To date, immune checkpoint inhibitors (ICIs) represent a cornerstone in treating various cancers as they harness the potential of the immune system to treat malignancies. However, their influence on immune pathways can lead to immune-related adverse events (irAEs). IrAEs are a spectrum of side effects that can occur because of treatment with ICIs (1). These adverse events arise from the dysregulation of the immune system by immunotherapeutic drugs, leading to immune-mediated inflammation and tissue damage in various organs and tissues throughout the body (2). The spectrum of irAEs is broad and can involve any organ system, including the skin, gastrointestinal tract, liver, endocrine glands and lungs (3). Common irAEs include dermatitis, colitis, hepatitis and thyroid dysfunction, with pneumonitis standing as a particularly significant concern (4). Pneumonitis, characterized by inflammation of lung tissue, emerges as one of the notable irAEs due to its potential for severe morbidity and mortality if not promptly recognized and managed (5). However, the severity and specific manifestations of irAEs can significantly vary among patients depending on the type of immunotherapy, the underlying cancer, and the immune status of patients (6). The clinical presentation of irAEs can range from mild, self-limited symptoms to severe, life-threatening complications (7). Rapid identification and management of irAEs are crucial to prevent severe morbidity and mortality (8). Treatment typically involves the temporary or permanent discontinuation of immunotherapy and the initiation of immunosuppressive medications, such as corticosteroids or other immunomodulators such as infliximab or vedolizumab related to the severity and nature of the adverse event (9). The mechanisms underlying irAEs are complex and need to be fully elucidated. However, the dysregulation of immune checkpoints and the resultant immune activation against normal tissues is considered to play a central role (10). The diversity of irAEs underscores the need for a multidisciplinary approach to diagnose and manage these adverse events best, involving collaboration between oncologists, immunologists, rheumatologists and other specialists as needed.

ICI-related pneumonitis is relatively rare compared with other irAEs, such skin reactions, flu-like- and gastrointestinal symptoms, yet it is the most fatal complication associated with programmed cell death protein 1 inhibitors (PD-1/PD-L1) (1). Studies indicate that ICI-related pneumonitis is responsible for a substantial proportion of deaths attributed to PD-1/PD-L1 inhibitor monotherapy, accounting for ~35% of such fatalities (11-13). The overall incidence rate of ICI-related pneumonitis in clinical trials involving ICI monotherapy is 2.5-5.0%, while that in trials involving ICI combination therapy is higher, at 7-10% (12). Clinical trials typically enroll patients without underlying lung disease or autoimmune conditions, and thus, real-world data reveal a broader incidence of 7-19% (13). Additionally, studies have demonstrated that PD-1/PD-L1 inhibitors exhibit a greater incidence and severity of pulmonary toxicity compared with anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) agents (14,15). Specifically, PD-1 inhibitors have been found to have a higher occurrence and severity of pulmonary toxicity than PD-L1 inhibitors (14). Moreover, the incidence of ICI-related pneumonitis tends to be higher in non-small cell lung cancer compared with other tumor types, such as melanoma and renal cell carcinoma (15). The overall incidence of ICI-related pneumonitis for all grades is 1.4-5.8% in patients with non-small cell lung cancer (NSCLC), 1-4% in patients with melanoma and 1-4.8% in those with renal cell carcinoma (15). These statistics underscore the importance of cautious monitoring and prompt management of pneumonitis in patients undergoing ICI therapy.

The pathogenesis of ICI-related pneumonitis is complex and multifactorial, involving dysregulated immune responses against pulmonary tissues triggered by the blockade of immune checkpoints such as CTLA-4 and PD-1 or its ligand PD-L1(16). While the exact mechanisms remain not fully understood, several vital processes contribute to the development of pneumonitis in ICI therapy. As depicted in Fig. 1, the disruption of immune tolerance lies at the core of ICI-related pneumonitis pathogenesis (17). Due to the action of these immunotherapeutic drugs, including checkpoint inhibition and blockade, aimed to disrupt immune regulation in tumor tissue, such alteration, may also occur in normal tissues, such as lungs, even though a full elucidation of the mechanisms underlying irAEs is still lacking. Consequently, the irAE mechanism appears similar to insufficient immune regulation of tissue homeostasis rather than activation of the immune system. This is supported by the lack of laboratory confirmation of autoimmunity, since in most cases, auto-antibodies are absent.

Immune checkpoints are crucial in maintaining self-tolerance and preventing excessive immune activation against normal tissues (18). Blockade of CTLA-4, PD-1, or PD-L1 releases the ‘brakes’ on the immune system, leading to increased activation of T cells (19). In some cases, this heightened immune response may result in recognizing self-antigens in lung tissue, triggering an autoimmune reaction (20). Consequently, the release of pro-inflammatory cytokines and the infiltration of immune cells into the lung parenchyma perpetuate tissue damage and contribute to the development of pneumonitis (21). The activation of effector T cells plays an essential role in the pathogenesis of lung inflammation. ICIs promote the activation and proliferation of effector T cells, crucial for mounting an effective antitumor immune response (20-22). However, in the context of pneumonitis, the activation of effector T cells may lead to their infiltration into the lung parenchyma. Once within the lung tissue, these activated T cells release a cascade of pro-inflammatory cytokines and chemokines, including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interferon-γ (IFN-γ) (20-22). This inflammatory milieu contributes to tissue damage and exacerbates the immune-mediated lung injury characteristic of pneumonitis (20-22). The dysregulated cytokine production (TNF-α, IL-6 and IFN-γ) orchestrates a cascade of inflammatory responses, recruiting immune cells to the injury site and amplifying the immune-mediated lung injury process (22). Moreover, they can disrupt the delicate balance between pro-inflammatory and anti-inflammatory signals, further exacerbating tissue damage and contributing to the severity of pneumonitis (23). Lastly, genetic and environmental factors play crucial roles in influencing the development of ICI-related pneumonitis (24). Specific genetic polymorphisms, such as the gamma-aminobutyric acid type A receptor subunit pi, the desmocollin and the bromodomain adjacent to zinc finger domain 2B genes, related to immune regulation and inflammation have been implicated in the susceptibility to irAEs, although further research is needed to elucidate their particular roles in pneumonitis (23,24). Additionally, factors such as microbiota composition, prior lung injury, smoking history and concomitant use of other medications may modulate the risk of developing pneumonitis in patients receiving ICIs (25,26).

ICI-related pneumonitis typically presents nonspecific respiratory symptoms that can mimic other pulmonary conditions such as infection or malignancy (27). Patients may initially complain of nonspecific symptoms such as dyspnea, cough, pain and chest discomfort, which can gradually worsen (28). In more severe cases, respiratory distress and hypoxia may develop rapidly, warranting urgent medical attention (29). Constitutional symptoms such as fatigue, malaise and low-grade fever may accompany respiratory complaints, further complicating the clinical picture (Table I) (30). It is important to note that the onset of symptoms can vary widely, occurring weeks to months after initiating ICI therapy (31). Clinical suspicion should be high in patients receiving ICIs who develop new or worsening respiratory symptoms, especially in the absence of alternative etiologies and particularly in patients receiving PD-1/PD-L1 inhibitors (32). Close monitoring for respiratory symptoms and early intervention is paramount to mitigate the risk of disease progression and minimize morbidity and mortality associated with this adverse event.

Diagnosing ICI-related pneumonitis requires a comprehensive assessment encompassing clinical, radiological and laboratory findings (1-3). The detailed description of these examinations extends beyond the scope of the present review. Pulmonary function tests (PFTs), including spirometry and diffusion capacity testing, provide valuable information about lung function and may reveal restrictive or obstructive patterns indicative of lung involvement (1-3). However, PFT findings can be nonspecific and should be interpreted with clinical and radiological findings (3). The European Society for Medical Oncology and the American Society for Clinical Oncology recommend bronchoscopy with bronchoalveolar lavage, and, in some cases, transbronchial lung biopsy may be performed to obtain samples for analysis (33,34). Bronchoalveolar lavage fluid analysis, including cell counts, protein level analysis and microbiological cultures, can evidence a high lymphoid infiltrate consistent with immune-mediated pneumonitis, helping to exclude alternative diagnoses and guide therapeutic decisions (35). Transbronchial biopsy may be utilized in cases of diagnostic uncertainty or severe disease to obtain histological samples for pathological evaluation (33-35). Surgical lung biopsy using video-assisted thoracoscopic surgery to ascertain differential diagnosis from tumor progression may be used in cases where the suspicion of progressive cancer persists (33,34). However, these investigations must be integrated with clinical and radiological findings. Specifically, CT scanning of the chest serves as the cornerstone in radiological evaluation, revealing characteristic patterns of pneumonitis such as ground-glass opacities (GGOs), consolidations or interstitial infiltrates (1-3,36-38).

Pneumonitis is a rare irAE following ICI therapy, and it manifests as interstitial lung disease (36). Table II summarizes the main CT patterns observed in ICI-related pneumonitis. Pneumonitis secondary to ICI treatment presents in four distinct patterns: i) Organizing pneumonia (OP); ii) nonspecific interstitial pneumonia (NSIP); iii) hypersensitivity pneumonitis (HP); and iv) diffuse alveolar damage (DAD) (36). While chest X-ray findings in ICI-related pneumonitis may be nonspecific, characteristic abnormalities can aid the diagnostic process (37). Common radiographic manifestations include patchy or diffuse opacities, consolidations and interstitial infiltrates, which may be bilateral and involve multiple lung lobes (37,38). Additionally, air bronchograms or a ‘ground-glass’ appearance may suggest alveolar involvement and inflammatory changes within the lung parenchyma as shown in Fig. 2, Fig. 3 and Fig. 4, which report on a case of gastric, lung and rectal cancer, respectively. However, it is essential to recognize that chest X-ray findings alone may not be sufficient to diagnose or exclude pneumonitis (37) definitively. Further imaging with CT of the chest is often necessary to delineate the extent and nature of pulmonary abnormalities and guide subsequent management decisions (38).

At present, there are no validated recommendations for ICI-related pneumonitis treatment; patient management relies on clinical experience and a multidisciplinary approach (3,35). The ASCO expert consensus developed clinical practice guidelines according to The Common Terminology Criteria for Adverse Events (35). The grading was as follows: i) Grade 1, asymptomatic disease; ii) grade 2, symptomatic disease with limited instrumental activities of daily living (ADL) needing medical intervention; iii) grade 3, severe symptoms limiting self-care ADL requiring oxygen; and iv) grade 4, life-threatening respiratory compromise requiring urgent intervention (35). Managing ICI-related pneumonitis necessitates a tailored approach balancing immunosuppression with oncologic efficacy (48,49). Treatment algorithms involve prompt cessation of ICIs and initiation of corticosteroids, typically prednisone or methylprednisolone, at a dose of 1-2 mg/kg/day (48). Close monitoring of clinical and radiological response is paramount, with gradual tapering of corticosteroids guided by symptom resolution and radiographic improvement (49). In refractory cases or those with severe pneumonitis, additional immunosuppressive agents such as infliximab or mycophenolate mofetil may be considered, although their efficacy remains uncertain (50). Infliximab or cyclophosphamide have been proposed in clinical trials and initially approved by the US FDA for patients receiving ipilimumab, especially for severe, immune-mediated gastrointestinal side effects (33,50). Anecdotal reports have suggested the use of interleukin-17 blockade may provide relief from immune-mediated skin and gastrointestinal toxic effects (33,50). Collaborative efforts between oncologists, pulmonologists and rheumatologists are essential in optimizing patient outcomes and minimizing treatment-related complications (33).

Distinguishing between ICI-related pneumonitis and disease progression in lung cancer demands a comprehensive evaluation incorporating multiple criteria, including variations in tumor growth rate and tumor growth kinetics (51-53). It typically represents a diagnosis of exclusion, necessitating the comprehensive exclusion of alternative etiologies such as infection and radiation-related pneumonitis (54). Given the overlapping clinical and radiological features of these conditions, a thorough evaluation is essential to differentiate ICI-related pneumonitis from other potential causes of pulmonary symptoms (Table III). Firstly, the clinical context is crucial, as recent initiation or ongoing treatment with ICIs raises suspicion for pneumonitis (51-53). At the same time, a history of lung cancer or evidence of disease progression suggests tumor advancement (51-53). Secondly, the temporal relationship plays a pivotal role, with ICI-related pneumonitis typically manifesting weeks to months after therapy initiation, contrasting with the more gradual progression of lung cancer (33). Symptomatology, including respiratory and constitutional symptoms, offers additional insight, as does the response to treatment; improvement with corticosteroids favors pneumonitis, while lack thereof may indicate disease progression (16). Radiographic findings, mainly CT, provide further differentiation, with characteristic patterns such as GGOs favoring pneumonitis and progressive nodules suggesting tumor growth (44).

ICI-related pneumonitis represents a clinically significant irAE associated with immunotherapy, necessitating timely recognition and management to mitigate morbidity and mortality. A systematic diagnostic approach integrating clinical, radiological and laboratory findings is imperative for accurate diagnosis and appropriate therapeutic interventions (55). Future research endeavors should focus on elucidating the underlying mechanisms of pneumonitis and identifying predictive biomarkers to guide personalized treatment strategies in this evolving field of oncology.