ADC-Associated ILD: An Emerging Challenge
July 3rd, 2026
Drug-Induced Interstitial Lung Disease (DI-ILD) encompasses a heterogeneous group of ILDs resulting from adverse drug reactions, leading to inflammation and fibrosis of the lung parenchyma. More than 400 drugs have been implicated, among which antibody–drug conjugates (ADCs), particularly those used in breast and lung cancer, are increasingly recognised as clinically important and emerging causes.1.
ADCs have become an important part of modern cancer therapy due to their ability to selectively deliver cytotoxic agents to tumour cells, thereby reducing systemic exposure and the potential for off-target toxicities. However, despite this targeted approach, pulmonary toxicities are being reported more frequently as their clinical use expands.
Although DI-ILD accounts for a relatively small proportion of ILD cases (approximately 3-5%), its relevance is increasing in oncology with the expanding use of agents such as ADCs, and it is associated with significant morbidity and mortality. Early diagnosis remains challenging due to the nonspecific clinical features and the need for high-resolution CT imaging, which is often only performed after significant damage has occurred.
Given these challenges, improved awareness and timely recognition of DI-ILD are essential. This blog provides an overview of ADC-associated DI-ILD, including its clinical features, underlying mechanisms, and key clinical implications.
Characteristics of ADC-Associated ILD
ADC-associated ILD refers to a spectrum of pulmonary toxicities occurring in patients treated with ADCs, characterised by inflammation and/or fibrosis of the lung tissue. It is considered a subset of DI-ILD and is defined by its association with targeted anticancer agents composed of a monoclonal antibody, a cytotoxic payload, and a chemical linker.
Clinically, ADC-associated ILD presents across a broad spectrum, ranging from asymptomatic radiographic changes to symptomatic pneumonitis and, in severe cases, rapidly progressive respiratory failure. It is typically suspected following the onset of new or worsening respiratory symptoms and/or characteristic findings on high-resolution CT, such as ground-glass opacities or organising pneumonia patterns, although presentations can be variable. Diagnosis also requires the exclusion of other potential causes, including infection, disease progression, and radiation-induced lung injury.
ADC-associated ILD is not uniform across agents or tumour types. The incidence, severity, and timing of onset vary between different ADCs and treatment settings and may be influenced by patient-specific risk factors such as pre-existing lung disease or prior thoracic therapies. As ADC use continues to expand across oncology, awareness of this toxicity profile is increasingly important for early recognition and appropriate management.
Mechanisms Behind ADC-Related ILD
The pathophysiology of ADC-associated ILD is not well understood, but is likely multifactorial, with different drugs likely exerting their effects through different mechanisms. Possible pathways may include direct cytotoxic injury as well as immune-mediated processes.
Direct cytotoxic injury occurs when alveolar epithelial, airway epithelial cells, or capillary endothelial cells are exposed to the drug itself or its reactive metabolites. This can result in cellular damage through oxidative stress, increased endothelial permeability, or phospholipid deposition 3. The initial injury triggers tissue repair mechanisms, leading to the activation of inflammatory pathways and pro-fibrotic signalling. Cytokine-mediated processes stimulate the recruitment of inflammatory cells and proliferation of fibroblasts, resulting in excessive extracellular matrix deposition and progressive structural and functional lung changes 4.
Immune-mediated mechanisms have also been implicated, involving hapten-mediated modification of tissue-resident proteins or the development of antibody-antigen immune complexes, both of which can trigger downstream inflammatory responses 3.
Additional mechanisms that may contribute specifically to ADC-related lung toxicity include the target-mediated uptake and intracellular catabolism of ADCs, and off-target uptake by pulmonary epithelial cells 5. Premature deconjugation in circulation may also lead to early release of the cytotoxic payload, allowing systemic diffusion into healthy tissues 5. Furthermore, ADCs with cleavable linkers may induce the bystander effect, whereby released cytotoxic agents diffuse into neighbouring cells, amplifying local tissue injury 5.
Clinical Implications of ADC-associated ILD
ADC-associated ILD is a clinically significant toxicity that can impact treatment delivery and patient outcomes, often necessitating interruption or permanent discontinuation of therapy. Management is guided by severity and typically includes corticosteroids alongside withdrawal of the causative agent. For example, with trastuzumab deruxtecan, grade 1 ILD may allow treatment interruption and possible re-challenge depending on resolution, whereas Grade ≥2 events generally require permanent discontinuation and corticosteroid therapy, with severe cases often requiring hospitalisation 6.
Beyond pulmonary toxicity, patients receiving ADCs often experience systemic adverse effects such as fatigue, pain, and dyspnoea, which can further reduce functional status and treatment adherence. When ILD develops, respiratory symptoms only add to this burden. These toxicities, alongside necessary treatment modifications, may also reduce therapeutic exposure and potentially compromise treatment efficacy, particularly in patients with advanced or refractory disease.
In conclusion, ADC-associated ILD represents an important and increasingly recognised toxicity in oncology, reflecting the expanding use of antibody–drug conjugates across multiple tumour types. There is a clear need for improved awareness, early detection, and coordinated multidisciplinary management to mitigate risk while preserving the therapeutic benefit of these therapies.
References
(1) Spagnolo, P.; Bonniaud, P.; Rossi, G.; Sverzellati, N.; Cottin, V. Drug-Induced Interstitial Lung Disease. European Respiratory Journal 2022, 60 (4), 2102776. https://doi.org/10.1183/13993003.02776-2021.
(2) Skeoch, S.; Weatherley, N.; Swift, A. J.; Oldroyd, A.; Johns, C.; Hayton, C.; Giollo, A.; Wild, J. M.; Waterton, J. C.; Buch, M.; Linton, K.; Bruce, I. N.; Leonard, C.; Bianchi, S.; Chaudhuri, N. Drug-Induced Interstitial Lung Disease: A Systematic Review. J. Clin. Med. 2018, 7 (10), 356. https://doi.org/10.3390/jcm7100356.
(3) Conte, P.; Ascierto, P. A.; Patelli, G.; Danesi, R.; Vanzulli, A.; Sandomenico, F.; Tarsia, P.; Cattelan, A.; Comes, A.; De Laurentiis, M.; Falcone, A.; Regge, D.; Richeldi, L.; Siena, S. Drug-Induced Interstitial Lung Disease during Cancer Therapies: Expert Opinion on Diagnosis and Treatment. ESMO Open 2022, 7 (2), 100404. https://doi.org/10.1016/j.esmoop.2022.100404.
(4) Fontes e Sousa, M.; Campainha, S.; Marques, I. D.; Dinis, R.; Inácio, J. R.; Mendes, J. J.; Luís, R.; Ferreira, A. M.; Racha-Pacheco, R.; Rolo, R.; Sousa, G.; Cortes, P. Diagnosis and Management of Drug-Induced Interstitial Lung Disease in the Context of Anti-Cancer Therapy: A Multidisciplinary Viewpoint by Portuguese Experts. Clin. Drug Investig. 2024, 44 (11), 801–810. https://doi.org/10.1007/s40261-024-01400-z.
(5) de Goeij, B. E.; Lambert, J. M. New Developments for Antibody-Drug Conjugate-Based Therapeutic Approaches. Curr. Opin. Immunol. 2016, 40, 14–23. https://doi.org/10.1016/j.coi.2016.02.008.
(6) European Medicine Agency. Enhertu (Trastuzumab Deruxtecan). Summary of Product Characteristics; 2021. https://www.ema.europa.eu/en/documents/product-information/enhertu-epar-product-information_en.pdf (accessed 2026-01-20).