Impact of Emphysema on Therapeutic Efficacy and Immune-Related Pneumonitis Risk in NSCLC Patients Receiving ICIs: A Meta-Analysis of Improved Survival but Increased Toxicity.

Introduction
Non-small cell lung cancer (NSCLC) is one of the most prevalent and deadly malignancies worldwide.1 In recent years, immune checkpoint inhibitors (ICIs), such as programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors, have achieved significant progress in the treatment of NSCLC and have become a crucial therapeutic option for patients with advanced NSCLC. Clinical studies have shown that ICIs can significantly prolong progression-free survival (PFS) and overall survival (OS) in some patients, particularly those with high PD-L1 expression or a high tumor mutation burden (TMB).2,3 However, the response of NSCLC patients to ICIs varies substantially, with reported objective response rates (ORR) ranging from 20% to 50% between responders and non-responders, so that only a subset of patients achieve meaningful clinical benefit. Currently, predicting treatment efficacy remains challenging due to the lack of precise and reliable biomarkers, the complexity of the tumor microenvironment, and the heterogeneity of patients’ immune status. Although PD-L1 expression levels and TMB are widely studied as predictive markers for ICI efficacy, their sensitivity and specificity are still limited.4,5 Additionally, multifactorial interactions involving the tumor immune microenvironment (TME), gut microbiota, and genetic mutations further complicate efficacy prediction.5 Despite the clinical benefits of ICIs, their use is frequently accompanied by immune-related adverse events, among which immune checkpoint inhibitor–related pneumonitis (ICIP) is one of the most serious and potentially life-threatening toxicities. ICIP often leads to treatment interruption or discontinuation and can markedly affect patients’ prognosis. However, its incidence varies widely across studies, and the clinical course remains unpredictable, underscoring the importance of identifying patients at increased risk. To date, the risk factors associated with ICIP have not been clearly established, and current evidence remains insufficient to guide individualized risk assessment.
Computed tomography (CT)-defined emphysema is a common but often underrecognized comorbidity in patients with NSCLC. Epidemiological studies have shown that the prevalence of emphysema in NSCLC patients is relatively high with the incidence over 30%, largely due to shared risk factors such as smoking and chronic lung inflammation.6,7 However, emphysema is frequently overlooked in clinical practice, which may lead to inadequate risk assessment and management. Recent studies have indicated that emphysema is associated with poor prognosis in NSCLC patients, particularly in those undergoing surgical treatment.8,9 Patients with emphysema are more prone to postoperative pulmonary complications, including pneumonia, prolonged air leakage, and respiratory failure, which can adversely affect recovery and overall survival.10,11 While previous studies have focused on emphysema’s impact on surgical outcomes and prognosis in NSCLC, few have systematically evaluated its effect on immunotherapy efficacy and toxicity. Understanding this relationship could guide patient selection and risk stratification in clinical practice. Notably, a meta-analysis reported that emphysema was associated with favorable clinical outcomes, including improved survival and response rates, but also with a higher risk of immune-related adverse events, particularly immune checkpoint inhibitor–related pneumonitis (ICIP).12 Although this evidence suggests a potential predictive role of emphysema in patients undergoing ICI therapy, the available data remain limited. The prior meta-analysis included a relatively small number of studies, and several newly published cohorts were not incorporated. Moreover, important efficacy endpoints—such as complete response, partial response, stable disease, progressive disease, and disease control rate—were only partially evaluated. Therefore, up to now, the impact of emphysema on the efficacy and safety of ICIs in NSCLC patients remains unclear. Specifically, it is not well understood whether emphysema influences treatment outcomes or increases the risk of immune-related adverse events, such as immune-related pneumonitis. This may be partly explained by emphysema-induced alterations in the pulmonary immune microenvironment and chronic baseline inflammation, which could modulate both the antitumor response and susceptibility to pneumonitis.12
Previous observational studies assessing emphysema in NSCLC patients were limited by potential confounding factors such as smoking history, tumor stage, and treatment heterogeneity, highlighting the need for a pooled analysis to obtain more robust and generalizable conclusions. Therefore, this study aimed to further identify the impact of CT-defined emphysema on the therapeutic efficacy and risk of immune checkpoint inhibitor-related pneumonitis (ICIP) among NSCLC patients receiving ICIs.

Materials and Methods
This meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020.13

Literature Search
The PubMed, EMBASE, Web of Science and CNKI databases were searched from database inception to January 8, 2025 with following terms: emphysema, PD-1, PD-L1, CTLA-4, immune checkpoint inhibitor, immunotherapy and ICI. Detailed search strategy in the PubMed was as follows: (emphysema) AND (PD-1 OR PD-L1 OR CTLA-4 OR immune checkpoint inhibitor OR immunotherapy OR ICI). Besides, the MeSH terms and free texts were applied and references in included studies were reviewed.

Inclusion Criteria
Studies met following criteria were included: 1) patients were pathologically diagnosed with primary NSCLC and received the ICIs; 2) the presence or absence of emphysema was evaluated according to the CT images before ICIs use; 3) patients were divided in to emphysema or non-emphysema groups; 4) the relationship between emphysema and at least one of the endpoints including the PFS, OS, complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), objective response rate (ORR), disease control rate (DCR) and immune checkpoint inhibitor-related pneumonitis (ICIP) was explored; 5) articles published in English or Chinese and full texts were available.

Exclusion Criteria
Studies met following criteria were excluded: 1) case reports, reviews, animal trials, letters, meeting abstracts or editorials; 2) duplicated or overlapped data; 3) low quality studies with the Newcastle-Ottawa Scale (NOS) score <6;14 4) studies lacking hazard ratio (HR)/odds ratio (OR) values were excluded.

Data Extraction
Following information was collected from each included studies: the first author, publication year, country, sample size, number of patients with emphysema, age, ICI drug, combination of other therapies, definition of CT-defined emphysema, primary outcomes including the PFS, OS, CR, PR, SD, PD, ORR and DCR, secondary outcomes including the ICIP, HR, OR and corresponding 95% confidence interval (CI).
In several of the included studies, detailed patient characteristics—such as age, smoking history, pulmonary comorbidities (eg, COPD), PD-L1 expression levels, and prior treatments—were not consistently reported or fully accessible. As a result, these variables could not be incorporated into subgroup analyses, adjusted analyses, or sensitivity assessments. Therefore, the present meta-analysis was primarily based on the available outcome data rather than comprehensive patient-level covariates. This limitation was taken into account when interpreting the pooled estimates.

Methodological Quality Assessment
In our meta-analysis, the quality of included studies was evaluated by the NOS score tool and studies with a NOS score >5 were defined as high-quality studies and included.14
Two authors performed the literature search, selection, data extraction, and methodological quality assessment independently, and all disagreements were resolved by team discussion.

Statistical Analysis
All statistical analyses were conducted using STATA (version 15.0) software. Heterogeneity between included studies was assessed by I2 statistics. If significant heterogeneity was detected (I2 > 50%), the random-effects model was applied; otherwise, the fixed-effects model was applied. HRs and ORs with 95% CIs were combined to identify the impact of emphysema on the therapeutic efficacy and incidence of ICIP among ICIs treated NSCLC patients. Sensitivity analysis was conducted to detect the sources of heterogeneity and assess the stability of the overall results. Begg’s funnel plot and Egger’s test were conducted to detect publication bias.

Results

Literature Search
A total of 529 records were searched from the four databases and 79 duplicated records were removed. After reviewing the titles and abstracts, 409 and 26 publications were excluded. Eventually, nine studies were included in this meta-analysis after reviewing the full texts.15–23 (Figure 1)

Basic Characteristics of Included Studies
All nine studies were from China or Japan and published between 2018 and 2024. A total of 1076 patients were enrolled with the sample size ranged from 56 to 188 and 39.2% (422/1076) of them were divided into the emphysema group. Other detailed data were presented in Table 1.

Impact of Emphysema on the Primary Outcomes Among ICIs Treated NSCLC Patients
Pooled results demonstrated that presence of emphysema was significantly related to better PFS (HR = 0.43, 95% CI: 0.28–0.67, P < 0.001; I2= 0.0%, P = 0.492) (Supplementary Figure 1A), OS HR = 0.433, 95% CI: 0.25–0.75,P = 0.0033; I2= 20.1%,P = 0.2633) (Supplementary Figure 1B), PR OR = 2.100, 95% CI: 1.18–3.75,P = 0.0122; I2= 0.0%,P = 0.4388) (Supplementary Figure 1C), DCR OR = 1.488, 95% CI: 1.14–1.94,P = 0.0044; I2= 0.0%,P = 0.7322) (Supplementary Figure 1E) and decreased PD rate OR = 0.600, 95% CI: 0.43–0.83,P = 0.0022; I2= 0.0%,P = 0.9188) (Supplementary Figure 1D). However, no significant association between the emphysema and CR OR = 1.588, 95% CI: 0.31–7.90,P = 0.5800) (Supplementary Figure 1F), SD OR = 1.099, 95% CI: 0.72–1.65,P = 0.6788) (Supplementary Figure 1G) or ORR OR = 1.555, 95% CI: 0.58–4.15,P = 0.3800) (Supplementary Figure 1H) was observed (Table 2).

Impact of Emphysema on the Secondary Outcome Among ICIs Treated NSCLC Patients
Seven studies explored the relationship between the presence of emphysema and risk of ICIP.15,16,18–22 Pooled results manifested that emphysema was significantly associated with increased incidence of ICIP (OR = 1.32, 95% CI: 1.15–1.53, P < 0.001; I2= 46.3%, P = 0.083; Figure 2).

Sensitivity Analysis and Publication Bias
Sensitivity analysis for the ICIP was performed (Figure 3), which manifested that our results were stable and none of included studies had an obvious impact on the overall findings. Furthermore, according to the Begg’s funnel plot (Figure 4) and Egger’s test (P = 0.111), no significant publication bias was observed.

Discussion
This meta-analysis demonstrated that the presence of emphysema was associated with improved therapeutic efficacy among NSCLC patients who received ICIs but was related to increased risk for ICIP. Therefore, CT-defined emphysema might serve as a prognostic indicator for the prediction of efficacy and ICIP among this group of patients.
The improved efficacy of ICIs in NSCLC patients with emphysema may be related to several mechanisms. Emphysema is typically caused by long-term smoking and chronic inflammation. This chronic inflammatory state leads to the persistent activation and accumulation of immune cells, such as macrophages, T cells, and dendritic cells, within lung tissue. These changes may promote specific alterations in the tumor immune microenvironment, including increased PD-L1 expression and higher CD8⁺ T-cell infiltration, which can enhance anti-tumor immune responses and sensitivity to ICI therapy.24 Smoking is a common risk factor for both emphysema and NSCLC. Prolonged smoking can cause the accumulation of genetic mutations, resulting in an increased TMB. A high TMB generates more neoantigens, making tumor cells more easily recognized and attacked by the immune system, thereby enhancing the therapeutic efficacy of ICIs.25 Some studies have suggested that chronic inflammation may lead to the upregulation of PD-L1 expression in tumor tissues. High PD-L1 expression is associated with better responses to ICIs, which may allow NSCLC patients with emphysema to benefit more from PD-1/PD-L1 inhibitors.25 Additionally, emphysema patients may exhibit higher infiltration of immune cells, such as CD8+ T cells and macrophages, in lung tissue. This immune-activated state can further enhance the anti-tumor effects of ICIs.16 Emphysema may also lead to structural damage and vascular remodeling in localized lung tissue, potentially affecting the hypoxic state of the tumor microenvironment. Hypoxia can suppress immune cell activity, but the microenvironmental changes induced by emphysema may alleviate hypoxia, thereby improving the efficacy of ICIs.24
On the other hand, NSCLC patients with emphysema are more prone to developing ICIP after receiving ICI therapy. Emphysema causes alveolar wall destruction and reduced lung elasticity, making the lung tissue more fragile. This structural damage lowers the lung’s ability to tolerate immune-mediated inflammation, increasing the risk of irP.26 Chronic inflammation in emphysema leads to the persistent activation of immune cells. ICIs further enhance immune responses by lifting immune suppression, which can result in excessive immune activation and lung tissue damage.27 Emphysema changes the lung’s immune microenvironment, increasing pro-inflammatory cytokines and chemokines. This inflammatory setting may amplify immune responses after ICIs treatment, leading to pneumonitis.28 Damaged lung tissue in emphysema has a reduced capacity for repair. When immune cells become overactive due to ICIs, the lungs cannot effectively recover, making inflammation more severe. Emphysema-induced hypoxia can activate pathways like HIF-1α, which may intensify immune responses. ICIs may worsen this effect, promoting lung inflammation.24
Actually, there are many fields worth further exploration regarding the impact of emphysema on the efficacy and adverse effects of ICIs in NSCLC patients. For example, the relationship between the severity of emphysema (mild, moderate, severe) and ICI efficacy, as well as the risk of ICIP could be investigated. Quantitative CT imaging techniques can be utilized to assess the extent and severity of emphysema, providing insights into its predictive value for treatment response and adverse reactions. It is also necessary to analyze the impact of different types of emphysema (such as centrilobular, paraseptal, or mixed types) on ICI efficacy and ICIP incidence to determine whether different emphysema subtypes exhibit distinct clinical outcomes and risks. By analyzing the characteristics of immune cell infiltration, PD-L1 expression, TMB, and cytokine levels in the TME of emphysema patients, the potential mechanisms influencing ICI efficacy and ICIP risk can be elucidated. Additionally, exploring emphysema-related genetic mutations (such as TP53 and KRAS mutations) and inflammatory markers (such as IL-6 and TNF-α) for their predictive roles in ICI efficacy and ICIP risk may help identify molecular targets for precision therapy.
CT-defined emphysema may serve as a stratification biomarker in precision oncology. Identifying patients with emphysema could help tailor ICI therapy, guide proactive monitoring for pneumonitis, and improve trial design by accounting for differential efficacy and toxicity profiles. Moreover, the consistency between our findings and those of previous analyses further strengthens the evidence that CT-defined emphysema may serve as a clinically meaningful prognostic marker for predicting ICI efficacy and identifying patients at elevated risk of pneumonitis or other irAEs. These converging results highlight the importance of conducting prospective studies to validate emphysema-based risk stratification and to determine whether early monitoring or prophylactic strategies are warranted in this high-risk population.
However, there are several limitations in this meta-analysis. First, since all included studies were conducted in East Asian populations, caution is needed when generalizing the findings to other ethnic or geographic populations. Second, due to the lack of original data, we are unable to perform more detailed analysis to further identify the impact of emphysema among patients with different clinical characteristics such as age, smoking history and pulmonary comorbidities. Third, only two or three studies investigating the impact of emphysema on primary outcomes. Thus, more studies are still needed to verify our findings. Four, the definition methods for emphysema differed in included studies, which may cause some bias. Five, in addition to the limitations previously noted, all included studies were retrospective in nature, with variability in treatment lines and follow-up durations across studies. These factors may contribute to heterogeneity and should be considered when interpreting the results.

Conclusion
CT-defined emphysema is associated with better therapeutic efficacy with longer PFS and OS, but increased risk of ICIP among NSCLC patients receiving ICIs based on current available evidence. These findings highlight the potential utility of incorporating emphysema assessment into clinical decision-making and risk stratification, which may help guide personalized immunotherapy strategies. However, as most included studies were conducted in East Asian populations and were retrospective in nature, the generalizability of these results is limited, and further prospective studies in diverse cohorts are needed to confirm these findings.