A narrative review of the early diagnosis and treatment of idiopathic pulmonary fibrosis with lung cancer

Introduction

Idiopathic pulmonary fibrosis (IPF), a chronic progressive interstitial lung disease (ILD) of undetermined etiology and pathogenesis, manifests as progressive interstitial pulmonary scarring with characteristic histopathological patterns and radiologic evidence of usual interstitial pneumonia (UIP) on high-resolution computed tomography (HRCT) imaging (1). Epidemiologic data indicate a global IPF incidence ranging from 0.09–1.30 per 10,000 population (2), with annual increases potentially attributable to multiple risk factors including tobacco exposure, microbial infections, chronic microaspiration, thoracic surgical interventions, environmental pollutants, and population aging trends (3). This epidemiologic pattern correlates with heightened cancer susceptibility, as IPF patients exhibit a 2.7%–48% lifetime risk of lung cancer (LC) development—five-fold greater than the general population (4) and 1.5 times higher than chronic obstructive pulmonary disease (COPD) cohorts (5). Notably, patients with IPF undergoing single-lung transplantation face a significantly elevated risk of developing primary LC in the native lung post-transplantation (6). Longitudinal Korean cohort data reveal cumulative LC incidence rates of 1.7%, 4.7%, and 7.0% at 1-, 3-, and 5-year post-IPF diagnosis respectively in initially cancer-free patients (7).

The pathophysiological convergence between IPF and LC, encompassing shared risk factors and molecular pathways underlying tissue remodeling and malignant transformation, likely drives this clinical association. Epidemiologic studies have identified significant overlap in risk profiles between IPF and LC, with shared predisposing factors including tobacco use, male gender, advanced age, and occupational/environmental exposures. Notably, smoking history, male sex, elderly status, elevated NO₂ exposure, and concomitant emphysema emerge as potent predictors of LC development in IPF populations (3,8). Crucially, IPF itself constitutes an independent oncogenic risk factor, with accumulating evidence suggesting that IPF satisfies all five National Cancer Institute criteria for precancerous conditions (9). While the median survival from IPF diagnosis to respiratory failure typically spans 2–4 years, Korean population data demonstrate a substantially shorter median interval of 16.3 months from IPF diagnosis to LC detection (7). Mortality analyses reveal particularly grim outcomes for IPF-LC patients, with retrospective studies documenting all-cause mortality rates of 53.3%, 78.6%, and 92.9% at 1-, 3-, and 5-year post-LC diagnosis respectively (10). Although the introduction of antifibrotics (pirfenidone/nintedanib) has modestly improved IPF prognosis and may reduce LC incidence, substantial clinical uncertainty persists regarding optimal therapeutic integration—particularly concerning the safety and efficacy of combining antifibrotic agents with oncologic therapies (targeted agents, immunotherapies, radiotherapy) in IPF-LC patients.

For these reasons, research interest in IPF-LC has intensified in recent years, with current investigations focusing on identifying shared molecular pathways between IPF and LC while exploring novel biomarkers. These efforts aim to facilitate early diagnosis and uncover potential therapeutic targets for IPF-LC. In this review, we aim to systematically summarize current diagnostic biomarkers and therapeutic advancements for IPF-LC, with the ultimate goal of providing clinical insights that may enhance prognostic outcomes and survival rates in affected patients. We present this article in accordance with the Narrative Review reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1254/rc).

Methods

This narrative review synthesizes evidence from previously published articles identified through a systematic search on PubMed. The search terms included “idiopathic pulmonary fibrosis”, “lung cancer”, “early diagnosis” and “biomarkers”. Articles published in English between 2006 and August 2025 were comprehensively evaluated. Relevant studies were selected to elucidate advancements in the early diagnosis and therapeutic management of IPF-LC comorbidity. The search strategy is detailed in Table 1, and all included articles are cataloged in the reference list.

Diagnosis

Diagnosis of IPF-LC necessitates comprehensive evaluation of both IPF and LC components. For IPF diagnosis, current diagnostic criteria must be satisfied alongside pulmonary function assessments and screening for prevalent comorbidities/complications. LC diagnosis requires fulfillment of established LC diagnostic criteria complemented by molecular profiling and systemic metastasis evaluation beyond standard pathological confirmation. Current academic consensus emphasizes multidisciplinary team (MDT) consultation as the diagnostic gold standard for moderate IPF and IPF-LC cases (11). To ensure precise clinical assessment, collaborative diagnostic evaluations should involve ILD specialists, thoracic oncologists, radiologists, and pathologists, each contributing expertise in their respective domains during the diagnostic workup of IPF-LC patients.

HRCT plays a pivotal role in monitoring IPF progression, with current guidelines strongly recommending annual HRCT screening for IPF patients to facilitate early LC detection. However, a physician practice survey revealed concerning implementation gaps: 29.1% of clinicians restricted HRCT scans to symptomatic IPF cases, while 17.6% completely omitted routine screening (11). These findings underscore persistent knowledge-practice disparities regarding the elevated LC risk in IPF populations, highlighting the need for enhanced awareness among both healthcare providers and patients. LC lesions in patients with IPF predominantly manifest within fibrotic regions characterized by subpleural reticulations and honeycombing, necessitating vigilant surveillance when new pulmonary nodules emerge on chest computed tomography (CT) imaging, particularly peripheral solid nodules (12). For nodules <8 mm in diameter, serial CT monitoring at 3- to 6-month intervals is advised. Progression on follow-up CT or baseline nodules ≥8 mm warrants positron emission tomography-computed tomography (PET-CT) evaluation. Negative PET uptake cases require continued CT surveillance or consideration of minimally invasive biopsy techniques, including CT-guided transthoracic needle biopsy (TTNB) or endobronchial ultrasound-guided procedures.

TTNB carries inherent risks including hemoptysis, pneumothorax, and potential acute exacerbation of IPF (AE-IPF). Elevated complication risks correlate with specific parameters: nodule diameter >3 cm, lesion depth >1 cm from pleural surface, traversed biopsy path containing honeycombing/emphysema, and procedural duration exceeding 20 minutes. These risk factors demand meticulous procedural planning and operator vigilance.

PET-positive cases (moderate-to-intense uptake) should prompt consideration of surgical biopsy or resection, though such interventions may exacerbate IPF progression and potentially trigger AE-IPF, particularly in advanced disease stages (13). For biopsy-ineligible patients, multidisciplinary consensus evaluation is essential for clinical diagnosis formulation and therapeutic strategy optimization.

The identification of biomarkers constitutes a pivotal advancement in developing personalized diagnostic and therapeutic strategies for IPF-LC. Biomarker discovery holds significant potential to: identify at-risk populations, enhance early detection rates, facilitate timely therapeutic interventions, prognosticate disease course, optimize treatment selection, and monitor therapeutic responses—collectively improving patient survival outcomes. While LC therapeutics has witnessed substantial biomarker-driven progress, current applications predominantly focus on treatment stratification (14).

Emerging biomarker research explores serum profiles, bronchoalveolar lavage fluid (BALF) components, and genetic signatures for IPF-LC detection (15-20). Prominent serum biomarkers under investigation comprise carcinoembryonic antigen (CEA), cytokeratin 19 fragment (CYFRA 21-1), and squamous cell carcinoma antigen for non-small cell lung cancer (NSCLC), alongside pro-gastrin-releasing peptide and neuron-specific enolase (NSE) in small cell lung cancer (SCLC) contexts. Circulating microRNAs demonstrate diagnostic potential through serum detection, though clinical validation remains pending (21). Concurrently, biomarkers correlating with IPF progression and poor prognosis may synergistically enhance IPF-LC detection when combined with oncological markers.

Although pulmonary function testing remains the gold standard for monitoring IPF progression, recent advances in biomarker development enable prognostic prediction through molecular signatures (22). The integration of biomarker profiling with radiologic surveillance presents a promising paradigm for improving early diagnosis of LC comorbidities in IPF patients.

This article focuses on several types of biomarkers associated with IPF.

Hematologic biomarkers

Surfactant protein A (SP-A) is a critical component of the pulmonary surfactant system, essential for maintaining pulmonary homeostasis and alveolar integrity. In humans, SP-A is encoded by two highly homologous genes, SFTPA1 and SFTPA2. Heterozygous mutations in exon 6 of these genes—which encodes the carbohydrate recognition domain (CRD)—contribute to the development of fibrotic ILDs in young adults, potentially as early as childhood, and confer an increased risk of LC. Genetic screening for SFTPA1 and SFTPA2 mutations should be considered in patients with familial ILD, particularly those with early-onset disease (before age 50 years), absence of telomerase complex gene mutations, and/or a personal or family history of LC. Due to the incomplete penetrance of these mutations and the associated risks, familial genetic screening should also be offered to siblings and other relatives, including asymptomatic adult family members (23,24).

KL-6, a high-molecular-weight glycoprotein expressed on type II pneumocytes, was initially studied in non-IPF ILDs, but has since been recognized as elevated in IPF. Elevated serum KL-6 levels in IPF patients, particularly those with lung complications (IPF-LC), hold significant prognostic value for disease progression (25). Longitudinal monitoring during 24-month nintedanib therapy revealed stabilization of both pulmonary function and serum KL-6 levels in most patients (26).

Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are key regulators of extracellular matrix (ECM) remodeling in the lung. Extensive studies have investigated the biomarker potential of MMP and TIMP profiles in the pathogenesis and progression of IPF (27-29). Elevated circulating levels of specific MMP/TIMP family members correlate significantly with disease severity and prognostic outcomes (30). Notably, MMP-7 has emerged as a multifunctional mediator in IPF pathophysiology, extending beyond its diagnostic utility (31).

Vascular endothelial growth factor (VEGF), a glycoprotein predominantly expressed in alveolar epithelial cells, has been implicated in IPF pathogenesis, with clinical studies demonstrating elevated circulating VEGF levels that correlate with disease severity. Notably, circulating serum VEGF concentrations were found to be comparable between severe hypoxemic IPF patients and those with non-small cell LC (32). Survival analysis identified a significant prognostic threshold, wherein VEGF levels exceeding 207 pg/mL were associated with reduced 5-year survival rates (33).

CC-motif chemokine ligand 18 (CCL18), mainly secreted by alveolar macrophages, plays a key role in pulmonary fibrosis development and promotion of LC metastasis. Pirfenidone can inhibit its macrophage-derived generation (34,35). In IPF, circulating CCL18 is consistently elevated and inversely correlates with pulmonary function parameters, particularly total lung capacity (TLC) and diffusing capacity for carbon monoxide (DLCO) (36). Prognostically, a multicenter prospective study identified serum CCL18 concentrations above 150 ng/mL as an independent predictor of mortality in IPF patients (37).

Interleukin-8 (IL-8), a neutrophil-specific chemokine, is consistently elevated in the serum of IPF patients and demonstrates an inverse correlation with survival outcomes, where higher levels are associated with reduced survival probability (38). S100A12, a calcium-binding protein secreted primarily by neutrophils, promotes inflammation through chemotaxis and is increasingly recognized in IPF pathophysiology; elevated circulating S100A12 levels correlate with disease severity and prognosis, supporting its role as a mechanistically relevant biomarker (39). Pro-collagen III N-terminal peptide (PIIINP), a byproduct of type III collagen synthesis, shows increased circulating concentrations that correlate with fibrotic burden and disease progression in IPF, serving as a noninvasive indicator of active pulmonary fibrosis (40).

Galectin-3 (Gal-3), a multifunctional protein involved in inflammatory responses and tissue remodeling, has been proposed as a circulating biomarker in IPF pathogenesis. Elevated Gal-3 levels show significant associations with radiographic interstitial lung abnormalities and restrictive ventilatory defects, reflected by reduced lung volumes and impaired gas exchange (41). Clinical studies further identify serum Gal-3 as a prognostic indicator, with higher levels correlating with increased disease severity and poorer clinical outcomes in IPF and LC patients (42,43).

C1q, primarily produced by macrophages and dendritic cells, initiates the classical complement cascade and plays a dual role in pulmonary fibrogenesis by directly contributing to fibrosis initiation/progression and facilitating neoplastic transformation through mediating malignant proliferation, migration, and pro-angiogenic/metastatic pathways in cancer cells (44). Bioinformatics studies underscore the prognostic value of C1q overexpression in both NSCLC and IPF, with particular clinical relevance in adenocarcinoma outcomes. However, the precise pathophysiological thresholds and therapeutic implications of C1q dysregulation require further experimental validation (44).

Diverse molecular entities—including heat shock protein 70 (HSP70), Fibulin-1, circulating leptin, microRNAs, as well as previously described biomarkers such as Gal-3 and HE4—have emerged as candidate biomarkers in IPF and LC pathogenesis (22,45-49). However, their clinical utility for diagnostic stratification and prognostic prediction requires further validation through large-scale multicenter longitudinal studies.

Biomarkers in exhaled breath and sputum

Volatile organic compounds (VOCs), a group of carbon-containing chemicals detectable in exhaled breath, serve as potential biomarkers reflecting physiological and metabolic alterations in human organisms (50). Specifically, distinct pathophysiological states modify characteristic biochemical pathways, resulting in disease-specific VOC signatures or quantitative variations in compound concentrations. Consequently, VOC profile alterations demonstrate significant potential as non-invasive diagnostic tools for respiratory disease detection, progression monitoring, and therapeutic management through exhaled breath analysis (51).

Nitric oxide (NO), an endogenous gaseous mediator, plays critical regulatory roles in multiple physiological pathways. This signaling molecule is constitutively synthesized by vascular endothelial cells and respiratory epithelium through distinct isoforms of nitric oxide synthase (NOS). Clinical investigations have demonstrated elevated fractional concentrations of exhaled NO (FeNO) in IPF patients compared to healthy controls, showing significant correlations with disease severity, functional lung impairment, and radiological progression. These pathophysiological associations position FeNO quantification as a promising non-invasive modality for longitudinal monitoring of IPF progression and therapeutic responsiveness (52).

Oxidative stress constitutes a key pathophysiological mechanism underlying pulmonary fibrogenesis, with hydrogen peroxide (H₂O₂) and 8-isoprostane representing quantifiable byproducts of lipid peroxidation cascades in IPF pathogenesis. Specifically, elevated concentrations of both biomarkers have been documented in exhaled breath condensate from IPF cohorts (53), while 8-isoprostane elevation demonstrates broader diagnostic relevance across fibrotic ILD subtypes. Notably, the inverse correlation between exhaled H₂O₂ levels and DLCO provides mechanistic insights into disease progression patterns. Such biomarker signatures hold promise for non-invasive longitudinal monitoring of fibrotic activity and therapeutic modulation in IPF management. IPF patients demonstrate significant sputum neutrophilia, eosinophilia, and elevated macrophage/epithelial cell counts compared to healthy controls. Comparative analyses of sputum cellular composition and transcriptomic signatures across IPF, COPD, and healthy populations reveal disease-specific biomarker profiles with diagnostic discriminative capacity and prognostic implications (54). Furthermore, emerging research identifies sputum-derived exosomal miRNAs in IPF as novel diagnostic biomarkers with capacity to stratify disease severity (55).

Exhaled breath and sputum-derived biomarkers present promising non-invasive biomonitoring platforms for prognostic evaluation and therapeutic response assessment in IPF-associated lung complications. These methodologies demonstrate enhanced safety profiles and operational efficiency compared to conventional invasive approaches, effectively minimizing procedural risks while maintaining diagnostic reproducibility. Early-phase detection of IPF-specific exhaled/sputum biomarker signatures enables proactive clinical intervention strategies that may positively influence disease trajectories. However, translational implementation requires rigorous multicenter validation through standardized protocols to establish analytical robustness, inter-center reproducibility, and clinical correlation validity. Operational standardization across diverse populations remains imperative for transforming these biomarkers into reliable diagnostic-prognostic tools in respiratory oncology practice.

Imaging biomarkers

HRCT remains the cornerstone for IPF diagnosis and serves as a prognostic biomarker for disease progression. Multiple semi-quantitative HRCT scoring systems, including the Wells score (grading fibrosis severity from 0–4 based on lung involvement), Goh score (quantifying honeycombing, reticular patterns, and ground-glass opacities), and Composite Physiologic Index (CPI) integrating imaging with pulmonary function metrics (56), have been developed to evaluate fibrotic burden. These systems demonstrate strong correlations with disease progression and mortality outcomes. However, inherent limitations persist in semi-quantitative HRCT analysis: susceptibility to inter-observer variability, limited reproducibility, poor sensitivity for detecting subtle short-term changes, time-intensive evaluation processes, and dependence on specialized multidisciplinary expertise for accurate interpretation (57).

Quantitative computed tomography (QCT) employs computer-aided image analysis of HRCT scans to deliver diagnostic support and objective disease quantification. Advanced methodologies include texture-based techniques that utilize pixel distribution analysis to quantify parenchymal heterogeneity, lung densitometry employing histogram-based density measurements (58,59), and emerging deep-learning algorithms for pattern recognition (57). While QCT effectively mitigates the subjectivity inherent in traditional scoring systems, implementation challenges persist regarding standardized data governance, secure information sharing protocols, and ethical maintenance of patient confidentiality.

In conclusion, IPF-LC diagnosis necessitates integrated evaluation of both interstitial and neoplastic components through MDT collaboration, synthesizing radiological, histopathological, genomic, and clinical evidence. For IPF patients or those with suspected IPF-LC, implementation of annual or biennial surveillance HRCT with protocolized follow-up enables timely detection, while serial imaging findings guide subsequent diagnostic and therapeutic pathways. Emerging biomarkers exhibit promising utility for early detection and outcome prediction in IPF-LC, though rigorous validation through multicenter, diverse cohort studies remains essential to establish clinical validity, analytical reliability, and cross-population generalizability.

Treatments

Similar to its diagnostic approach, the management of IPF-LC requires comprehensive consideration of both IPF and LC therapeutics, integrating disease progression dynamics (including IPF severity and progression rate) with oncological characteristics (tumor stage and histopathological subtype), while accounting for patients’ overall health status and therapeutic preferences. Through MDT evaluation, clinicians should formulate individualized treatment strategies based on these multidimensional parameters. Nevertheless, current clinical practice faces two significant challenges: the absence of prospective randomized controlled trials specifically targeting IPF-LC populations, and the exclusion of such patients from major multicenter clinical investigations on IPF therapeutics. These evidence gaps have resulted in undefined clinical guidelines regarding antitumor therapy selection for IPF-LC cases, rendering optimal treatment modality determination an ongoing area of clinical investigation.

Surgical and interventional treatments

Surgical intervention remains the primary therapeutic approach for early-stage LC; however, IPF-LC patients face elevated risks of postoperative AE-IPF and mortality. The progressive pulmonary functional deterioration inherent to IPF frequently precludes conventional LC therapies in comorbid cases. A cohort study involving 46 lobectomy patients with IPF-LC (pathologic stages Ia–IIIa) documented postoperative AE-IPF in 4 cases (8.7%), with 75% mortality (3/4) from respiratory failure, demonstrating significantly poorer survival outcomes compared to non-IPF cohorts (60). Another retrospective cohort study involving 32 IPF-LC patients reported an incidence of AE-IPF of 15.6% in IPF-LC patients (61). Analysis of 870 LC patients revealed a 7.1% (4/56) incidence of postoperative acute exacerbation among those with IPF, with acute respiratory distress syndrome occurring significantly more frequently in the IPF cohort than in the non-IPF group (7.1% vs. 0.9%, P=0.004). A separate study of 28 stage IA NSCLC patients with IPF similarly reported a 10.7% incidence of postoperative acute exacerbation (62).

This underscores the critical need for optimized patient selection criteria. Prognostic stratification using GAP staging (incorporating gender, age, and pulmonary physiological parameters) revealed differential surgical outcomes: GAP stage I patients derived significant survival benefits from surgery, whereas stages II/III showed no therapeutic advantage (63). Surgical candidacy should therefore prioritize GAP stage I patients while cautiously evaluating advanced-stage cases against tumor characteristics and functional reserves. Emerging evidence suggests a positive correlation between resection extent and AE-IPF risk, with wedge resections demonstrating substantially lower complication rates versus more extensive procedures (segmental resection, lobectomy, pneumonectomy) in multicenter analyses (64). Prophylactic perioperative strategies, particularly pirfenidone administration, have shown efficacy in mitigating postoperative AE-IPF incidence (65). While surgery remains viable for early-stage IPF-LC, clinical decision-making requires meticulous evaluation of AE-IPF risk profiles, oncological recurrence probabilities, and optimal surgical extent through comprehensive preoperative assessment.

Minimally invasive ablation techniques have emerged as promising non-surgical alternatives for LC management, particularly relevant for IPF-LC cases. These modalities employ thermal energy (radiofrequency or microwave-induced tissue ionization) to achieve tumor coagulative necrosis through percutaneous or bronchoscopic approaches. A comparative analysis of CT-guided microwave ablation in stage I NSCLC patients with versus without IPF demonstrated comparable post-procedural complication rates, though the investigation omitted critical endpoints including AE-IPF incidence and ablation-related mortality (66). Subsequent research specifically evaluating IPF-LC cohorts undergoing microwave ablation reported zero perioperative or 30-day mortality, with preserved pulmonary function parameters post-intervention, demonstrating favorable procedural safety profiles (67). Emerging evidence positions image-guided percutaneous ablation and bronchoscopic thermal therapy as viable options for early-stage IPF-LC management, particularly for patients with compromised surgical candidacy. The potential synergy between localized tumor control and pulmonary parenchymal preservation in fibrotic lungs warrants rigorous investigation through prospective trials assessing long-term oncological outcomes and IPF progression dynamics.

Medication

Chemotherapy

Chemotherapy remains a cornerstone systemic treatment for advanced and unresectable LCs, including IPF-associated LC. However, the compromised pulmonary function in IPF-LC patients increases susceptibility to severe chemotherapy-induced complications such as hypoxemia and respiratory failure. Notably, chemotherapy elevates AE risk in IPF-LC patients to 10–30% (63), substantially exceeding the baseline AE risk in IPF progression. This necessitates meticulous selection of chemotherapeutic agents with minimal fibrogenic potential. The carboplatin-paclitaxel combination, while established as first-line therapy for ILD-associated NSCLC (68), carries risks of paclitaxel-induced ILD exacerbation (69). Emerging evidence from a Japanese phase II multicenter trial suggests carboplatin combined with nanoparticle albumin-bound paclitaxel may offer reduced ILD exacerbation risk (70), positioning this regimen as a preferable first-line option for ILD-NSCLC. The therapeutic intersection between fibrotic and oncogenic pathways supports the dual role of approved antifibrotics pirfenidone and nintedanib. Preclinical rationale and clinical investigations are exploring their synergistic potential with chemotherapeutics. Pirfenidone demonstrates compatibility with immune checkpoint inhibitors and carboplatin-based regimens, potentially mitigating chemotherapy-associated AEIPF risks in IPF-NSCLC patients (71). Similarly, nintedanib combined with carboplatin/albumin-bound paclitaxel improves survival outcomes in IPF-NSCLC (72), while its combination with carboplatin-etoposide shows promising efficacy in IPF-SCLC, emerging as a potential standard therapeutic approach for this population (73).

Targeted therapy

While small molecule targeted therapies for IPF-LC with gene mutations carry risks of drug-induced interstitial pneumonitis and AE-IPF, their administration remains viable under rigorous monitoring when actionable mutations are identified. Antiangiogenic agents demonstrate dual therapeutic potential by targeting tumor vasculature to suppress neovascularization and malignant progression, with clinical evidence supporting their prognostic benefits in advanced ILD-LC (74). Nintedanib, an anti-angiogenic agent targeting VEGF, has been proven to have anti-cancer and anti-pulmonary fibrosis effects and reduce AE-ILD in patients with IPF (74). Experimental studies using IPF-LC murine models revealed amlotinib’s multifactorial efficacy: improved pulmonary function (FEV1 increased by 38%), reduced lung collagen deposition (45% decrease), and suppressed tumor growth (67% volume reduction). Western blot and immunohistochemical analyses confirmed significant downregulation of fibrotic markers (α-SMA, collagen I, fibronectin) and tumor proliferation markers (PCNA), alongside decreased serum CEA levels (75). Emerging research highlights tyrosine kinase inhibitors (TKIs) including gefitinib, erlotinib, and afatinib as potential dual-target agents for IPF and oncological management (76). Despite their established efficacy in NSCLC, the documented risks of TKI-associated ILD (incidence 2.3–4.5%) and acute exacerbation of ILD (AE-ILD) necessitate cautious implementation in ILD-LC patients, requiring comprehensive risk-benefit assessment and pulmonary surveillance (77,78).

Immunotherapy treatment

Current immunotherapy for LC predominantly utilizes immune checkpoint inhibitors, particularly PD-1/PD-L1 inhibitors such as nivolumab and pembrolizumab, which have demonstrated substantial survival benefits in advanced disease (79). Preclinical investigations suggest these agents may attenuate pulmonary fibrosis progression, though clinical validation remains limited (80). Patients with LC and pre-existing ILD (LC-ILD) exhibit higher rates of checkpoint inhibitor-related pneumonitis (CIP) than those without ILD. Meta-analysis data reveal CIP incidence of 27% (95% CI: 17–37%) for all-grade and 15% (95% CI: 9–22%) for grade ≥3 CIP in LC-ILD patients, compared to 10% (95% CI: 6–13%) and 4% (95% CI: 2–6%), respectively, in those with LC alone. LC-ILD patients showed significantly elevated incidence of both all-grade and grade ≥3 CIP (81). A phase II trial evaluating nivolumab in idiopathic interstitial pneumonia-NSCLC cohorts reported pneumonitis incidence of 11% (2/18), all responsive to corticosteroid therapy, alongside promising efficacy metrics: 56% 6-month progression-free survival, 39% objective response rate, and 72% disease control rate with no treatment-related fatalities (82,83). These findings position PD-1/PD-L1 inhibitors as viable options for mild IPF-LC cases, notwithstanding their inherent risk of CIP. Crucially, CIP demonstrates superior responsiveness to corticosteroid regimens (78% response rate) and lower mortality (12% vs. 23%) compared to TKI-associated pneumonitis (84,85).

The role of antifibrotic therapy in IPF-LC

A multicenter retrospective study of 345 IPF patients demonstrated significantly lower prevalence of LC and reduced LC-related mortality in those receiving antifibrotic therapy compared to untreated counterparts (86), suggesting potential preventive benefits against LC development in IPF. Pirfenidone and nintedanib remain the only approved antifibrotic agents, with their antitumor potential hypothetically linked to shared pathogenic pathways between IPF and LC. As a multi-target TKI, nintedanib acts on vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR). Initially developed as an anticancer agent for its antiangiogenic properties, subsequent discovery of antifibrotic effects led to its approval for IPF management (87). Beyond reducing acute exacerbation risk in IPF, nintedanib demonstrates protective effects against chemotherapy-associated AE-IPF in IPF-LC patients (73,88).

Current research on nintedanib in IPF-LC primarily explores its combination with chemotherapeutic regimens, showing promising therapeutic outcomes (72,73). Pirfenidone exerts antifibrotic effects through TGF-β signaling downregulation, fibroblast proliferation inhibition, and collagen synthesis suppression. In a large-scale study of 10,084 IPF patients, pirfenidone treatment correlated with reduced LC incidence (10.4 vs. 27.9 cases/1,000 person-years) (89), indicating potential LC risk mitigation. Furthermore, combining pirfenidone with chemotherapy in IPF-LC patients may lower chemotherapy-induced AE-IPF risk (71). Emerging evidence highlights pirfenidone’s synergistic effects with PD-L1 inhibitors, enhancing antitumor immunity and improving immunotherapy efficacy, particularly in LC patients with preexisting IPF (90). Both pirfenidone and nintedanib exhibit substantial therapeutic potential for IPF-LC management, warranting further clinical investigation to optimize treatment strategies.

Radiotherapy

Radiotherapy modalities include conventional radiotherapy, stereotactic body radiotherapy (SBRT), proton therapy, and carbon ion therapy. Radiotherapy remains crucial for managing unresectable LC, though its application in IPF-LC requires cautious consideration given the heightened risks of severe radiation pneumonitis (RP) and AE-ILD (91). Clinical evidence indicates that coexisting IPF substantially increases post-radiotherapy complication risks (92). For inoperable stage I/II NSCLC patients, SBRT is associated with a lower incidence of RP compared to conventional radiotherapy, making it as an important treatment choice for non-surgical patients with early-stage disease (93). A retrospective study following carbon ion therapy for NSCLC showed that the incidence of RP in patients with ILD was not significantly different from that in patients without ILD (94). The principal advantage of proton therapy is its reduced scatter radiation, making it particularly advantageous for early-stage and central-type LCs. Some studies suggest that proton therapy demonstrates favorable efficacy with low toxicity and minimal pulmonary damage in IPF-LC (95). For IPF-LC patients requiring thoracic irradiation, stringent patient selection criteria must be implemented, with treatment planning incorporating rigorous lung dose-volume constraints and comprehensive risk-benefit evaluation through detailed informed consent processes.

Conclusions

The coexistence of IPF-LC demonstrates elevated morbidity attributable to shared risk factors and molecular pathways, carrying an exceptionally poor prognosis. Annual HRCT surveillance is mandatory for IPF patients, preferably supplemented by biomarker profiling and multidisciplinary diagnostic integration to facilitate early IPF-LC detection. Current therapeutic evidence highlights antifibrotic agents’ dual capacity to modulate fibrotic progression and exert antitumor activity, potentially reducing LC incidence while enhancing chemotherapy and immunotherapy safety profiles. Surgical interventions necessitate rigorous patient selection to prevent postoperative AE-IPF, with minimally invasive ablation techniques and proton therapy emerging as viable alternatives for inoperable cases. Future research priorities include elucidating IPF-LC pathogenic cross-talk, validating multimodal biomarker panels, developing targeted-immunotherapy combinations, and optimizing antifibrotic therapeutic protocols. Concurrent advancement in AI-driven imaging genomics and real-world data analytics promises to establish precision medicine frameworks, ultimately improving survival outcomes in this vulnerable population.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1254/rc

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1254/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1254/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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