likely to present with adenocarcinoma histology and oncogene-addicted tumors (especially for EGFR and ALK), making them candidates for targeted therapies [11]. Multiple studies have demonstrated that a high prevalence of actionable driver mutations (~80%) is found in LCINS, in contrast to LCS [1,12–15]. Pivotal immune checkpoint inhibitor (ICI) trials consistently show that patients with lung cancer who have never smoked, unlike those who have smoked, are significantly less responsive to ICI regimens, partly because LCINS tumors have a lower mutational burden [16]. These findings reinforce the concept that LCINS represents a distinct biological entity compared to patients with a smoking history.
Lung cancer prevention is an area still in its infancy. Studies testing therapies at the earliest stages of disease, even prior to transformation, are being carried out in both preclinical and clinical settings. These include targeted therapies, immunotherapies, and cancer vaccines. All these approaches could have major benefits for patients, but these benefits must outweigh the risk of toxicity, iatrogenic complications, and economic costs to health care systems. Targeted therapies, such as EGFR and ALK TKIs and KRAS G12C inhibitors, commonly cause dermatologic and gastrointestinal toxicities. These side effects are usually low grade but can significantly impact patient quality of life [17–19]. Immunotherapies can cause nausea, fatigue, and diarrhea, as well as immune-related adverse events such as pneumonitis, which can be life-threatening [20–23]. Cancer vaccines, in general, have a higher safety profile than both targeted therapies and immunotherapies, with some studies showing only mild to moderate adverse events [24,25]. For all these therapies, evidence of benefits that outweigh risks is needed in the relevant patient population—individuals at high risk of lung cancer or with preneoplastic lung lesions [24–26].
Risk factors for LCINS
Identifying those at risk of lung cancer in a never-smoker population is particularly challenging. Environmental and genetic factors have been implicated in the etiology of lung cancer in nonsmoking populations. These include germline variants in oncogenes and DNA damage response genes (e.g., EGFR, TP53, and ATM, among others) [27–29], clonal hematopoiesis [30], radon exposure [31], secondhand smoke [1,32–35], inflammatory diseases [36], and air pollution [37] (Figure 1). However, much of the supporting evidence is retrospective, and the relative risk associated with each of these exposures is modest, so justifying costly screening or therapy is difficult. Together, the global disease burden from each of these factors results in a significant number of deaths annually [38] (https://www.healthdata.org/research-analysis/library/transport-health-global-burden-disease-motorized-road-transport), supporting more work aimed at lung cancer prevention in a never-smoker population.
Figure 1Schematic of the innate and extrinsic risk factors for lung cancer in patients who have never smoked.
Inherited or acquired predisposition
Germline alterations
It is estimated that up to 4.5% of patients with lung adenocarcinoma have germline variants that correlate with increased lung cancer risk [39]. Specific germline mutations in known oncogenes, such as EGFR p.Thr790Met (T790M), have been associated with increased lung cancer risk (>50% diagnosed with lung cancer by age 60) [40,41]. Individuals with these mutations are at high risk of developing multifocal lung lesions consistent with adenocarcinoma spectrum diagnosis, even at a very early age, with a high risk of developing invasive EGFR-driven lung cancer [40,41]. In addition to canonical germline variants, early developmental mosaicism has recently been investigated as a distinct mechanism of genetic predisposition to EGFR-mutant lung cancer [42].
Germline alterations in the apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3 (APOBEC3) family of cytosine deaminases are also linked with elevated lung cancer risk [27–29]. APOBEC3 genes normally function as part of the body’s defense against viruses, attacking and mutating viral RNA and DNA [43]. Unfortunately, APOBEC3 genes can also mutate the host genome and are linked with DNA damage and mutational signatures in up to 70% of human cancer types [43]. The APOBEC3A/B germline deletion correlates with significantly increased non-small cell lung cancer (NSCLC) risk, with a 2.7-fold increase in risk in a southern Chinese population after adjusting for age, sex, and smoking history [29]. In another study based on a Norwegian population, the APOBEC3A/B germline deletion polymorphism was associated with a younger age at diagnosis of both lung and prostate cancer, with a 2.2-fold increase in risk [27]. The impact of this germline alteration is likely population-dependent. In an East Asian population (APOBEC3A/3B prevalence 37%), about 15% of NSCLC cases were attributable to the APOBEC3A/B germline deletion, while in Native American populations, where the APOBEC3A/B germline deletion is more prevalent (57.7%), the impact was greater, with about 30% of NSCLC cases potentially attributable to the APOBEC3A/B germline deletion [44]. Screening for the APOBEC3A/B germline deletion polymorphism is simple and low cost, as it uses polymerase chain reaction [27,44]. [Emphasis Added]
Clonal hematopoiesis
Another potential at-risk population comprises individuals with an expansion of somatic alterations in the DNA of hematopoietic stem cells, called clonal hematopoiesis of indeterminate potential (CHIP). CHIP is associated with an elevated risk of developing several types of solid cancers [45,46]. Recent data demonstrate that CHIP carriers with a high variant allele fraction (≥ 0.1) have an increased risk of lung cancer, independent of smoking status [30,45,46]. CHIP alterations significantly associated with increased lung cancer include the most frequently mutated CHIP genes—DNMT3A, TET2, and ASXL1[30,45,46]. The mechanism behind the increased risk of lung cancer with CHIP is complex. Research points to the involvement of increased inflammatory processes [47,48]. Macrophages show elevated secretion of cytokines and chemokines, including CXCL1, CXCL2, CXCL3, CXCL4, IL-1β, and IL-16 [47–49]. In mouse models, inhibiting IL-1β reduces lung cancer [37], while decreased lung cancer incidence was observed in patients treated with a therapeutic monoclonal antibody targeting IL-1β [50,51]. However, recent evidence suggests that the effect may not be as significant as initially observed [52]. Despite these conflicting findings, anti-IL-1β therapy could be an approach for lung cancer prevention in individuals classified as high risk. Studies have also revealed that tumor-infiltrating clonal hematopoiesis increases the risk of lung cancer progression by driving tumor immune evasion and growth, underscoring how age-related clonal hematopoiesis fuels cancer evolution [45]. However, there are currently no standard guidelines for screening cancer patients or those at high risk of cancer for CHIP [53].
The exposome
Radiation exposure
Exposure to radon, a radioactive gas, is a risk factor for lung cancer development. As a decay product of uranium-238, radon can accumulate in poorly ventilated buildings. Because radon levels fluctuate, exposure is difficult to assess; however, geographic mapping has identified areas with persistently elevated levels, enabling targeted public health interventions and risk mitigation [31]. Initial studies of radon and lung cancer focused on miners with high exposures and found that cumulative radon exposure was associated with increased lung cancer risk [31,54]. Researchers have investigated links between radon exposure and specific genomic alterations that drive lung cancer, but findings are mixed [31]. In vitro studies have linked radiation exposure to mutations in the tumor suppressor TP53, and in rats, radon exposure has induced chromosome losses in regions harboring tumor suppressor genes [31]. More work is required to understand the mechanism behind the increased risk of lung cancer from radon exposure. Without this knowledge, prevention through monitoring is the most effective strategy [31,54,55].
In developed countries, the expanded use of CT scanners has substantially increased diagnostic exposure to ionizing radiation. Recent epidemiological modeling studies suggest that a large proportion of malignancies could be a result of diagnostic imaging exposure [56]. A recent examination of mutational signatures in the cancer genomes from patients with lung cancer who have never smoked highlighted that 87% of indel drivers in EGFR (predominantly exon 19 deletions) occur in the context of the mutational signature related to radiation exposure [57]. A cumulative estimate of a person’s exposure to environmental and medical radiation could inform risk stratification for screening or interception strategies.
