Impact of smoking on the effectiveness of different non-small-cell lung cancer therapies

Introduction

The objective of this review is to critically examine how smoking status influences the efficacy and clinical outcomes of the major treatment modalities for lung cancer including chemotherapy, immunotherapy, radiation therapy, surgery, and targeted therapy, and to elucidate the underlying biological and pharmacokinetic mechanisms that drive these differences (1). Through comparing and contrasting key findings on how current smokers, former smokers, and never-smokers respond to various treatments, readers will gain an appreciation of why tobacco use impacts survival, complication rates, and treatment resistance (2). At the same time, this review draws attention to the practical implications of these findings, emphasizing the importance of smoking cessation strategies (3), potential dosage adjustments, the interplay between tumor mutational burden (TMB) and immune responses (4), and how future research might better integrate lifestyle factors with molecular biomarkers to personalize therapy. By presenting and synthesizing this information, the review ultimately seeks to guide clinicians, researchers, and policymakers in refining treatment protocols for patients across the smoking-status spectrum. This article is presented in accordance with the Narrative Review reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-145/rc).

Methods

This review was conducted by systematically identifying and analyzing peer-reviewed articles reporting on the influence of smoking status on the effectiveness of major lung cancer treatment modalities, including chemotherapy, immunotherapy, radiation therapy, surgery, and targeted therapies (Table 1). Literature searches were performed using electronic databases such as PubMed, Google Scholar, and Web of Science, covering all publications available up to the time of this study’s initiation. The primary search terms included combinations of “lung cancer”, “smoking”, “immunotherapy”, “chemotherapy”, “radiation therapy”, “surgery”, “targeted therapy”, and “treatment efficacy”. Additional filters included the terms “NSCLC”, “survival”, “treatment outcomes”, and “predictive factors”. Articles were restricted to English-language publications to ensure consistency in data interpretation.

Studies included quantitative or qualitative outcomes related to lung cancer treatment efficacy stratified by smoking status. Both randomized controlled trials and observational studies (prospective and retrospective cohorts) were considered, as well as relevant meta-analyses. Case reports, editorials, and conference abstracts without full data were excluded. Titles and abstracts were screened independently by two reviewers, and potentially relevant full-text articles were retrieved for detailed assessment. Discrepancies in inclusion were resolved by consensus or by a third reviewer. Key information extracted included: study design, patient population characteristics, smoking status definitions (never, former, current smoker), type of lung cancer [e.g., non-small-cell lung cancer (NSCLC)], treatment modality, primary outcome measures [overall survival (OS), progression-free survival (PFS), response rates, or complication rates], and relevant effect sizes [hazard ratios (HR), confidence intervals (CI), P values, or incidence rates]. Data were organized into standardized extraction tables to facilitate comparison.

Included studies were critically appraised for methodological quality using standardized assessment tools appropriate to their design (e.g., the Cochrane Risk of Bias tool for randomized trials or the Newcastle-Ottawa Scale for observational studies). Studies deemed of insufficient quality or reporting incomplete data were excluded from quantitative synthesis.

Whenever available, effect sizes (HRs with 95% CIs) comparing treatment efficacy or complication rates by smoking status were recorded. In cases where multiple studies reported similar outcome measures, their results were qualitatively compared to identify consistent patterns.

Given the heterogeneity of study designs and outcome definitions, a full quantitative meta-analysis was not performed for all treatment modalities. However, when a sufficient number of studies provided comparable endpoints, summary estimates were calculated using a random-effects model to account for between-study variability. All statistical tests were performed using standard software packages (e.g., RevMan for meta-analytical calculations, R software for descriptive statistics and subgroup analyses). HRs and 95% CIs were extracted directly from the source studies or calculated from reported survival curves and P values when appropriate. Heterogeneity across studies was assessed using the I² statistic, and publication bias was explored through funnel plot asymmetry where data were sufficient. Due to the exploratory nature of this review and the variability of included studies, the focus remained on identifying trends, rather than achieving a formal pooled estimate for each treatment modality. In addition, as this work is a literature review with no direct involvement of human participants or patient data, no ethical approval was required. All included studies were from publicly available scientific literature, and data were used solely for research synthesis.

Impact of smoking on different NSCLC treatments

Chemotherapy

Chemotherapy represents a cornerstone in the treatment NSCLC. The therapeutic strategies against NSCLC are generally based on systemic pharmacological agents (5), which act through the selective action against neoplastic cells with rapid proliferation rates. These agents include platinum-containing compounds, such as cisplatin and carboplatin, normally combined with the third-generation cytotoxic drugs paclitaxel, docetaxel, or gemcitabine. While treatments based on cisplatin are frequently much more effective, they also create serious toxic risks. The wide array of chemotherapy exerts its effects on cells through various mechanisms-from alkylation of DNA-cisplatin, inhibition of dynamic assembly of microtubules-paclitaxel, to interference with DNA synthesis or cell cycle antigens antimetabolites-such as gemcitabine. Success, however, is counterbalanced by the problems of intrinsic or acquired drug resistance. Events that decrease the effective delivery of chemotherapy include mutations in critical markers such as p53 or beta-tubulin overexpression of DNA repair proteins. Recent studies have involved the use of chemotherapy in combination with targeted therapies, including VEGF inhibitors such as bevacizumab, to increase efficiency and reduce resistance. However, drug side effects are still a major problem, and less toxic alternatives, including natural compounds, should therefore be considered. Thus, the recent development of natural agents in combination with chemotherapeutic agents brings new hope for better management with less harm.

The biological pathways (6) associated with tobacco use would significantly affect the outcome of the chemotherapy on lung cancer patients in terms of increased resistance and toxicities of the tumors. This could further reduce the ability of chemotherapy (7) to reach the site of cancerous cells at appropriate quantities and kill them, hence reducing its effectiveness and increasing the possibilities for side effects. One of the most critical ways that smoking impacts chemotherapy involves increasing the mutational burden that already characterizes tumors. In general, lung cancers developing in smoking patients tend to develop tumors with high TMB and increased genetic instability. The ultimate outcome is a heterogeneous tumor that is more resistant to chemotherapy. These tumors are more genetically variable due to smoking and enhance the propensity for the development of resistant clones that are more refractory to chemotherapeutic agents. Moreover, smoking-induced alterations of genes (8), for example, p53 and β-tubulin, can modify the response of a tumor to chemotherapeutic agents. For example, alterations in the p53 gene, responsible for controlling the cell cycle and mechanisms of DNA repair, may result in a failure of apoptosis-the programmed cell death-and hence impede the possibility of chemotherapy-induced death of tumor cells. Moreover, smoking may alter the tumor microenvironment and thereby could affect the efficacy of chemotherapy. The smoke of cigarettes enhances inflammation and oxidative stress, each capable of setting up an immunosuppressive environment that promotes tumor growth. Such tumor-evoked inflammatory milieus may develop conditions that protect tumor cells from the deleterious effects of chemotherapy.

For example, the release of various pro-inflammatory cytokines and growth factors (9) may initiate survival pathways in tumor cells, rendering them resistant to chemotherapy. Another factor is that smoking could increase the production of reactive oxygen species (ROS), which might alter the pharmacokinetics and effectiveness of chemotherapy drugs. Sometimes ROS modify the structural conformation of chemotherapy drugs, leading to less killing of the cancerous cells. One crucial aspect of the impact of smoking on chemotherapy refers to drug-metabolizing enzyme induction. It is also well established that smoking increases the activity of the group of enzymes known as cytochrome P450, responsible for metabolizing many chemotherapeutic agents. This increases the rate at which chemotherapy drugs are cleared from the body, hence reducing its therapeutic concentration and efficacy. The implication is that higher doses or more frequent modes of administration are required for smokers to obtain the same efficacy as in nonsmokers, thereby running the risk of toxicity. It can also increase the side effects of chemotherapy, especially in the pulmonary and cardiovascular systems. Smokers are at a much higher risk of chemotherapy-induced lung toxicity, including pneumonitis and fibrosis, because smoking-induced damage synergistically interacts with the cytotoxic effects of chemotherapy. Such complications can significantly degrade a patient’s quality of life and may require treatment alterations-such as dose reductions or delays-that can compromise the effectiveness of chemotherapy. In general, smoking significantly influences chemotherapy efficiency in lung cancer patients due to increased tumor resistance by means of genetic changes, modification of the tumor microenvironment, and modification of drug metabolism. Moreover, smoking increases the risk of toxicity due to chemotherapy, especially to pulmonary tissues, which further complicates treatment modalities. These considerations are very significant in the strategic plan of chemotherapy and show the need to have appropriate methodologies tailored to reduce the impacts of smoking-related complications.

Immunotherapy

Immunotherapy so far has dramatically altered the treatment paradigm in the management of advanced non-small cell lung cancer and given new hopes for the conventionally dismal prognosis of the disease. Immune checkpoint inhibitors like nivolumab, pembrolizumab, and atezolizumab exploit the body’s immune response against the tumor cells by targeting immune pathways such as the programmed death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) axes (10). Indeed, these agents have demonstrated durable responses and significant survival benefits compared to standard therapies, especially in those with either high programmed death-ligand 1 (PD-L1) expression or high TMB. Food and Drug Administration (FDA) approval of immune checkpoint inhibitors (ICIs) has redefined not only the first line but also the second-line treatments of NSCLC. While all those therapies originally came into prominence as a monotherapy for patients with advanced disease, the use of these therapies in combination with chemotherapy (11) further improves survival in broader patient populations without restriction in PD-L1 status. Ongoing studies are also investigating the role of ICIs in earlier stages of NSCLC, including adjuvant and neoadjuvant settings, further extending their therapeutic possibilities. Despite such advances, not all patients have responded to immunotherapy (12), and primary-acquired resistance requires deep examination of the tumor immune microenvironment. Indeed, efforts in finding reliable biomarkers and optimization of combination strategies with chemotherapy, targeted agents, or radiation therapy further improve the effectiveness and applicability of immunotherapy in NSCLC. These breakthroughs showcase the revolutionizing power of immunotherapy in the treatment of lung cancer and its potential to redefine outcomes for patients everywhere.

A study (13) investigates how smoking status influences the efficiency of ICIs on lung cancer. ICIs enhance anti-tumor immune responses by blocking inhibitory pathways such as PD-1/PD-L1 and CTLA-4, critical for tumor immune escape. It is considered a high-risk factor for lung cancer and complicates treatment outcomes. This large meta-analysis of 17 Phase III clinical trials included 10,283 patients and showed that the benefit of immunotherapy extends to both smokers and nonsmokers. The aggregated HRs for OS were 0.74 (95% CI: 0.59–0.92) in nonsmokers and 0.73 (95% CI: 0.67–0.80) in smokers, showing equal advantage with respect to survival outcome. Further analysis by smoking status among ever smokers revealed that former smokers had an HR of 0.79 (95% CI: 0.68–0.91), while current smokers had an HR of 0.71 (95% CI: 0.59–0.87). Such data support the notion of the efficacy of immunotherapy irrespective of the smoking status. Notably, the tumors of smokers expressed higher PD-L1 expression and higher mutation burden, both characteristics associated with superior responses against immunotherapy. More importantly, alterations affecting DNA repair mechanisms or genes implicated in immunity increase the neoantigen load so that the tumors become more discernible to the immune system. Certainly, these biological changes may underpin the similarities.

Another study (14) researched the effects of tobacco on the outcomes associated with ICI therapy in malignancies of the lung, head and neck, and melanoma. This retrospective cohort of 458 subjects brings into view how smoking affects the outcomes of the therapy. Forty-eight (10.48%) were never smokers, while 410 (89.52%) were current or former smokers. This means a significantly different survival rate of 41% in 5-year nonsmokers, while in smokers, it was 28% (P=0.01). Mortality of tobacco users was 1.55 times more likely as compared to nonusers, with an HR of 1.55 (95% CI: 1.00–2.39). Also, their median survival reflected this difference: whereas the nonsmokers survived an average of 40 months, those who used tobacco survived 19 months on average. In fact, there was a remark that the survival rate between current smokers and ex-smokers does not differ that much. It would appear that the negative impact of tobacco on immunotherapy outcome is long-lasting, with changes in immunity and genetics due to smoking persisting well after smoking cessation. These data thus give reason for mechanistic, prospective studies aimed at discerning drivers of poor outcome in smokers, whether smoking cessation programs might improve ICI efficacy. Data justify personalized immunotherapy approaches in relation to smoking history for the improved survival of cancer patients.

In addition, it was found that smoking drastically influences the pharmacokinetics and effectiveness of immunotherapeutic ICIs cornerstones in the management of lung cancer (15). Another important observation included the fact that smokers undergoing immunotherapy, especially ICI targeted at the PD-1/PD-L1 pathways, had modified drug metabolisms along with response rates. As an example, certain ICI drugs are eliminated more quickly in smokers by the inducing effect of smoking on cytochrome P450 enzymes. This metabolic induction results in subtherapeutic drug levels and can affect clinical efficacy. On the other hand, paradoxically, the same study commented that smokers more frequently have a higher TMB, thus more visible to the immune system, which theoretically would favor the response to immunotherapy. This double effect underlines the complexity of the influence of smoking on the outcome of immunotherapy: in some circumstances, survival benefit is possible depending on the genetic and molecular features of the tumor. Further, it suggests the inclusion of quitting smoking into the treatment to heal patients who are already undergoing immunotherapy.

In one study (8), it is clearly identified how smoking history has impacted the survival outcome of patients with NSCLC undergoing immunotherapy, especially from ICI treatments, which mainly targeted the PD-1/PD-L1 pathways. By pooling data from 23 clinical trials and 7 real-world studies, this meta-analysis contributes to the claim that smokers have superior OS and PFS when treated with ICIs compared to chemotherapy or placebo. Thus, in the case of smokers, receiving immunotherapy yielded an OS HR of 0.76, 95% CI: 0.69–0.83, P<0.001, while in the case of non-smokers, the OS did not show any significant benefit, HR 0.91, 95% CI: 0.78–1.06, P=0.25. Similarly, the PFS HRs were 0.65 for smokers, 95% CI: 0.56–0.75, P<0.001, versus 0.68 for non-smokers, 95% CI: 0.45–1.03, P=0.07. This was also supported by similar analyses in results obtained for smokers versus nonsmokers, where smokers had a better OS (HR: 0.86, 95% CI: 0.75–0.99, P=0.04) and PFS (HR: 0.69, 95% CI: 0.60–0.81, P<0.0001). These are improvements in smokers with higher TMB and increased expression of PD-L1, thus enabling better tumor recognition and response to ICIs. However, an important critique from this review about the low numbers of nonsmokers enrolled in clinical trials is that it may detract from observing statistical significance of benefits for this group.

Radiation therapy

Radiation therapy plays an integral role in the treatment of NSCLC and mainly for those patients in whom surgical intervention is not indicated (16). Traditional two-dimensional radiotherapy techniques have evolved significantly with the advent of current modalities (17) including three-dimensional conformal radiation therapy (3D-CRT), intensity-modulated radiation therapy (IMRT), and stereotactic body radiation therapy (SBRT), which offer more precise and effective treatments. It has also grown to be the standard of treatment for medically inoperable early-stage NSCLC. There is superior local control while treating early-stage tumors with SBRT; it often exceeds 90% (18). This is achieved by giving an enormously high dose of radiation in pin-point accuracy over fewer sessions. It minimizes radiation exposure to surrounding healthy tissues, reducing toxicity while achieving biologically effective doses unattainable by conventional fractionation. Several studies are showing that SBRT can provide comparable survival outcomes to surgical resection in highly selected patients. In locally advanced NSCLC, 3D-CRT and IMRT remain the standard treatments, as they are most often used concurrently with chemotherapy to maximize therapeutic gain. New technologies of image-guided radiation therapy (IGRT) (19) allow for real-time tumor tracking that can surmount respiration and other forms of anatomic changes during the treatment course. These newer technologies allow the benefits of tighter tumor targeting with reduced treatment margins, dose escalation, and hence better local control, with a likely survival benefit. Despite these developments, radiation therapy continues to show some resistance and toxicity. This current research focuses on optimization of therapeutic modalities, radiotherapy administration in combination with systemic therapies, identification of predictive biomarkers of therapeutic response, and optimizing the therapeutic index of radiation therapy, thereby contributing to NSCLC management.

Radiation therapy

For radiation therapy, smoking significantly reduces the effectiveness of radiation therapy in lung cancer patients by inducing radioresistance in tumors and enhancing the toxicity of normal tissues. The adverse impacts of smoking on the effectiveness of therapy are really multifunctional (20): genetic changes, inflammatory processes, hypoxia of the tumor, and impairment of the tissue repair mechanisms-all factors that may reduce the therapeutic gain from radiation therapy. One of the impacts smoking has on radiation treatment is through an increased mutational burden carried by the lung cancer cells. In active smokers, neoplasms often present an increased TMB, generally associated with higher levels of genetic instability. This genetic heterogeneity may actually give rise to a more aggressive tumor phenotype with lower responsiveness to radiation therapy. It is possible that the changes induced by smoking enhance the tumour’s capability of repairing DNA damage inflicted by radiation, thus allowing cancer cells to survive and proliferate despite the radiation treatment. With this enhanced DNA repair capability, radiation treatment will be less effective because this prevents the accumulation of lethal mutations in the tumor cells. Apart from the genetic effects, the smoking habit creates a pro-inflammatory environment that reduces the effectiveness of radiotherapy. Products of cigarette smoke initiate inflammatory cytokines and growth factors that, in turn, facilitate changes in tumor vasculature to promote increased development of hypoxic regions in the tumor. Indeed, it is well established that hypoxia enhances radioresistance, because small amounts of oxygen limit the generation of ROS, which are key players in generating DNA damage by radiation. This eventually renders neoplasms in regular smokers less responsive to radiotherapy, therefore controlling tumors less efficiently, and thus translates into poor PFS. It also impairs the post-radiation tissue reparative mechanisms (21) of the body. This leads to increased radiolytic injury to tissues by oxidative stress and inflammation due to smoking, increasing the risk for complications such as lung fibrosis, pneumonitis, and impaired wound healing. These side effects not only reduce the quality of life of the patient but may also require treatment modification, including dose reduction or treatment breaks, which further compromise the effectiveness of radiotherapy. Smokers will be more vulnerable to toxicity due to additive effects from smoking-related lung damage and radiation-induced inflammation, setting the stage for some serious complications like respiratory distress and infection. Furthermore, chronic smoking exacerbates any pre-existing pulmonary diseases like chronic obstructive pulmonary disease (COPD) and complicates treatment. So, any patient with impaired lung function can be at great risk of severe pulmonary toxicity during and after radiotherapy treatment; this makes for greater admissions and delays in the delivery of planned treatments. In summary, cigarette smoking reduces the effectiveness of radiation therapy in lung cancer through several pathways, including enhanced DNA repair, tumor hypoxia, increased inflammation, and higher toxicity of normal tissues. These aspects denote the importance of considering smoking status in radiation treatment planning, as complications induced by smoking can strongly negatively affect possible benefits from radiotherapy. Interactions providing evidence for personalized treatment modalities to deal with the negative effect of smoking on radiotherapy.

Surgeries

Surgeries are still the mainstay of treatment for NSCLC and, in fact, the only curative treatment for the early stages of the disease, stages I and II (22). Long-term survival depends on complete surgical resection, and the five-year overall survival of completely resected stage I patients ranges between 60% and 80% (23), depending on tumor size and lymph node status. Lobectomy, given its balance between tumor clearance and lung function preservation, has been the gold standard in the management of early-stage NSCLC. Other surgical modalities (24), like segmentectomy or wedge resection, have been considered in patients with compromised pulmonary reserve or with significant comorbidities but are again associated with higher recurrence rates. It is less invasive when compared to video-assisted thoracoscopic surgery (VATS) and robot-assisted thoracoscopic surgery (RATS) approaches. They are associated with fewer post-operative complications (25), less hospital stay, and equal survival rates compared to open thoracotomy. Surgery also has a selected role in the treatment of locally advanced NSCLC-stage III disease, particularly in the setting of downstaging post-neoadjuvant therapies. Complete surgical resection with thorough mediastinal lymph node dissection is thus indicated for complete staging and optimization of outcome. Where perioperative management and surgical methodologies have vastly improved, operative mortality and complication rates have reached a minimum. Nevertheless, very high-risk surgeries such as pneumonectomy require extreme caution in patient selection and extensive preoperative workup. Since the continuous evolution of surgical techniques happens, their combination with systemic therapy and personalized approaches to treatment keeps increasing optimization of outcomes in patients with lung cancer.

For surgeries, the influence of smoking on surgical outcome in relation to lung cancer patients is immense, and one such study (26) explored the association in relation to thoracoscopic surgical techniques. The smoking patients undergoing lobectomy or segmentectomy had a significantly higher complication rate to develop postoperative pulmonary complications (PPCs) as compared to the nonsmokers: 4.6% versus 0.9%, P<0.001. Complications included pneumonia, bronchopleural fistula, and pleural effusion, all related to adverse action of smoking on impaired lung function and increased airway inflammation. Importantly, the research outlined the role of preoperative smoking cessation in reducing the risk. Thus, patients who stopped smoking for more than two months before surgery had a lower complication rate, 4.0%, compared with patients who gave up smoking within two months, 8.5%. However, even in those who had given up smoking over the long term, the complication rate remained significantly higher, 4.0% versus 0.9%, respectively, P<0.001, reflecting long-term effects of smoking on pulmonary health. For short-term cessation, the odds ratio for PPC among smokers was 10.78 (95% CI: 4.02–28.94), whereas that for longer cessation was 4.85 (95% CI: 2.13–11.02). The findings reveal smoking cessation strategies in the setting of surgical care for lung cancer. It is further suggested that cessation for a period of no less than two months may reduce, but not completely remove, the risk for PPCs.

In the study by Fox et al. (27), smoking history was indeed a major predictor of surgical outcome in NSCLC, as reflected in one study focusing on postoperative complications: 21.3% and 17.8% developed pulmonary and circulatory complications, respectively. Current and recent smokers comprised the highest-risk groups. More precisely, while the complication rate in current smokers was 41%, in lifelong nonsmokers, it was only 8.3%. The timing of cessation has been found to be critical. Thus, those patients who stopped smoking between 8–10 weeks before surgery had the fewest complications, 29%, and thus, it seems, a threshold beyond which risk can be significantly reduced. Conversely, those patients who stopped less than 2 weeks prior to surgery had risks equivalent to those of current smokers due to increased mucus production and an impaired cough reflex shortly after cessation. Interestingly, there was no significant relation of complication rates with the intensity or duration of smoking, in pack-years, which implies that the timing of cessation itself is more important than cumulative exposure in the short-term surgical context. This would therefore support the incorporation of smoking cessation programs into preoperative care, particularly in high-risk smokers who will undergo thoracoscopic surgery.

Targeted therapy

Targeted therapies has been recognized as an effective therapeutic approach against NSCLC; thus, targeted therapy offers a more specific and effective treatment potential compared with conventional chemotherapies.

These treatments (28) exert their functions by inhibiting specific molecules or cascade signal transmissions involved in the growth and spread of malignant cells. These therapeutic approaches target genetic mutations, altered proteins, or other molecular changes that drive tumor progressions while limiting harm to normal cells. Targeted therapies apply quite effectively to the treatment of tumors with certain genetic mutations (29) such as EGFR mutations, anaplastic lymphoma kinase (ALK) rearrangements, and c-ros oncogene 1 (ROS1) fusions in NSCLC. These have resulted in significantly improved PFS and quality of life in patients with EGFR-mutant tumors and include erlotinib, gefitinib, and osimertinib (30). Equally, ALK inhibitors such as crizotinib and alectinib have transformed the treatment of NSCLC harboring rearrangements in ALK, resulting in very substantial response rates and increased duration of disease control. Other targets (31) currently under investigation in clinical trials include B-Raf Proto-Oncogene (BRAF) mutations and MET proto-oncogene, receptor tyrosine kinase (MET) amplifications. Targeted inhibitors such as dabrafenib for BRAF mutations and capmatinib for MET amplifications demonstrated efficacy in early-phase trials. Combinations of ICIs (32) with targeted therapies are another active area of investigation, with a strategic perspective to increase anti-tumor immune responses and overcome resistance mechanisms associated with targeted therapy administered alone.

Despite these encouraging results, one of the big challenges that clinicians are facing is resistance to targeted therapy. This can occur via several routes, including secondary mutations within the same target gene-for example, T790M in EGFR-through the activation of other signaling pathways, or even by the histological transformation of the tumor. Thereby, recent studies focused on explaining these resistance mechanisms and contemporarily developing next-generation therapies that might surmount such resistance.

In all, targeted therapy represents a key step forward in the management of lung cancer and offers patients with particular genetic profiles a more individualized and effective option. Integration of targeted therapy with multiple modalities of treatment, such as chemotherapy, radiation, and immunotherapy, will be important in continued efforts to improve long-term patient outcomes as multiple resistance mechanisms continue to emerge.

For targeted therapy, the work of Yamamichi et al. (33) and others (8,34,35) have been an important contribution to information on how smoking status affects the use of molecularly targeted therapies, including EGFR-TKIs and ALK inhibitors, in patients with advanced NSCLC. Significant differences in PFS between never-smokers and smokers, particularly those underlining the need for consideration of smoking status in making treatment decisions, were noted. Never-smokers had significantly superior outcomes from first-line EGFR-TKIs compared with smokers. PFS HR was 0.32 (95% CI: 0.23–0.44) for never-smokers versus 0.54 (95% CI: 0.41–0.71) among smokers, with a P value of 0.02. Such divergence is explained through various factors, including higher TMB and reduced drug exposure in smokers as a result of the influence of smoking on the way drugs are metabolized. For instance, erlotinib, a common EGFR-TKI, shows lower pharmacokinetic exposure among smokers, thus perhaps requiring higher dosing in efforts to reach its therapeutic efficacy. By contrast, the results for ALK inhibitors were homogeneous between never-smokers and smokers. The pooled HR for PFS in never-smokers was 0.43 (95% CI: 0.35–0.53), and for smokers, it was 0.56 (95% CI: 0.44–0.71; P=0.406). In contrast to EGFR-TKIs, the effect of smoking seems less marked with ALK inhibitors, possibly because of the divergent metabolic pathways and tumor biology related to ALK rearrangements, which are more common in nonsmokers. Importantly, this work underlines personalized treatments with regard to smoking status. Specifically, in smokers, clinical outcomes of modified dosing of EGFP-TKIs may be improved, while the efficacy of ALK inhibitors is consistent regardless of smoking status. However, there remains plenty in the field of targeted therapy to be found out, as most studies had similar findings on EGFR and ALK inhibitors.

Discussion

The findings emphasize that smoking status has a complex, modality-specific impact on the outcome after various types of treatments for lung cancer. Certain tendencies are emerging that could provide an explanation for different responses of smokers and nonsmokers to the same therapeutic approach and possibly a way to undertake more personalized evidence-based interventions. While results in immunotherapy show that ICIs confer survival benefits irrespective of the smoking status, subtle differences seemingly make a difference molecularly and metabolically. In the present or former smokers, the tumors tend to have higher mutation burdens and neoantigen loads and are therefore more immunogenic and theoretically responsive to ICIs.

Concurrently, alterations in drug metabolism linked to smoking, as well as ongoing immune dysfunction, may lead to suboptimal long-term outcomes or reduced durability of response. In fact, several reports have shown poorer survival among smokers when follow-up time is extended, or when accounting for other confounding factors. These discordant observations reflect the underlying biologic complexity and point to the need for prospective studies to refine patient selection based on further intervention, one of which involves adding smoking cessation to immunotherapeutic regimens.

Targeted therapies are quite different in this respect. Though the EGFR-driven NSCLC, more common in never-smokers, responds almost unbelievably to EGFR-TKIs, it has less pronounced benefits among smokers, probably due to enhanced drug clearance and the presence of resistance-associated genetic changes. The reduced efficacy in smokers brings into sharp relief the need for judicious selection and dosing of targeted agents in keeping with the patient’s smoking history. On the other hand, ALK inhibitors appear to have lower sensitivity to smoking status, likely reflecting intrinsic biologic differences in ALK-rearranged tumors that are somewhat resistant to the mutagenic effects of tobacco. Taken together, these data support the growing consensus that genotype-driven therapy should also consider modifiable factors, including smoking, for maximizing personalized treatment.

Surgical outcomes reflect how tobacco use affects not only the long-term tumor biology but also complicates the perioperative and postoperative course. While never complete, prolonged preoperative smoking cessation decreases surgical complications; it therefore should be included in the routine preparation for surgery. The persistence of elevated complication rates after prolonged abstinence would thus point toward long-lasting structural and functional alterations induced by smoking in the lungs. These findings agreed with those in the literature that early and sustained smoking cessation is required to widen safety margins and thus enhance long-term survival.

Furthermore, in relation to radiation and chemotherapy, smoking becomes a very important predictor of poorer overall treatment outcome as a result of altered tumor and host biology. Increased DNA repair within the tumoral compartment, increased hypoxia, proinflammatory settings, and disturbed pharmacokinetics of chemotherapeutic agents all contribute to a lowered therapeutic ratio. The above mechanisms confirm earlier observations of increased toxicity and reduced therapeutic benefit associated with tobacco consumption.

The necessity of incorporating supportive strategies is emphasized—such as rigorous management of concomitant pulmonary conditions, pharmacological treatments aimed at inflammation modulation, and dosage modifications—to alleviate resistance or toxicity associated with smoking. While existing data robustly indicate that cessation of smoking would be advantageous for patients, it remains essential to specify the precise timing, intensity, and supportive approaches for cessation in forthcoming randomized trials. Despite such progress, our understanding remains partial: not all studies are concordant regarding the magnitude or even direction of smoking’s effect-particularly with respect to immunotherapy-which reflects variability in trial populations and endpoints and underrepresentation of never-smokers in many clinical studies. Furthermore, the observed heterogeneity in response and toxicity suggests several potential confounders, including genetic predispositions, different intensities and durations of smoking, and comorbidities. In short, smoking strongly affects the effectiveness of treatments for lung cancer. Potential benefits of immunotherapy may be enhanced by appropriate patient selection and/or cessation support when possible. The effectiveness of targeted therapy depends on the molecular profiles linked with smoking status. Outcomes after surgery also improve with structured preoperative cessation programs. Radiation therapy and chemotherapy may also need dose adjustments or additional therapies to overcome the resistance and toxicity associated with smoking. These findings are in concert with and extend prior literature to reaffirm that no single intervention is adequate; personalized treatment needs to incorporate molecular, clinical, and behavioral parameters. Explicit incorporation of smoking cessation and tailored treatment adaptation may increase the therapeutic yield and advance the standard of care for patients with lung cancer.

Table 2 suggests the summary of impact of smoking along with the mechanisms on each therapy. Further implications are also included.

Looking ahead, tailored treatment strategies for smokers, former smokers, and never-smokers will likely hinge on recognizing how tobacco exposure shapes tumor biology, immune function, and pharmacokinetics. In active smokers, the higher TMB and increased PD-L1 expression can favor immunotherapy response, yet metabolic enzyme induction may shorten drug half-life and increase toxicities; combining ICIs with structured smoking cessation programs and dose adjustments could help maximize benefit. In former smokers, the underlying damage to lung tissue and persistent epigenetic changes necessitate vigilant monitoring for long-term postoperative or chemoradiation-related complications, highlighting the need for enhanced supportive care and continued risk reduction strategies. By contrast, never-smokers more commonly harbor specific driver mutations such as EGFR or ALK alterations, making them prime candidates for targeted therapies, although ongoing research is needed to address acquired resistance in these groups. Future clinical trials that stratify patients based on detailed smoking histories, integrate real-time biomarker assessments, and incorporate rigorous cessation support will be instrumental in advancing precision oncology paradigms for all lung cancer patients, regardless of tobacco exposure level.

Since tobacco and cannabis can both induce drug-metabolizing enzymes such as CYP1A2, physicians must be aware that smoking can alter the clearance of numerous co-prescribed medications, potentially lowering their therapeutic efficacy. Conversely, abrupt smoking cessation can quickly downregulate these enzymes, raising drug levels and posing toxicity risks. Nicotine’s own metabolism largely depends on CYP2A6 and is influenced by genetic polymorphisms, hormonal factors (e.g., oral contraceptives), and co-administered inducers or inhibitors (like rifampicin or methoxsalen). Meanwhile, cannabinoids like THC and CBD rely on CYP2C9, CYP3A4, and CYP2C19, and their metabolism can be affected by potent inducers including rifampicin or inhibitors such as ketoconazole. Understanding these pharmacokinetic pathways is essential for accurately dosing medications and ensuring safe transitions particularly as smoking cessation therapies such as bupropion,a CYP2B6 substrate, and varenicline, subject to renal transporter interactions, can themselves interact with concurrently administered drugs.

As the development of artificial intelligence (AI), it has been widely applied in the field of lung cancer. Building on a ontology-informed, interpretable machine learning approach (6), traditional trial-based predictive modeling is expanded to include a patient’s smoking history alongside molecular or genomic data, thereby enabling a richer understanding of treatment efficacy, resistance patterns, and patient prognosis. By coding molecular markers such as gene variants influencing nicotine metabolism or susceptibility to dependence as additional features within the same ontology-driven framework, machine learning could learn how these biological indicators interact with specific behavioral interventions, such as tailored counseling strategies or pharmacotherapy choices. Clinicians can predict whether a patient with a particular genomic profile and heavier daily cigarette consumption will benefit more from an intervention employing certain behavior change techniques in combination with varenicline versus bupropion. Such precision insights not only highlight resistance risks in subgroups less likely to respond to standard treatments but also help refine patient-specific therapeutic strategies, boosting the potential for successful smoking cessation and improved long-term health outcomes.

Conclusions

The relationship between smoking and treatments of lung cancer well illustrates that smoking status is not only a demographic feature but also a clinically relevant variable which influences the treatment outcome. Smokers often develop altered tumor biology and different pharmacokinetics that can reduce the efficacy of chemotherapy and radiotherapy. On the other hand, the influence on immunotherapies and targeted therapies is complex, since certain subgroups could benefit from increased mutation burdens. The inclusion of treatment planning, such as smoking cessation therapy, adjustment of drug dosing, and supportive therapy, may improve the outcome and minimize complications. From an evidence-based perspective, a view on how behavioral modification increasingly becomes integral in strategies of precision oncology seems warranted. For this reason, future research needs to be directed at the establishment of optimum cessation modalities, refining predictive biomarkers for choosing a therapy approach, and designing prospective studies that integrate both molecular and lifestyle variables to better enhance the therapeutic index and overall survival of lung cancer subjects.

Acknowledgments

None.

Footnote

Reporting Checklist: The author has completed the Narrative Review reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-145/rc

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Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-145/coif). The author has no conflicts of interest to declare.

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