Year: 2025
Type: article
Abstract: Dear Editors, We read with great interest the article by Tang and Chen, addressing the potential cancer risk associated with interleukin-13 (IL-13) inhibitors.1 The IL-13-specific monoclonal antibodies tralokinumab and lebrikizumab, as well as the dual IL-4/IL-13 inhibitor dupilumab, are approved for the treatment of atopic dermatitis (AD).2 Both clinical trials and an increasing number of real-world studies have demonstrated favorable efficacy and safety profiles for these agents.3, 4 Moreover, a growing body of literature is focusing on their use in special populations and patients with comorbidities, including those with a history of malignancy.5 IL-13 inhibitors act by selectively targeting the Th2 immune response, which is primarily involved in allergic and anti-parasitic immunity, without significantly affecting the Th1 and cell-mediated pathways that are crucial for anti-tumor immune surveillance. Due to this mechanism of action, as well as their expanding role in clinical practice, current guidelines and expert consensus statements support the use of IL-13 inhibitors in patients with AD and a personal history of cancer or concurrent neoplastic disease, particularly when compared to conventional immunosuppressants (e.g., cyclosporine) or Janus kinase (JAK) inhibitors.3-5 Despite their relatively recent approval, safety concerns have emerged. A study by Lavin et al., utilizing data from the FDA Adverse Event Reporting System (FAERS), identified dupilumab as having both the highest absolute number and the highest reporting odds ratio of cutaneous T-cell lymphoma (CTCL) reports among all biologics analyzed, including TNF-α inhibitors, IL-12/23 inhibitors, IL-23 inhibitors, and IL-17 inhibitors.6 This finding suggests a modest but statistically significant increased risk of CTCL in patients treated with dupilumab. Furthermore, FAERS data also include cases of CTCL associated with tralokinumab and lebrikizumab. Several hypotheses have been proposed to explain this association, including the potential for misdiagnosis between chronic inflammatory skin diseases and CTCL, as well as the possibility that modulation of the tumor microenvironment may accelerate CTCL progression or unmask previously undiagnosed disease.7 By contrast, the impact of IL-13 inhibition on the progression of solid tumors remains insufficiently understood. The study by Tang and Chen – a Mendelian randomization analysis – reported a significant causal association between IL-13 inhibition and increased risk of several solid tumors, including ureteral cancer, pancreatic neuroendocrine tumors, cutaneous melanoma, and breast cancer.1 Similarly, a case series by Rupprecht et al. described three cases of rapidly progressive solid tumors following the initiation of dupilumab therapy: glioblastoma multiforme, pancreatic carcinoma, and paranasal sinus cancer.8 Conversely, IL-13 inhibition has been observed to exert beneficial effects in other malignancies, such as basal cell carcinoma, hepatocellular carcinoma, ovarian cancer, gastrointestinal stromal tumors (GIST), and neoplasms of bone and articular cartilage.1 This observation aligns with the traditional view that a dominant Th2 response may impair anti-tumor immunity.9 However, recent findings have challenged this paradigm, suggesting that Th2 responses may also exert anti-tumor effects under specific conditions. For example, IL-4 has been shown to support CD8+ T-cell function in exhausted states, inhibit angiogenesis, and modulate the tumor immune microenvironment in a manner that may suppress tumor progression.7, 10 Taken together, these findings underscore the complexity and evolving nature of the relationship between Th2 cytokines and tumor immunity. As such, this field remains a subject of active investigation and ongoing debate. Rigorous preclinical studies, as well as large-scale post-marketing surveillance through national and international registries, are essential to elucidate the true incidence, mechanisms, and clinical relevance of rare oncologic adverse events associated with IL-13 inhibition.2
DOI: 10.1111/ddg.15999
Institution: University of Ferrara
Language: English
Subfield: Dermatology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4415460402