Narrative review of the similarities and differences between immune checkpoint inhibitor- and antibody-drug conjugate-associated pneumonitis

Introduction

Immune checkpoint inhibitors (ICIs) exert antitumor effects by blocking the binding of immune checkpoints to their ligands, thereby relieving the immunosuppression caused by immune checkpoints and reactivating immune cells. The advent of ICIs has transformed the landscape of clinical cancer treatment, providing novel therapeutic options (1). At present, prevalent ICIs include monoclonal antibodies targeting programmed cell death protein 1 (PD-1), programmed cell death ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), with PD-1/PD-L1 inhibitors being the most widely used (2).

In the field of precision cancer therapy, the development of antibody-drug conjugates (ADCs) has attracted increasing research interest. Since the first ADC drug (gemtuzumab ozogamicin) was approved by the United States (US) Food Drug Administration (FDA) in 2009, ADCs have undergone three generations of evolution (3). The technology of the first generation was immature; antibodies and linkers were optimized in the second generation, although certain issues remained; and technologies such as highly potent payloads and cleavable linkers were introduced in the third generation, achieving a “bystander effect” that enables the killing of neighboring tumor cells (4).

Due to the widespread clinical use of ICIs and ADCs, their associated adverse events (AEs) have become a critical concern. The early identification and effective management of AEs directly affect patient prognosis and treatment adherence; thus, the proper management of these AEs is crucial to ensure patient safety. As the combined use of immunotherapy and ADCs becomes more common, research should focus on identifying and differentiating among overlapping AEs (5).

A narrative review on checkpoint inhibitor-associated pneumonitis (CIP) and ADC-associated pneumonitis was thus conducted to clarify the similarities and differences between these two conditions in terms of epidemiological characteristics, pathogenesis, clinical manifestations, and management. It is hoped that the discussion of these AEs will inform clinical practice and future research. We present this article in accordance with the Narrative Review reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0173/rc).

Methods

On September 1, 2025, a targeted literature search was conducted of the PubMed and China National Knowledge Infrastructure databases. The search strategies included key terms related to ADCs, drug-related AEs, pneumonitis, and CIP (the complete search strings can be found in Appendix 1). Studies were selected based on their relevance to pneumonitis associated with ADCs and ICIs. The literature was required to either discuss the association between ADCs or ICIs and related pneumonitis or elucidate the results regarding the clinical management or mechanisms of these drugs. Articles that solely discussed AEs other than pneumonitis or only involved pneumonitis not related to ADCs and ICIs were excluded. The literature search strategy is detailed in Table 1.

This narrative review focuses on the key areas of epidemiological characteristics, pathogenesis, clinical manifestations and management, rechallenge, and future research directions. It further compares these areas to comprehensively reflect the differences between ADC-associated pneumonitis and CIP.

Results

Epidemiological characteristics

Epidemiological characteristics of CIP

ICIs can enhance the body’s antitumor immune response by blocking immune checkpoint proteins (e.g., PD-1, PD-L1, and CTLA-4) and have achieved remarkable results in the treatment of various tumors including melanoma, lung cancer, and renal cell carcinoma. The incidence and mortality of CIP vary by cancer type. One meta-analysis indicated that the incidence rates of all-grade and high-grade CIP following ICI treatment are higher in patients with lung cancer, particularly those with non-small-cell lung cancer (NSCLC) than in those with other malignant tumors (6). For example, in patients receiving monotherapy with nivolumab or pembrolizumab, the incidence of any-grade pneumonitis in NSCLC is 4.1%, significantly higher than that in melanoma (1.6%). However, most studies on this topic did not perform stratified analyses of CIP incidence by tumor type, and robust comparisons across cancer types remain insufficient. Previous studies have reported the all-grade incidence of CIP to be approximately 3–5% (7). Notably, in NSCLC, incidences exceeding 5–10% have been reported when real-world data have been included, providing a more balanced epidemiological perspective (8). The difference may reflect the broader application of ICIs in routine practice and the strict inclusion criteria applied in clinical trials. In terms of mortality, CIP accounts for a significant proportion of fatal immune-related adverse events (irAEs), with anti-PD-1/PD-L1 monotherapy being a prominent contributor (9). Moreover, in a recent study, the median survival time of patients with CIP was shorter than that of the cohort without CIP (428 vs. 1,240 days) (6).

The risk of CIP varies across different ICIs. The incidence of CIP associated with PD-1 inhibitors (3.6% for any grade and 1.1% for high grade) is typically higher than that associated with PD-L1 inhibitors (1.3% for any grade and 0.4% for high grade), which may be related to differences in the mechanisms of action of different ICIs in immune regulation (10). In a multicenter real-world study of 2,031 Chinese patients with lung cancer receiving immunotherapy, the incidence of CIP in Chinese patients with lung cancer was 7.2%, with a severe CIP rate of 2.6% and a fatality rate of 0.4%. This study also revealed that the onset of CIP exhibits a bimodal distribution throughout the treatment course (7). The first peak typically occurs during the initial phase of ICI treatment, appearing within 2 to 3 months of the first dose, which might be related to the drug response during the initial immune system activation phase. The second peak occurs in the late stage of treatment or even months to years after discontinuation, which is potentially related to the long-term activation of the immune system and the role of memory cells.

These findings indicate that the long-term follow up and monitoring of patients receiving ICI treatment are necessary in clinical practice. The onset of CIP also exhibits a seasonal trend, with the autumn and winter seasons being associated with a higher risk. This may be related to the high incidence of respiratory viral and bacterial infections during these seasons, as infections may act as triggers in initiating or exacerbating the occurrence and development of CIP. Enhanced monitoring and preventive measures for patients receiving ICI treatment during peak seasons may help reduce the risk of disease onset (11).

Epidemiological characteristics of ADC-associated pneumonitis

ADCs combine the targeting specificity of monoclonal antibodies with the potency of cytotoxic drugs, enabling the specific identification and killing of tumor cells. Accordingly, their toxicity mechanisms are quite complex. ADC-related pulmonary adverse events (PAEs), particularly interstitial lung disease (ILD) and pneumonitis, have a relatively high overall incidence and are receiving increasing attention. A pooled analysis of 1,277 cases of ADC-related ILD found that the incidence rates of ILD, pneumonitis, and acute respiratory distress syndrome (ARDS) were 40.6%, 27.9%, and 7.6%, respectively (12).

The risk of pneumonitis varies across ADC types due to differences in their targets and payloads. Human epidermal growth factor receptor 2 (HER2)-targeted ADCs carry a higher risk of pneumonitis than do ADCs targeting other antigens (13). For example, trastuzumab deruxtecan (T-DXd) employs a cleavable linker with a highly membrane-permeable payload [deruxtecan (DXd)], which may enhance the bystander effect by releasing cytotoxic drugs in the tumor microenvironment or normal lung tissue. However, evidence on the biological mechanisms underlying its higher risk compared to other target ADCs is limited.

The incidence of ADC-related ILD depends on the cancer being treated. Patients with NSCLC have a higher risk of developing ADC-related ILD when receiving ADCs (14). Approximately 10–15% of patients receiving T-DXd develop ILD within a median time of 5–6 months, with a fatality rate of about 5.8% (calculated based on fatal cases among those who developed ILD). This may be due to the varying levels of HER2 expression in different tumor types and the response of lung tissue to the drugs.

Established risk factors for ADC-related ILD include the prior use of other HER2-targeted ADCs and a history of pre-existing ILD/pneumonitis (13). The peak incidence mostly occurs within the first 3 months of treatment (median 86 days), and the overall incidence is significantly higher than that with control drugs, such as ado-trastuzumab emtansine (T-DM1) (15). In one study, the occurrence of ADC-associated pneumonitis was positively correlated with the drug dosage, and high doses of ADCs increased the incidence of pneumonitis (16).

Real-world data also indicate that the risk of developing pneumonitis increases dramatically as the ADC dosage increases. The incidence of ILD is estimated to be 10–15% in lung cancer treatment. Specifically, the DESTINY-Lung01 trial reported an incidence as high as 26% (17), while the DESTINY-Lung02 trial reported that the incidences of the dose groups differed (5.9% in the 5.4 mg/kg group and 14% in the 6.4 mg/kg group) (18). Thus, the dosage of ADCs should be cautiously adjusted to minimize the risk of pneumonitis while efficacy should be ensured to safeguard patient safety and tolerance to treatment.

Pharmacokinetic and pharmacodynamic models indicate that drug exposure, peak concentration, and dosage are significantly correlated with the occurrence of ILD (18). Additionally, real-world data shows that increased drug exposure (e.g., prolonged or repeated administration) is significantly correlated with an increase in the ILD reporting rate, with the mechanism possibly involving direct damage to lung tissue by the drug or its metabolites (18). The maximum concentration in pharmacokinetics is also significantly correlated with ILD risk, potentially causing acute lung injury or exacerbating inflammatory responses.

Common influencing factors

Comorbidities of chronic pulmonary diseases, such as chronic obstructive pulmonary disease (COPD) and ILD, can markedly increase the risk of pneumonitis during ICI or ADC treatment. These underlying conditions often cause damage to abnormal lung tissue, subsequently leading to changes in the normal structure and function of the lungs. These comorbidities can also result in immune dysfunction, reducing patient tolerance to medications and rendering them more susceptible to pneumonitis during antitumor therapy (19).

Drug dosage is also a critical factor influencing the incidence of pneumonitis. The occurrence of pneumonitis is positively correlated with the dosage, as high-dose ICIs or ADCs may increase the risk of pneumonitis (16). This is likely because, while high-dose medications enhance therapeutic efficacy, they also amplify drug toxicity and potential damage to lung tissue (20).

Environmental and genetic factors also figure prominently in this context. For example, smoking and air pollution can exert long-term negative effects on lung health. Smoking causes chronic inflammation and oxidative stress in lung tissue, heightening the sensitivity to drug toxicity and thereby increasing the probability of pneumonitis. However, these risk factors are still under investigation. Certain genetic factors, such as the polymorphism of human leukocyte antigen alleles, may be associated with the immunogenicity of drugs, which also increases the risk of pneumonitis (21).

ILA has been identified as an independent risk factor for both CIP and T-DXd-associated pneumonitis (22). Given the increasing recognition of ILA in thoracic oncology, the omission of this factor is a significant limitation. Prior radiation-induced lung injury has also been reported as a risk factor (23).

Pathogenesis

Pathogenesis of CIP

The complex pathogenesis of CIP can primarily be attributed to the dysregulation in T-cell activity and proportion, reduction in B-cell count and function, alterations in the inflammatory cytokine profile, and changes in autoantibodies (24). There are two primary explanations for the changes in T-cell activity and ratios during the occurrence of irAEs: tissue-specific antigen theory and neoantigen theory. When ICIs block immune checkpoint proteins, T cells become overactivated and may attack the cross-antigens shared between tumors and normal lung tissue, leading to off-target toxicity, particularly against alveolar epithelial cells and bronchial epithelial cells in the lung tissue. During this process, cytokine storms and the imbalance between T helper 17 (Th17) cells and regulatory T cells (Tregs) may further exacerbate the inflammatory response. Th17-cell proliferation and limited Treg function also contribute to the occurrence of CIP. The interleukin (IL)-17 secreted by Th17 cells can attract neutrophils, thereby promoting the inflammatory response; meanwhile, the inhibition of Treg function weakens the regulatory capacity against inflammation, resulting in the excessive secretion of proinflammatory cytokines such as IL-17 and interferon-gamma (IFN-γ) (25). Overactivated T cells secrete large amounts of proinflammatory cytokines, attracting more immune cells to accumulate in the lungs and triggering a cytokine storm, further exacerbating tissue damage.

A recent study linked the functional defects of regulatory B cells (Bregs) to immunotherapy toxicity, noting that Bregs in patients with toxicity were unable to produce anti-inflammatory cytokines (i.e., interleukin-10) or proinflammatory factors (e.g., IFN-γ and IL-6). In addition, due to the lack of auxiliary naive B cells, T follicular helper cells, which are typically more abundant during autoantibody production in autoimmune diseases, may also be involved in the development of CIP. In summary, the loss and dysfunction of Bregs may lead to changes in downstream immune cells and cytokines, thereby increasing the risk of CIP (26).

The accumulation of the mononuclear phagocytes (MPs) in lung tissue may also promote CIP. These cells enhance antigen presentation via the major histocompatibility complex (MHC) class II pathway, further promoting T-cell activation and thereby creating a vicious cycle (27).

Blockade of the PD-1/PD-L1 pathway results in a significant increase in the infiltration of cluster of differentiation 8 positive (CD8⁺) T cells in lung tissue. These cells directly damage lung cells by releasing perforin and granzymes (25). Perforin creates pores in the cell membrane, while granzymes enter the cells to induce apoptosis; their synergistic action leads to the structural destruction and dysfunction of the lung tissue.

Pathogenesis of ADC-associated pneumonitis

ADC-induced pneumonitis is associated with direct cytotoxic lung injury and immune-mediated lung injury. Four potential mechanisms underlying the pathogenesis of these conditions have been proposed thus far: (I) target-dependent internalization; (II) target-independent internalization; (III) the bystander effect of the payloads; and (IV) toxicity from the payloads released into the bloodstream.

ADCs enter cells via target-dependent internalization, a process that is the key mechanism by which ADCs exert their therapeutic effects (28). In addition to this intended targeting effect, target-independent internalization may also occur, leading to the uptake of ADCs by lung epithelial cells and the subsequent triggering of cytotoxic responses (29). ADCs may be taken up by non-target cells upon contact during their in vivo distribution and metabolism.

The bystander effect is another potential mechanism contributing to ADC-associated pneumonitis (30). When the cytotoxic payloads of an ADC are released outside the target cells, they can diffuse to surrounding healthy lung cells. This bystander effect causes more extensive tissue damage, which is not limited to cells directly expressing the target antigen. T-DXd conjugates the antibody to the cytotoxin DXd via an enzyme-sensitive tetrapeptide-based linker. Following internalization in target cells, the linker is cleaved by lysosomal proteases (e.g., cathepsin B), releasing free DXd. The released DXd has high membrane permeability, allowing it to cross the cell membrane and diffuse into the adjacent tumor microenvironment, thereby killing tumor cells with low or negative HER2 expression—a phenomenon known as the “bystander effect”. This characteristic is one of the core mechanisms that distinguishes T-DXd from other ADCs.

Payloads are a class of small-molecule cytotoxic drugs capable of inducing cell-killing effects. They are crucial for realizing the cytotoxic effects of ADCs against tumor cells. However, the cytotoxic payloads [e.g., microtubule inhibitor monomethyl auristatin E (MMAE) and topoisomerase inhibitors] of ADCs may be released prematurely in the circulation due to linker instability or nonspecific internalization. Microtubule inhibitors exert their effects by causing DNA damage or blocking tubulin synthesis, which then leads to apoptosis. Meanwhile, DNA alkylating agents form irreversible covalent bonds with electron-containing groups in DNA molecules, disrupting processes such as replication and transcription and ultimately leading to cell death (29). These free payloads can accumulate in lung tissue, directly damaging alveolar epithelial cells and vascular endothelial cells, triggering inflammatory responses and interstitial injury (31). For example, in a case of grade 4 pneumonitis associated with tisotumab vedotin (containing the MMAE payload), severe lung injury was caused by the accumulation of payloads in the lung tissue (32).

The activation of the FcγR-SPP1 pathway [Fc gamma receptor (FcγR), osteopontin (SPP1)] is also considered a potential mechanism of ADC-associated pneumonitis. After the drug DXd carried by T-DXd is released in lung tissue, it may be taken up by surrounding healthy cells, leading to DNA damage and cell death; additionally, the activated Fcγ receptors raise the activity of lung fibroblasts and promote collagen deposition via the SPP1 pathway, causing pulmonary fibrosis and aggravating lung injury (33).

Recent research also suggests that immunoglobulin G (IgG) antibodies, non-cleavable linkers, tubulin-binding payloads, and a drug-to-antibody ratio (DAR) greater than 4 are linked to a higher risk of respiratory AEs. Moreover, IgG1 antibodies increase the likelihood of PAEs by 107-fold, and non-cleavable linkers increase the likelihood of PAEs by 3.4-fold. Tubulin-binding payloads reduce the risk of pulmonary toxicity by 86%, while a DAR greater than 4 increases the risk by 1.8- to 2.6-fold (34).

The pathogenesis of ADC-associated pneumonitis is complex and multifaceted, with various mechanisms acting synergistically to cause lung tissue damage and inflammatory responses. Advances in research on ADC-associated pneumonitis are crucial for enabling next-generation ADCs to fully realize their therapeutic potential and reducing serious AEs. Clarifying the relevant mechanisms could facilitate the more rational prediction and control of ADC-associated pneumonitis, which may in turn improve treatment safety and efficacy.

Similarities and differences in pathogenesis

The core driver of CIP is the overactivation of the immune system. After ICIs block immune checkpoint proteins, T cells become abnormally activated and attack lung tissue, causing inflammation. Such abnormal activation of the immune system is systemic and can affect multiple organs and systems (35). Therefore, the key consideration during CIP treatment is the regulation of immune system function and the suppression of excessive immune responses, which may alleviate inflammation and tissue damage. Clinically, immunosuppressants such as glucocorticoids are commonly used to control the condition, as they can inhibit the excessive activation of T cells and inflammatory responses, thereby reducing lung damage.

ADC-associated pneumonitis is primarily triggered by the direct toxic effects of the drug on lung tissue. After the ADC targets a specific antigen and releases its payload in the cell, antigen-independent internalization may also allow lung epithelial cells to take up the ADC, directly damaging alveolar epithelial cells, and triggering nonspecific inflammatory responses and epithelial repair barriers. The bystander effect further exacerbates this process, as the payload may diffuse out of target cells and damage neighboring normal lung cells. This type of pulmonary toxicity shows a degree of localized targeting, primarily affecting lung tissue.

The key objectives in the treatment of ADC-associated pneumonitis are detoxification and lung tissue protection. The ADC should be discontinued immediately to prevent further lung damage, and supportive treatments such as glucocorticoids should be administered to alleviate inflammatory responses. For severe cases, more aggressive treatment such as immunoglobulins or cytokine antagonists may be used to suppress inflammatory activity and reduce the risk of pulmonary fibrosis (12).

Clinical manifestations and diagnosis

Clinical manifestations

The typical symptoms of CIP are primarily respiratory, with dyspnea and cough being the core manifestations. A portion of patients also experience low-grade fever or chest pain, with fever occurring in approximately 12% of cases (24). Notably, about one-third of patients have no obvious clinical symptoms, with their lung abnormalities discovered only through imaging examinations. Such a “subclinical state” increases the difficulty of early diagnosis. The symptoms typically occur within weeks to months of the initiation of immunotherapy. In a study on the Chinese population, the median time to onset was 148 days, presenting a bimodal distribution (60–90 and 150–210 days), which was attributed to the type of medication: CIP caused by PD-1/PD-L1 inhibitors typically appeared 2–6 months after treatment, while pneumonitis associated with CTLA-4 inhibitors occurred earlier (7). The clinical features of CIP (e.g., cough, fatigue, and hypoxemia) are often nonspecific, which increases the risk of misdiagnosis or delayed recognition, leading to treatment delays (36).

The severity of CIP can range from mild to life-threatening, with some cases progressing rapidly. The severity of CIP is typically assessed using the standard Common Terminology Criteria for Adverse Events (CTCAE) grading system for irAEs (37). One study reported that CIP affects about 5% of patients, of whom 1–2% develop severe (grade 3 or higher) pneumonitis, which may lead to respiratory failure (27). CIP has a mortality rate of up to 35% and can cause permanent lung function impairment (38). In a case of fulminant CIP that occurred after a single ICI administration, the patient developed acute respiratory distress, highlighting the rapidly progressive nature of this condition (39).

The symptoms of ADC-associated pneumonitis are similar to those of CIP and primarily include shortness of breath, dry cough, fatigue, chest discomfort, and fever (40). Patients may experience fever, but its incidence varies by drug and is less well-defined than in CIP. In the mild stage, symptoms may be absent or limited to shortness of breath after activity or a dry cough, which can be easily overlooked. As the condition worsens, persistent dyspnea, hypoxemia [PaO₂/FiO₂ (oxygenation index) <300], fever (body temperature >38 ℃), and fatigue appear, and some patients experience pleuritic chest pain. The clinical presentation of ADC-associated pneumonitis shows a temporal relationship, with symptoms usually appearing after ADC administration. The time to onset of ADC-associated pneumonitis varies significantly: for T-DXd, it is approximately 5–6 months, while the FDA Adverse Event Reporting System database reports a median onset time of 51 days for ADC-related ILD (9,12,16).

Troponin, D-dimer, natriuretic peptide, electrocardiogram, echocardiography, pulmonary function tests (PFTs), chest computed tomography (CT), antigen testing, blood culture, sputum culture, and bronchoscopy [including bronchoalveolar lavage fluid (BALF) analysis] are vital diagnostic tools. These investigations guide clinicians in establishing accurate diagnoses (5).

Radiographic manifestations

The radiographic manifestations of CIP are diverse and nonspecific but may include interstitial pneumonitis-like changes (41). The typical features include ground-glass opacities (GGOs) (the most characteristic feature of CIP, often presenting as bilateral, diffuse, or patchy distribution and frequently involving the lower lung lobes), consolidation (commonly seen in the progressive stage of CIP, appearing alongside GGOs and potentially leading to lung atelectasis), and septal thickening and reticulation (associated with tissue inflammation and fibrosis, often seen in patients with chronic CIP). The radiological patterns of CIP are categorized into nonspecific interstitial pneumonia, cryptogenic organizing pneumonia, hypersensitivity pneumonia, and ARDS. CIP typically presents as a peripheral (near the pleura) or random distribution; a central distribution is less common. In addition, some other features such as thickening of bronchovascular bundles, centrilobular nodules, and pleural effusion may also be present; however, these manifestations are nonspecific and may overlap with those of other diseases (42).

CIP classification based on CT findings can guide clinical management. Overall, the organizing pneumonitis (OP) pattern (presenting as patchy consolidation distributed along the bronchovascular bundles) is the most common, accounting for approximately 43–44% of cases (43). A small portion of patients may develop nonspecific interstitial pneumonitis (NSIP), hypersensitivity pneumonitis (HP), acute interstitial pneumonitis (AIP), or diffuse alveolar damage (DAD), with the latter two progressing rapidly and associated with a poorer prognosis.

The radiographic manifestations of ADC-associated pneumonitis may include patterns such as OP, HP, and DAD, among which OP is the most common. ADC-associated pneumonitis exhibits more prominent characteristics of pulmonary fibrosis, which can manifest as honeycombing and traction bronchiectasis. For example, the primary patterns for T-DXd-induced pneumonitis include OP (63.1–72%), HP (16.9%), DAD/AIP/ARDS (11–14.6%), and NSIP (3.1%). The proportion of DAD is higher in critically ill patients and is associated with a higher mortality rate (44).

Distinguishing CIP from ADC-associated pneumonitis based on symptoms is difficult. However, although the radiographic manifestations overlap between these two conditions, ADC-associated pneumonitis tends to present with more fibrotic features, which may be related to the long-term toxic effects of ADCs (45).

Diagnostic strategies

The diagnosis of CIP and ADC-associated pneumonitis should be based on past medical history, drug exposure, and clinical manifestations, along with the exclusion of other potential pulmonary diseases such as infectious pneumonitis and pulmonary embolism (35). A detailed history should also include previous pulmonary diseases (e.g., structural lung disease), smoking history, and environmental exposure, as these factors influence the risk and clinical presentation of pulmonary diseases.

The diagnosis of CIP requires a combination of clinical, radiographic, and pathological findings. The multidisciplinary diagnostic workflow includes immunological assessment, PFTs, and bronchoscopy. Immunological assessment helps identify changes in CIP-associated autoantibodies and cytokine levels. For example, antibodies against BP180 and BP230 may be involved in the pathophysiological processes of CIP (35). PFTs can quantitatively assess the degree of pulmonary function impairment, providing key evidence for diagnosis and treatment. Bronchoscopy allows for the direct visualization of the internal conditions of the airways and the collection of tissue samples for pathological analysis, thereby clarifying the specific type of inflammation (46). However, in clinical practice, a significant proportion of these patients are unable to undergo PFTs or bronchoscopy (47).

The cytological features of BALF in patients with CIP mainly include a significant increase in lymphocytes, particularly CD8⁺ T cells, and a decreased or inverted CD4-to-CD8 ratio. One study reported significant differences in the composition of the lung microbiota between patients with CIP and those with pulmonary infection (PI). Microbial taxa exhibited different abundance patterns across different groups. A correlation analysis showed that the abundance of Candida was significantly and positively correlated with host immune inflammatory markers such as the neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, and systemic immune-inflammation index. Compared with patients with pure-type CIP, those with PI have more diverse biological and metabolic characteristics in their lung microbiota. In addition, research has shown that machine learning models based on BALF microbiota profiles can accurately diagnose CIP (48).

The early identification of CIP relies on the close tracking or monitoring of patients receiving ICI therapy and the timely evaluation of respiratory symptoms. During the course of treatment, respiratory symptoms, such as cough, shortness of breath, and chest pain, should be monitored regularly. Comprehensive physical and radiographic examinations, such as chest CT, should also be performed, as they are valuable for detecting early lung lesions. Chest CT can reveal manifestations such as GGOs, consolidation, and nodules, facilitating assessment of the extent and severity of the lesions.

ADC-associated pneumonitis (commonly manifesting as ILD) is a clinically significant and potentially fatal AE. Although its incidence is relatively low, early detection is crucial to improving patient outcomes. Biomarker testing—using blood, tissue, or molecular markers such as serum IL-6 levels and C-reactive protein (CRP)—shows promise in this field, potentially enabling the early identification of high-risk patients or the initial signs of the disease (5). Serum IL-6 levels may increase several weeks before the onset of ADC-associated pneumonitis, providing a window for early intervention. Regularly monitoring changes in these biomarkers during ADC treatment is of substantial significance for predicting and preventing ADC-associated pneumonitis (29).

A prospective study was conducted to identify blood biomarkers for assessing the risk of severe pneumonitis (e.g., CIP). A multicenter cohort analysis was conducted to establish a blood-based assay for predicting the occurrence of grade 3–5 pneumonitis, particularly in the early stages of treatment (within 6–12 weeks) (37). Although this study primarily focused on CIP, its methods can be extrapolated to ADC-associated pneumonitis, as the underlying mechanisms between these two conditions are similar (i.e., cell-mediated immunity and humoral immunity).

In the context of ADC treatment, the expression levels of target proteins [e.g., HER2 and trophoblast cell surface antigen 2 (TROP2)] may serve as biomarkers, indirectly correlating with the risk of pneumonitis. For example, detecting the expression of ADC target proteins [e.g., HER2, TROP2, human epidermal growth factor receptor 3 (HER3), and epidermal growth factor receptor (EGFR)] in NSCLC tissue via quantitative immunofluorescence can help evaluate patient response to ADC and potential toxicity risks (49). Although primarily used to predict efficacy, high target expression may increase the risk of off-target toxicity, thereby contributing to pneumonitis (50).

Whether treated with ICIs or ADCs, patients receiving multiple doses of medication are prone to concurrent bacterial or viral lung infections and may also be at risk of Pneumocystis jirovecii pneumonia (PJP) (51). When these infections occur alongside drug-associated pneumonitis, they present as a complex infection, complicating diagnosis.

Treatment and management strategies

Prevention

Identifying risk factors is critical for the early identification of CIP and ADC-associated pneumonitis. For patients with underlying lung diseases such as COPD or pulmonary fibrosis, the incidence of CIP is 2–3 times higher than that in the general population, and a history of smoking (especially current smoking) can increase the risk of CIP (52). Moreover, CT-detected pulmonary fibrotic findings or fibrotic interstitial lung abnormalities increase the risk of CIP by approximately 5–6-fold compared with patients without these findings (53). Compared to monotherapy, the combination of PD-1/PD-L1 inhibitors with CTLA-4 inhibitors or chemotherapy is associated with a significantly higher incidence of CIP. Moreover, when the chest radiation fields overlap with areas of lung inflammation, pneumonitis progresses more rapidly. Additionally, the incidence of CIP is higher in patients with NSCLC or melanoma than in those with other cancer types, and special attention must be paid to the risk of cytokine storm in patients with autoimmune diseases (40).

Several preventive measures are necessary before ADC treatment: (I) a comprehensive evaluation of individual risk factors; (II) baseline assessment of respiratory function, including vital signs, physical examination, and chest imaging; (III) patient education on the risks and clinical manifestations of ILD/pneumonitis to facilitate early recognition and treatment; and (IV) periodic CT scans every 9–12 weeks during treatment, along with ongoing symptom monitoring.

Graded management (Table 2)

Accurate severity grading for drug-associated pneumonitis is the foundation for treatment planning. Two major grading standards are widely adopted globally: the American Society of Clinical Oncology (ASCO) grading standard for PAEs (i.e., pneumonitis) in irAEs; and the pneumonitis grading standard in CTCAE (version 5.0) published, by the US National Cancer Institute (54). The National Comprehensive Cancer Network (NCCN) guidelines for irAEs are based on the ASCO grading system, while the Society for Immunotherapy of Cancer irAE guidelines employ the CTCAE (version 5.0) grading system (55). In China, the grading of CIP is primarily based on the CTCAE (version 5.0).

Both grading standards define PAEs/pneumonitis as the presence of focal or diffuse inflammation in the lung parenchyma. The ASCO grading system primarily focuses on the extent of PAE lung lobe involvement, categorizing pneumonitis into grades 1–5. Its advantage lies in quantifying the scope of lung lobe involvement, which facilitates the assessment of CIP progression risks. The CTCAE (version 5.0) grading system centers on symptom severity and interventions. It features high clinical usability, is applicable to various types of drug-associated pneumonitis, and is directly linked to treatment decisions. With distinct clinical foci, both standards provide a basis for the precise grading and treatment of drug-associated pneumonitis, facilitating tailored management.

Monitoring

Identifying biomarkers for the early prediction or accurate diagnosis of CIP and ADC-associated pneumonitis is an area of intense research interest, with the aim being to achieve the precise management of these two conditions. A multidimensional detection system is gradually emerging in the study of biomarkers for CIP. CIP-related biomarkers include core markers such as serum markers, BALF markers, radiomics, genomics, and liquid biopsy. For instance, blood biomarkers such as Krebs Von den Lungen-6​ (KL-6) play an important role as a lung immune prognostic index (56). CRP and IL-6 play a key role in diagnosis, severity stratification, and prognosis prediction. Among the BALF markers, an increase in CD3⁺ CD8⁺ lymphocytes or a decrease in the CD4/CD8 ratio has significant diagnostic value for CIP (57). Research is also driving the development of risk prediction models (based on machine learning and biomarkers) and novel therapeutic targets (e.g., the IL-6 pathway). Despite limitations in biomarker specificity, these advancements have provided more precise tools for the management of pneumonitis in immunosuppressed patients, helping to optimize initial treatment and reduce mortality.

Conversely, progress on specific predictive or diagnostic biomarkers for ADC-associated pneumonitis is slow. Previous research has focused on systemic inflammation (e.g., IL-6 and chimeric antigen receptor) and novel composite models (e.g., proadrenomedullin and chronic liver failure scores). Future research should seek to optimize biomarker combinations for improving specificity and to clarify their differential expressions in pneumonitis of different etiologies. Traditional ILD biomarkers such as KL-6 may still be valuable, but their specificity and sensitivity in ADC-associated pneumonitis require further validation.

Treatment

The treatment of patients with CIP is primarily based on immunosuppressive therapy, aiming to prevent progression to pulmonary fibrosis or death. First-line treatment mainly consists of corticosteroids. High-dose corticosteroids (e.g., prednisone, with an initial dose of 1–2 mg/kg/day) are the preferred initial treatment for CIP, as they can rapidly suppress inflammation. Treatment can be continued until symptoms resolve, followed by a gradual tapering of the dose (e.g., reducing by 10–20% weekly) to prevent recurrence. Studies indicate that more than 70% of patients respond to steroids (58), although the response time may vary depending on CIP severity (e.g., grade 2 or higher requires intravenous administration). Notably, during treatment with corticosteroids for immune-mediated pneumonia, precautions should be taken to prevent PJP (trimethoprim/sulfamethoxazole or atovaquone), peptic ulcers (proton pump inhibitors or H₂ receptor antagonists), and osteoporosis (calcium and vitamin D) (59).

Second-line treatment primarily includes immunomodulators and antifibrotic drugs. Steroid-refractory refers to a lack of response to steroids, while steroid-resistant indicates a partial response without resolution of the event or an inability to taper off steroids (60). For steroid-refractory CIP (cases that do not respond to steroids or relapse), the use of infliximab [anti-tumor necrosis factor (anti-TNF) antibody], mycophenolate mofetil, or cyclophosphamide is recommended to reduce inflammation-mediated lung injury (61). Since the PD-L1/PD-L2 and vascular endothelial growth factor (VEGF) pathways play a role in the pathogenesis of CIP (e.g., by promoting the infiltration of inflammatory cells), antifibrotic therapy combined with immunosuppression can improve prognosis. When CIP progresses to the fibrotic stage, antifibrotic drugs (e.g., pirfenidone or nintedanib) can serve as a supplementary treatment, particularly for patients who do not respond to long-term steroid therapy. These drugs target the TGF-β or VEGF pathways and can slow the progression of pulmonary fibrosis.

The core therapeutic strategy for CIP centers on the standardized use of glucocorticoids. According to relevant clinical guidelines and expert consensus, the following strategies are recommended: (I) for grade 1, immunotherapy should be maintained and monitored in terms of response, and regular follow-up chest CTs should be performed; (II) for grade 2, ICI therapy should be suspended until drug-induced lung disease (DILD) is reduced to ≤ grade 1, and intravenous methylprednisolone at 1–2 mg/(kg·d) or equivalent drugs should be administered. If symptoms improve after 48–72 hours of treatment, the dosage can be tapered by 5–10 mg per week over a period of 4–6 weeks; (III) for grades 3–4, immunotherapy should be permanently discontinued, and glucocorticoid therapy, consisting of intravenous methylprednisolone at 2 mg/(kg·d) or equivalent, should be initiated immediately. If clinical symptoms improve after 48 hours, the treatment should be continued until grade 1 or lower is achieved and can be followed by tapering over a period of 4–6 weeks.

In cases where clinical and radiological manifestations deteriorate following high-dose corticosteroid therapy, additional immunosuppressive agents should be considered for the treatment of ICI-associated pneumonia, including infliximab, cyclophosphamide, intravenous immunoglobulin, and mycophenolate mofetil. Infliximab, an antibody against TNF-α, is used to manage Crohn’s disease and ulcerative colitis and has also shown efficacy in patients with moderate-to-severe colitis induced by ICIs. It has been suggested that infliximab may also be effective in patients with ICI-related pneumonitis. Accordingly, in treatment algorithms for irAEs, infliximab is usually recommended in cases of steroid-refractory ICI-related pneumonitis (62). If there is no significant improvement, intravenous infliximab (5 mg/kg) (repeatable after 14 days), mycophenolate mofetil (1.0–1.5 g bid), or intravenous immunoglobulin can be considered. Research has indicated that patients who received IVIG alone as an immune suppressant beyond corticosteroids had improved survival (54).

For ADC-associated pneumonitis, the requirements for suspending medications are even more stringent, and corticosteroids should be initiated earlier (63). According to relevant clinical guidelines and expert consensus, the following strategies are recommended: (I) for grade 1, suspension of administration until complete recovery should be considered. If DILD resolves within ≤28 days, the medication should be maintained at the original dose; if it resolves in >28 days, the drug dose can be reduced; if it occurs after day 22 of the treatment course and has not resolved within 49 days of the last dose, the treatment should be discontinued; and (II) for grade 2 and beyond, permanent discontinuation of ICIs is required, and empirical corticosteroid therapy should be initiated. CIP can be treated with TNF inhibitors or IL-6 receptor antagonists during treatment, whereas for ADC-related ILD, there are currently no recommendations for such drugs (possibly due to a lack of clinical evidence).

The mechanism of ADC-associated pneumonitis may be related to inflammation and fibrosis. ADC-associated pneumonitis-induced pulmonary fibrosis can result in pulmonary diffusion dysfunction. According to the graded management of anticancer drug-related ILD outlined in the “Expert Consensus on the Diagnosis and Treatment of Anticancer Drug-Related Interstitial Lung Disease” and other clinical observations, antifibrotic drugs are indicated for patients with ADC-associated pneumonitis presenting as usual interstitial pneumonia (UIP) or NSIP, as antifibrotic therapy may benefit some patients (46). Progressive fibrosis is an indicator for the initiation of antifibrotic therapy in patients with UIP or NSIP (64). It has been recently proposed that progressive fibrotic interstitial pneumonitis (regardless of etiology or imaging patterns) can be treated with antifibrotic drugs and that relying solely on the imaging classification of UIP/NSIP or OP is unwarranted.

Regardless of the underlying etiology [e.g., rheumatoid arthritis-associated interstitial lung disease (RA-ILD), connective tissue disease-associated connective tissue disease-associated (CTD-ILD), or idiopathic interstitial pneumonitis], antifibrotic drugs (e.g., nintedanib) can delay the decline in lung function as long as the condition presents as a progressive fibrosing phenotype of ILD (65). Nintedanib significantly slowed the annual decline in forced vital capacity in both UIP and non-UIP patterns (including NSIP and CTD-ILD), reducing it by 91.0 ml/year (P=0.03) (66). Among patients with RA-ILD, abatacept can stabilize dyspnea, lung function, and radiographic progression in those with both UIP and NSIP patterns (improvement/stabilization rate >72%) (67). Indeed, in the INBUILD trial, nintedanib was found to be effective in Asian populations across both the UIP and non-UIP fibrotic subgroups (68,69).

OP is a type of acute/subacute inflammatory disease, often associated with drug reactions and postinfection changes. Its pathology consists mainly of granulation tissue and inflammatory cell infiltration rather than a chronic fibrotic process. Standard treatment primarily entails glucocorticoid administration or immunomodulation (e.g., discontinuation of the causative drug), with antifibrotic drugs having no clear role. As an antiangiogenic and antifibrotic drug, nintedanib is suitable for both tumors (e.g., NSCLC) and fibrotic ILD, as its mechanisms (inhibition of platelet-derived growth factor, fibroblast growth factor, and VEGF receptors) can simultaneously target both the tumor microenvironment and fibrotic pathways. However, there is no direct evidence supporting its application in patients with ADC-associated pneumonitis with an OP pattern.

The use of antifibrotic drugs requires a multidisciplinary team (MDT) to identify and rule out reversible factors (e.g., drug toxicity and infection) and to distinguish between the active inflammatory phase (immunotherapy) and the progressive fibrotic phase (antifibrotic therapy). Future research should clarify the predictors of fibrotic progression in patients with ADC-associated pneumonitis and the indications of antifibrotics for drug-induced lung injury to optimize clinical treatment protocols.

For refractory cases of CIP or ADC-associated pneumonitis, alternative immunosuppressive therapy can be initiated when glucocorticoid therapy is ineffective or contraindicated. For steroid-refractory grade 3–4 CIP, infliximab (5 mg/kg) or cyclophosphamide (500 mg/m²) can be used as second-line regimens to alleviate lung tissue inflammation via the inhibition of TNF or B-cell function. Tocilizumab (8 mg/kg) demonstrates unique advantages in patients with ADC-associated severe pneumonitis. Its ability to target IL-6 receptor can block cytokine storms, making it particularly suitable for T-DXd-induced DAD. Additionally, mycophenolate mofetil (1 g bid) and tacrolimus (3 mg bid) can serve as maintenance therapy options for patients with recurrent pneumonitis requiring long-term immunosuppression, although caution is advised due to the risk of infection (61).

Optimizing the dose and administration regimen of ADCs is an important strategy for lowering toxicity. A study on the mechanism of T-DXd-induced ILD reported at the 2025 American Association for Cancer Research (AACR) Annual Meeting proposed the innovative “ADC+A” intervention strategy, opening a new path for the prevention of ADC-associated pulmonary toxicity (70). Through single-cell transcriptomic sequencing and mouse model experiments, this study revealed that the core mechanism of T-DXd-induced ILD is associated with the activation of perivascular niche-resident alveolar macrophages. The authors proposed pretreatment with the payload-free parent antibody (e.g., trastuzumab) prior to ADC therapy. This approach can reduce the pulmonary accumulation of T-DXd by competitively binding to HER2 receptors on the surface of lung epithelial cells. The potential advantage of this strategy lies in leveraging the target space-occupancy effect of the parent antibody to reduce the nonspecific uptake of ADCs in the lungs while avoiding the reduction in antitumor activity associated with traditional dose adjustments. Ongoing clinical trials are examining this strategy, which may represent a new paradigm for the preventive management of ADC-associated pulmonary toxicity.

MDT management is emphasized in the diagnosis and treatment of both CIP and ADC-associated pneumonitis (71). As the primary coordinators of diagnosis and treatment, medical oncologists need to integrate patient characteristics, tumor features (e.g., cancer type, stage, and line of therapy), and drug exposure history (including the type, dose, and duration of ICIs or ADCs) to provide a foundational diagnostic and treatment context for the MDT.

Pulmonary and critical care medicine experts are responsible for symptom differentiation and graded management. They evaluate ventilation and diffusion function through PFTs (e.g., forced expiratory volume in one second and diffusing capacity of the lung for carbon monoxide), formulate oxygen therapy regimens based on the results of arterial blood gas analysis (PaO₂/FiO₂), and determine the specific duration of high-dose pulse corticosteroid therapy or combined immunosuppressive treatment for patients with grade 2 or higher pneumonitis.

Physicians specializing in pulmonary and critical care medicine are also responsible for performing bronchoscopy to exclude alternative diagnoses, such as lower respiratory tract infections. Further, they should monitor for corticosteroid-related adverse effects and ensure early detection of complications during follow up, including PJP, peptic ulcer disease, and osteoporosis.

The value of radiologists lies in the precise interpretation of radiographic features. For CIP, it is important to differentiate the distribution patterns of GGOs (peripheral vs. central) and the consolidation features of OP. For ADC-associated pneumonitis, dynamic monitoring of changes in consolidation volume and the absorption rate of GGOs is required. Some centers use radiomics to analyze CT texture features to assist in predicting the response to corticosteroid therapy.

The participation of pathologists and clinical pharmacists further enhances diagnostic accuracy. Pathologists determine the basis for selecting immunosuppressive agents by differentiating the lymphocytic infiltration patterns in CIP and the alveolar epithelial injury type in ADC-associated pneumonitis through BALF cytological analysis (e.g., proportions of lymphocyte subsets) or pathology of lung biopsy tissues. Conversely, clinical pharmacists focus on drug interactions and dose optimization. Pathologists also play an indispensable role in ruling out similar conditions, primarily infectious and immune-mediated diseases. For patients receiving T-DXd treatment, they formulate individualized dose adjustments based on therapeutic drug monitoring (TDM) and the analysis of drug-metabolizing gene polymorphisms (e.g., UGT1A1), thereby reducing the risk of pneumonitis.

When patients develop severe pneumonitis (e.g., grade 4 respiratory failure), intensivists take the lead in determining the respiratory support strategy (e.g., high-flow nasal cannula humidified oxygen therapy vs. invasive mechanical ventilation) and organ function protection, while collaborating with infectious disease experts for etiological screening to avoid the masking of infection signs and symptoms through hormonal treatment. The MDT model is particularly crucial in rechallenge decision-making: by assessing tumor progression risk and lung injury repair status, the timing and dosage for restarting treatment can be scheduled for patients with grade 2 or lower pneumonitis.

Rechallenge

For patients with severe CIP, permanent discontinuation of ICI is required; however, for some patients with rapidly progressing tumors, rechallenge may be attempted after the pneumonitis has resolved to grade ≤1 (54). Rechallenge decision-making is even more complex in ADC-associated pneumonitis. Patients with grade 1 pneumonitis may restart treatment at 50% of the original dose after remission, while those with grade 2 or higher should permanently switch to ADCs with different mechanisms of action (e.g., T-DM1) to avoid exposure to similar drugs. Multimodal monitoring, including symptoms, imaging, and biomarkers, can optimize the timing of rechallenge; for example, low-dose ADC therapy may be initiated only after CT shows complete absorption of GGOs and the KL-6 levels have returned to the normal range.

Differences in the clinical management of CIP and ADC-associated pneumonitis

The clinical management of ADC-associated pneumonitis and CIP differs in terms of the discontinuation criteria, timing of corticosteroid intervention, and selection of immunosuppressive agents. ADC-associated pneumonitis requires stricter control over discontinuation indications. For grade 1 pneumonitis, ADC treatment must be suspended and dose adjustment initiated. Generally, ICIs are discontinued after the diagnosis of grade 1 pneumonitis. Their re-administration requires careful consideration of the risks and benefits (5). However, many current studies and guidelines also suggest that grade 1 CIP cases can continue immunotherapy with observation. For grade-2-or-higher ADC-associated pneumonitis, permanent discontinuation or switching of drugs is often required, but for grade 2 CIP, restarting ICI may be attempted after symptom remission.

Corticosteroid interventions for patients with ADC-associated pneumonitis emphasize the principle of earlier administration. For immunosuppressive agents, the consensus supports TNF inhibitors (e.g., infliximab), IL-6 antagonists (e.g., tocilizumab), or mycophenolate mofetil as second-line options for steroid-refractory grade 3–4 CIP. However, evidence for such drugs in ADC-associated pneumonitis remains limited to case reports. Although tocilizumab has shown some efficacy in reducing inflammatory cytokines in T-DXd-associated severe pneumonitis, its use is not recommended as standard therapy in international guidelines (e.g., the NCCN guidelines) due to a lack of support from phase III trials. Further, the management of ADC-associated pneumonitis requires greater attention to drug metabolic characteristics, and TDM is used to adjust dosing to balance efficacy and toxicity. Conversely, CIP management involves a greater focus on the assessment of immune status, as it is well-known that the actions of ICIs are long-term and last even after the discontinuation of ICIs (35).

Additionally, the prevention strategies for ADC-associated pneumonitis (e.g., pretreatment with the parent antibody in the ADC+A regimen) differ from the risk factor avoidance strategies for CIP (e.g., avoiding combined radiotherapy). These differences reflect the distinct pathological mechanisms of these two conditions—CIP is primarily driven by T-cell-mediated immune overactivation, while ADC-associated pneumonitis is related to organ-specific drug distribution and target expression. Accordingly, clinical management should be tailored based on pathogenesis. Additionally, it should be noted that CIP may occur concurrently with irAEs affecting other organs.

Discussion

CIP and ADC-associated pneumonitis exhibit both significant differences and shared characteristics in epidemiology, pathogenesis, clinical manifestations, diagnosis, and therapeutic strategies. A comprehensive analysis of these similarities and differences is essential for optimizing clinical decision-making and improving the quality of life of patients with cancer. Future research directions are outlined below to advance the field and enhance clinical management.

Diagnosis: from biomarkers to mechanism

A recent study on CIP diagnosis found that aberrant basal-like cells (highly expressing SOX9) in BALF drive neutrophil infiltration via the CXCL3–5-CXCR2 pathway, with their proportion being 4.2-fold higher in patients with grade ≥3 CIP than in those with milder disease. This suggests that they may serve as a novel diagnostic biomarker for distinguishing between mild and severe CIP (24). Further, the proportion of peripheral blood MPs was found to be significantly elevated in patients with severe CIP, and their enhanced MHC class II antigen presentation function was positively correlated with the degree of T-cell activation in lung tissue (r=0.71), suggesting that they may serve as predictive indicators for CIP (27).

Another study revealed the critical role of the FcγR-SPP1 pathway in ADC-associated pneumonitis diagnosis. Specifically, the binding of the Fc fragment of T-DXd to alveolar macrophages induces the secretion of osteopontin (also known as SPP1). The serum SPP1 levels were 3.8-fold higher in patients with ADC-associated pneumonitis than in healthy individuals, and were positively correlated with the size of consolidation shadows (r=0.65); thus, SPP1 could serve as the first specific serum biomarker for ADC-associated ILD (33).

These findings are driving a shift in diagnostics from reliance on imaging to the use of molecular biomarkers. In the future, the accuracy of early diagnosis is expected to be improved through combined multi-marker testing (e.g., SOX9 and SPP1).

Treatment: mechanism-guided precision interventions

The ADC+A pretreatment regimen proposed at the 2025 AACR Annual Meeting shows potential for preventing pulmonary toxicity. This approach reduces the accumulation of T-DXd in the lungs by competitively binding FcγR with the parent antibody (e.g., trastuzumab). In mouse models, the regimen reduced the DXd concentration in lung tissue by 40% while maintaining antitumor efficacy (33).

At the 2025 AACR Annual Meeting, the Biocytogen team reported that a bispecific ADC (DLL3×B7-H3 bispecific ADC) could reduce off-target toxicity through a dual-target internalization mechanism. Preclinical data indicated that its efficacy against small-cell lung cancer was 2.1 times higher than that of single-target ADCs, and the incidence of lung toxicity was reduced by 50%, suggesting that it may aid in overcoming drug resistance.

In the field of neuro-immunomodulation, research has found that the brain-lung sympathetic pathway (CeA-GABA neurons → ADRB2+ macrophages) participates in the progression of severe pneumonitis. One study reported that inhibiting ADRB2 signaling reduced inflammatory cytokine levels in lung tissue by 62% in mice, thus providing a novel target for the development of neuromodulatory anti-inflammatory drugs (72).

These innovative strategies are beginning to address the limitations of traditional steroid therapy and contributing to the realization of precision treatment for patients with ADC-associated pneumonitis or CIP.

Prognosis: rechallenge decision-making

A study on rechallenge decisions, which incorporated seasonal factors to optimize monitoring frequency and explored temporal patterns for CIP in the Chinese population, established a bimodal distribution model (60–90 and 150–210 days) for CIP (7). To develop a graded rechallenge pathway for patients with CIP/ADC-associated pneumonitis, prophylactic combination with corticosteroids is recommended to reduce the risk of recurrence. Meanwhile, criteria for ADC dose adjustments—based on free drug concentration monitoring and dynamic assessment of hepatic and renal function—have been proposed to mitigate rechallenge toxicity. The integration of temporal patterns, biomarkers, and individualized interventions, constitutes a quantitative basis for developing clinical rechallenge strategies and may help reduce the risk of pulmonary toxicity while ensuring antitumor efficacy.

Conclusions

This narrative review consists of a detailed classification, overview, and comparison of the similarities and differences between CIP and ADC-associated pneumonitis across various dimensions of clinical practice. Based on the latest and most representative reviews, clinical and basic research, case reports, and consensuses, and guidelines published in recent years, it provides a comprehensive guide for managing these adverse drug reactions. CIP and ADC-associated pneumonitis exhibit both significant differences and shared characteristics in epidemiology, pathogenesis, clinical features, diagnosis, and treatment, necessitating distinct clinical management approaches. The development of accurate and effective treatment regimens must be based on a thorough understanding of these two pneumonitis types. This review also highlights future research directions, including advances in biomarker-based diagnostics and mechanistic studies, mechanism-guided precision interventions, and the optimization of prognosis prediction and rechallenge decision-making.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0173/rc

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Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0173/coif). The authors have no conflicts of interest to declare.

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(English Language Editor: J. Gray & L. Huleatt)