Immune checkpoint inhibitors (ICIs)-induced Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) in cancer treatment

Immune checkpoint inhibitors (ICIs)-induced Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) in cancer treatment | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 10 February 2026 V1 Latest version Share on Immune checkpoint inhibitors (ICIs)-induced Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) in cancer treatment Authors : Ziheng Wu , Huan Tian , Qiang Tao , Xiaoying Wu , Li Wang , Min Deng , Li Liu , Kaiwen Zhong , Chenya Zhuo , Wei Qin , and Songlin Peng [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.177071065.57520748/v1 112 views 62 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Immune checkpoint inhibitors (ICIs) have made remarkable progress in the field of cancer immunotherapy. Clinically, ICIs include antibodies against programmed cell death 1 (PD-1) and its ligand (PD-L1), and cytotoxic T lymphocyte-associated protein 4 (CTLA-4), which are approved for the treatment of a wide kind of solid tumors, prolonging remarkable survival of cancer patients. By blocking certain suppressive pathways, ICIs promote T-cell activation and exhibit an effective and safe antitumor immune response. However, ICIs could induce immune-related adverse events (irAEs), such as, drug reaction with eosinophilia and systemic symptoms (DRESS), which is one of the most severely and rarely reported ICIs-induced dermatologic adverse events. Understanding the mechanisms of ICIs-induced DRESS is crucial for offering insights into the biomarkers and clinical management strategies in ICIs-induced DRESS patients. Immune checkpoint inhibitors (ICIs)-induced Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) in cancer treatment Ziheng Wu 1, 2 | Huan Tian 3 | Qiang Tao 4 | Xiaoying Wu 5 | Li Wang 6 | Min Deng 1 | Li Liu 7 | Kaiwen Zhong 1 | Chenya Zhuo 8 | Wei Qin 1 | Songlin Peng 1 1 Department of General Surgery, the Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen 518107, China 2 Department of Urology, the Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen 518107, China 3 Department of Breast Surgery, the Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China 4 Department of Hepatobiliary and Pancreatic Surgery, the Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen 518033, China. 5 Department of Liver Surgery, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China 6 Department of Gynecology and Obstetrics, the Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen 518107, China 7 Institute of Organ Medicine, the Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen 518107, China Ziheng Wu, Huan Tian, and Qiang Tao are shared first co-authors. Correspondence: Songlin Peng, Department of General Surgery, the Seventh Affiliated Hospital, Sun Yat-sen University, No.628, Zhenyuan Rd, Guangming Dist., Shenzhen, China. E-mail: [email protected] Wei Qin, Department of General Surgery, the Seventh Affiliated Hospital, Sun Yat-sen University, No.628, Zhenyuan Rd, Guangming Dist., Shenzhen518107, China. E-mail: [email protected] or [email protected] Zhenya Zhuo, Institute of Organ Medicine, the Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen 518107, China. E-mail: [email protected] Abstract Immune checkpoint inhibitors (ICIs) have made remarkable progress in the field of cancer immunotherapy. Clinically, ICIs include antibodies against programmed cell death 1 (PD-1) and its ligand (PD-L1), and cytotoxic T lymphocyte-associated protein 4 (CTLA-4), which are approved for the treatment of a wide kind of solid tumors, prolonging remarkable survival of cancer patients. By blocking certain suppressive pathways, ICIs promote T-cell activation and exhibit an effective and safe antitumor immune response. However, ICIs could induce immune-related adverse events (irAEs), such as, drug reaction with eosinophilia and systemic symptoms (DRESS), which is one of the most severely and rarely reported ICIs-induced dermatologic adverse events. Understanding the mechanisms of ICIs-induced DRESS is crucial for offering insights into the biomarkers and clinical management strategies in ICIs-induced DRESS patients. KEYWORDS Cytotoxic T lymphocyte-associated protein 4, Drug reaction with eosinophilia and systemic symptoms, IgG4-related lymphadenopathy, Immune checkpoint inhibitors, Programmed cell death 1 | INTRODUNCTION Immune checkpoint inhibitors (ICIs) restore T cell-mediated antitumor effects by blocking immune checkpoints such as PD-1/PD-L1 and CTLA-4 (Zimmer et al., 2020; Topalian et al., 2012) . Nowadays, ICIs have been approved for the treatment of patients with malignancies, either as monotherapy or combination therapies with chemotherapy/targeted agents, significantly improving survival outcomes for cancer patients, especially in tumors with high PD-L1 expression or microsatellite instability-high (MSI-H) status (Zhang et al., 2023; Chu et al., 2023) . Although ICIs, as a cornerstone of cancer immunotherapy, have improved outcomes across numerous malignancies, safety concerns, particularly the management of immune-related adverse events (irAEs), remain a critical clinical focus (Kuo et al., 2022; Coleman et al., 2020; Pacha et al., 2025) . Among these, drug reaction with eosinophilia and systemic symptoms (DRESS), also known as drug-induced hypersensitivity syndrome (DiHS), represents a severe adverse drug reaction. Currently, ICIs-induced DRESS is poorly understood and rarely reported, highlighting its status as a unique side effect of ICIs. Elucidating the drivers of ICIs-induced DRESS, including the interplay between checkpoint inhibition, T cell dysregulation, eosinophil activation, and cytokine storms, is essential not only for improving patient safety but also for deciphering fundamental principles of immune dysregulation during checkpoint blockade. Further understanding of ICIs-induced DRESS will substantially help to clinical decision-making, disease management, and the broader comprehension of ICIs toxicities (Voskens et al., 2013; Brüggen et al., 2024). This review explores the clinical manifestations, pathogenic mechanisms, and therapeutic approaches for ICIs-associated DRESS, offering insights into the biomarkers and clinical management strategies in ICIs-induced DRESS patients. Planck-Scale Periodicity C. R. Gimarelli (December 25, 2025) \affiliation Independent Researcher 2. PATHOGENESIS Planck-Scale Periodicity C. R. Gimarelli (December 25, 2025) \affiliation Independent Researcher 2.1 | Immunological mechanisms Until now, the pathogenesis of DRESS remains incompletely understood, and little is known about ICIs-induced DRESS. Eosinophil-mediated immune responses are central to the pathophysiology of classical DRESS, driving systemic inflammation and tissue damage. In the classical DRESS patients, the recruitment of eosinophils to inflammatory sites is primarily mediated through a Th2-type immune response, with activated T cells secreting IL-5. Elevated IL-5 level is consistently observed in DRESS patients, underscoring its critical role in the pathogenesis (Gallo Marin et al., 2023; Mizukawa et al., 2022) . Dendritic cells in the dermis produce CCL17 (thymus and activation-regulated chemokine, TARC), a key mediator that recruits CCR4 + Th2 T cells to the skin, thereby amplifying the inflammatory response (Hama et al., 2022; Catherine & Roufosse, 2021) . Some studies showed that there are the infiltration of CD4+ and CD8 + T lymphocytes, plasmacytoid dendritic cells, and monocytes in the dermis of some classical DRESS patients. Furthermore, these lymphocytes are also identified in biopsies of internal organs (Hama et al., 2022; Takimoto et al., 2019) . Although the immunological essence of DRESS syndrome involves a Th2-dominant cytokine storm (centered on IL-5 and CCL17) driving systemic eosinophilic and T-cell infiltration, ICIs-related DRESS specifically results from PD-1 pathway blockade-induced immune dysregulation, leading to combined Th2/Th17 inflammatory responses and cytotoxic T-cell hyperactivation ( Figure 1 ). In 2021, Ai et al reported that a significant shift toward a Th2 response, an increase in Th17 cell populations, and a marked enrichment of granzyme B and perforin generated by CD8 + T cells were observed in the peripheral blood of Nivolumab-induced DRESS patient, with consistently elevated serum levels of IL-5, IL-17, IFN-γ, and IL-6 (Takimoto et al., 2019) . Furthermore, Nivolumab-induced DRESS may stem from the co-inhibitory function of PD-1. By alleviating tolerance to tumor and self-antigens, PD-1 blockade disrupts immune equilibrium, leading to aberrant responses, tumor regression and tissue damages (Ai et al., 2021) . More interesting, a Tislelizumab-induced DRESS intrahepatic cholangiocarcinoma patient, concurrent IgG4-related lymphadenopathy (IgG4-RLAD) was observed, presenting with lymphadenopathy and elevated IgG4 levels. Theoretically, PD-1 inhibitors might influence IgG4 production by modulating the differentiation of T and B cells. PD-1 blockade by Tislelizumab may dysregulate T follicular helper (Tfh) cell activity, promoting B-cell class switching to IgG4 and subsequent production of pathogenic IgG4 autoantibodies that contribute to tissue inflammation and immune complex formation, thereby triggering DRESS in the context of pre-existing IgG4-RLAD. This case raises the possibility that pre-existing IgG4-RLAD represents a specific risk factor for Tislelizumab-triggered DRESS syndrome, suggesting a complex pathogenesis that demands further in-depth investigation (Wöhner & Nimmerjahn, 2025; Qin et al., 2025) . 2.2 | Immunogenetic markers The strong HLA class I allele associations in drug-induced hypersensitivity DRESS support a CD8 + T-cell-mediated pathogenesis, which relies on CD4 + T-cell helper functions for effective antigen presentation and immune activation (Hama et al., 2022) ( Table 1 ). About 20 years ago, the discovery of HLA-B*57:01’s link to abacavir hypersensitivity and its integration into HIV screening established a clinical translation roadmap (Gibson et al., 2023) . Saag et al indicated that HLA-B57:01 screening for abacavir hypersensitivity has shown a 100% negative predictive value, consistently generalizable across diverse ethnic populations (Saag et al., 2008) . And HLA-B57:01 genotyping was identified as an effective biomarker for preventive strategy (Mallal et al., 2008) . However, these findings showed that abacavir induces a distinct HLA class I-restricted, and CD8 + T-cell-dependent drug hypersensitivity syndrome, rather than DRESS. Few studies have reported the relationship between HLA genotyping and ICIs-induced DRESS. Molecular profiling identified HLA-A*31:01 as a potential genetic risk allele for ICIs-induced DRESS, suggesting a pharmacogenetic predisposition to this severe adverse reaction (Ai et al., 2021) . This data suggests that Nivolumab-induced DRESS may result from type IV hypersensitivity-related ’off-target effect’ and PD-1 block-mediated ’on-target effect (Ai et al., 2021) . Moreover, these HLA class I alleles including HLA-A31:01, HLA-B58:01, HLA-B13:01, and HLA-A32:01were also well-established genetic risk factors for non-ICIs-induced DRESS (Ai et al., 2021) . Altogether, HLA genotyping may help to predict patients at higher risk of severe ICIs-induced DRESS, and screen for the vulnerable individuals. 2.3 | Viruses In addition to drug-induced immunity, the paradoxical clinical worsening after drug cessation in DRESS is also associated with Human Herpesviruses (HHVs) reactivation (such as HHV-6, HHV-7), Epstein–Barr virus (EBV), and Cytomegalovirus (CMV) in peripheral blood (Ramirez et al., 2023; Ingen-Housz-Oro et al., 2023) . HHV-6, the most frequently reactivated HHV, is associated with a more severe disease course, later onset after drug exposure, and is typically occurring during DRESS and up to 2-3 weeks after rash onset (Anci et al., 2020; Descamps & Brunet-Possenti, 2021) . Organ damages in ICIs-induced DRESS may be associated with sequential herpesvirus reactivation, especially HHV-6. In a case of Nivolumab-induced DRESS, sequential herpes zoster virus activation was observed in the patient’s left leg after five weeks (Takimoto et al., 2019) . Notably, EBV reactivation is closely linked to hematopoietic disorders. Chronic EBV-related disease originates from hematopoietic stem cells, leading to lymphoproliferative conditions through multi-lineage hematologic involvement (Wang et al., 2024; Xiong et al., 2023; Tawhari et al., 2018) . Strikingly, Tran et al indicated that a case of Pembrolizumab-induced DRESS patient presented with blistering lesions resembling herpes zoster and/or bullous pemphigoid (Tran & Bhatt, 2024) . Altogether, the immunological mechanisms underlying viral reactivation in ICIs-induced DRESS remain unclear, which may be linked to the impaired immune resistance of patients. Based on these findings, viral reactivation might be triggered by corticosteroid treatment for ICIs-induced DRESS. However, whether ICIs directly impairs antiviral response resulting in viral reactivation, needs to further study. 3 | CLINICAL FEATURES 3.1 | Skin and systemic involvement The clinical manifestations of ICIs-induced DRESS are different from those of non-ICIs-induced DRESS, particularly in patients with a history of ICIs exposure, thereby warranting heightened clinical vigilance. ICI-induced DRESS patients significantly exhibit longer latency period, accompanied by more severe multi-organ involvement with higher rates of hepatic dysfunction, renal impairment, and pulmonary complications, compared with those in classic DRESS patients ( Table 2 ). And ICIs-induced DRESS patients also present with a higher propensity for atypical cutaneous manifestations, such as extensive exfoliative dermatitis and facial edema, increased viral reactivation rates, and greater systemic morbidity including thrombocytopenia, hypotension, and mortality. Conversely, classic DRESS patients typically present with characteristic morbilliform rash, mild mucositis, and hematologic abnormalities like eosinophilia and lymphadenopathy without the same severity of organ damages or viral complications (Wei et al., 2024a) . Consistently, the US Food and Drug Administration Adverse Event Reporting System database also shows ICIs-induced DRESS exhibits a prolonged mean latency of 40 days, higher rates of concomitant allopurinol/antiepileptic use, and more severe outcomes including increased fatal and serious SCARs, compared to conventional anticancer therapies (Raschi et al., 2019) . Based on the full FAERS database, ICIs showed significantly higher reporting odds ratio of SCARs (Godfrey et al., 2024) . Our data involving 13 patients with ICIs-induced DRESS indicated that most patients exhibited clinical symptoms, such as fever (12/13,92%), exanthema covering 69%), enlarged lymph nodes (6/13, 46%), self-limiting oral mucosa involvement (3/13, 23%) ( Table 3 ). And the skin biopsy results showed that consistent with drug reactions, alongside biological changes including hyper eosinophilia (61.5%), hyperlymphocytosis (23%), elevated liver function tests (85%), renal involvement (38%), and lung involvement (15%), with viral replication detected in 38.5% of patients including HHV6, EBV, and CMV (Ramirez et al., 2023) . Similarly, a study of BRAF-related cutaneous adverse events showed that after ICI exposure, the median latency period for BRAF inhibitor-associated DRESS-like reactions was 8-10 days, with a higher risk of thrombocytopenia and hypotension, but a lower risk of lymphadenopathy, eosinophilia, atypical lymphocytosis, liver involvement, and kidney involvement (Naqash et al., 2019) . Altogether, compared to non-ICIs-induced DRESS, ICIs-induced DRESS exhibits more atypical skin manifestations and severe systemic symptoms, with a higher propensity for complications involving organ damages (Ingen-Housz-Oro et al., 2023; Awad et al., 2023) . Mechanistically, previous studies unveiled that ICIs activate the immune system and induce persistent immune alterations, which may promote the development of hypersensitivity reactions to targeted therapies, potentially explaining the diverse clinical manifestations observed in ICIs-induced DRESS (Maloney et al., 2022) . 3.2 | Histologic analysis features Clinically, DRESS is characterized by fever, rash, eosinophilia and atypical features including dysphagia, agranulocytosis, and chylous ascites (Di Palma-Grisi et al., 2019) . To our knowledge, the major pathological features of DRESS is the combination of non-specific epidermal and dermal changes, including dyskeratosis, epidermal spongiosis, interface vacuolization, perivascular lymphocytic infiltration, and eosinophilic infiltration (Wei et al., 2024b) . Although the dermatopathological features of ICIs-induced DRESS are atypical, these features are recognized as the diagnostic criteria for DRESS (Takimoto et al., 2019; Lu et al., 2019; Mirza et al., 2017) . Moreover, organ damages are observed in DRESS, especially more severe in ICIs-induced DRESS. In 2021, Ai et al reported acute kidney injury was observed 4 months after the onset of Nivolumab-associated DRESS. Histopathological analysis revealed that there was diffuse interstitial edema with intense infiltration of lymphocytes, plasma cells and neutrophils, and atrophy in the 10% of renal tubules (Ai et al., 2021) . 4 | BIOMARKERS IN ICIS-INDUCED DRESS Currently, the potential mechanisms of ICIs-induced DRESS have been identified, involving in the proposed genetic risk allele HLA-A*31:01 and cytokine-mediated eosinophil activation pathways (Gallo Marin et al., 2023; Mizukawa et al., 2022; Ai et al., 2021) . However, the diagnostic biomarkers of ICIs-induced DRESS still remain elusive. Further exploration of genetic susceptibility markers and dynamic biomarkers is also warranted. A retrospective study highlighted that the peripheral blood lymphocyte count >820 cells/mm³ at 2 weeks post-ICIs initiation was associated with irAEs including DRESS, indicating its potential as a predictive biomarker for ICIs-DRESS (Egami et al., 2021) . Additionally, preliminary evidence suggests that HLA-A31:01 genetic susceptibility, dynamic serum cytokine profiles (IL-5, IL-17, IFN-γ, IL-6), TARC/CCL17, viral DNA loads (HHV-6/EBV/CMV) and peripheral blood lymphocyte may serve as predictive biomarkers for ICIs-induced DRESS. However, it is necessary to perform clinically multicenter study to validate (Ai et al., 2021; Ingen-Housz-Oro et al., 2023; Egami et al., 2021; Miyagawa & Asada, 2021; Liu et al., 2022) . More strikingly, we recently reported that elevated IgG4 levels or pre-existing IgG4-RLAD represents potential risk factors for ICIs-induced DRESS. Mechanistically, dysregulated IgG4 may synergize with checkpoint inhibition to amplify Th2/Th17-skewed inflammation and cytotoxic CD8⁺ T-cell hyperactivation. This synergy may drive Tfh cell-mediated B-cell class switching toward pathogenic IgG4 autoantibodies, fostering immune complex formation and tissue inflammation. These autoantibodies contribute to tissue inflammation and immune complex deposition, ultimately leading to increase susceptibility to DRESS syndrome (Hsiao et al., 2014; Cramer et al., 2024) . This pathogenic cascade aligns with clinical observations wherein patients with pre-existing IgG4-RLAD developed ICIs-induced DRESS, evidenced by elevated IgG4 titers and systemic eosinophilic infiltration (Qin et al., 2025) . Consequently, pre-therapeutic screening of IgG4 status may help to mitigate ICIs-induced DRESS risk in susceptible populations. 5 | EVALUATION AND MANAGEMENT 5.1 | Diagnosis Since the initial delineation of DRESS, three distinct sets of diagnostic criteria have been established as follows: (1) the seminal criteria articulated by Bocquet et al in 1996 (Bocquet et al., 1996) , (2) the J-SCAR criteria formulated by a Japanese consensus panel in 2006 (Shiohara et al., 2006; Shiohara et al., 2007) , and (3) the RegiSCAR criteria developed by the European Registry of Severe Cutaneous Adverse Reactions to Drugs and Collection of Biological Samples consortium in 2007 (Kardaun et al., 2007) . Nowadays, although the RegiSCAR scoring system is recommended as the diagnostic criteria for DRESS (Sasidharanpillai et al., 2022) , Godfrey et al indicated that there was an association between DRESS and ICIs independent of tumors (Godfrey et al., 2024) , and eosinophilia in ICIs-induced DRESS is atypical. Therefore, the diagnosis criteria for DRESS is flexible. More importantly, because of viral reactivation triggered by ICIs, viral reactivation testing could be considered as part of the diagnostic indicator for ICIs-induced DRESS. In addition, ICIs-induced DRESS tends to cause more severe organ damages than that in classical DRESS. Imaging examination (such as CT and MRI) and more comprehensive laboratory tests (such as liver function, kidney function, and pulmonary function tests) should be incorporated into the diagnostic workflow for ICIs-induced DRESS ( Table 4 ). As mentioned above, the proposed expanded diagnostic framework for ICIs-induced DRESS necessitates: (1) incorporating viral reactivation biomarkers, particularly HHV-6 and CMV (Ingen-Housz-Oro et al., 2023; Wei et al., 2024b; Miyagawa & Asada, 2021) . (2) quantifying specific immune mediators including serum TARC/CCL17, demonstrating superior diagnostic discrimination over eosinophil counts, alongside cytokine profiling (IL-5, IL-17, IFN-γ) to detect Th2/Th17 skewing and CD8 + T-cell cytotoxicity (Ai et al., 2021; Wei et al., 2024b; Miyagawa & Asada, 2021) , and (3) advancing histopathological assessment through cutaneous biopsies revealing mixed lymphocytic-eosinophilic infiltrates with interface dermatitis to differentiate from GVHD/viral exanthems, and visceral biopsies to confirm tissue-specific immune injury patterns (Ai et al., 2021; Ingen-Housz-Oro et al., 2023) . Thus, ICIs-induced DRESS exhibits distinct clinical features requiring diagnostic recognition: (1) temporally, it demonstrates accelerated onset with biphasic evolution potentially triggering immunoreconstitution syndromes post-cessation (e.g., CMV reactivation) (Ingen-Housz-Oro et al., 2023; Miyagawa & Asada, 2021) . (2) systemically, it manifests attenuated hepatic involvement (85% incidence but predominantly grade 1-2 enzyme elevations), which is contrasted by heightened renal injury risk (38.5% acute kidney injury incidence and rigorous creatinine/proteinuria monitoring) (Ai et al., 2021; Ingen-Housz-Oro et al., 2023) . Remarkably, both ICIs-induced DRESS and classical DRESS share core pathogenic mechanisms centered on Th2/Th17 immune skewing and eosinophilic infiltration, accompanied by viral reactivation (e.g., HHV-6) and strong HLA allele-associated T-cell activation (Hama et al., 2022; Ai et al., 2021; Wei et al., 2024b) . Clinically, both entities manifest with hallmark features including fever, cutaneous eruptions, and multi-organ involvement (e.g., hepatic and renal dysfunction) (Coleman et al., 2020) . However, ICIs-induced DRESS is distinguished by its unique pathogenesis involving sustained T-cell activation through PD-1/CTLA-4 blockade, which may disrupt peripheral tolerance and trigger cross-reactive immune responses (Wei et al., 2024b; Xu et al., 2024) . Notably, ICIs-induced DRESS exhibits a prolonged latency period (mean 40 days) and more severe organ damages, particularly renal tubular interstitial nephritis, compared to conventional drug-induced DRESS ( Figure 2 ) ( Table 3 ) (Godfrey et al., 2024) . 5.2 | Treatment Currently, there is no consensus on the treatment of ICIs-induced DRESS. The management of ICIs-induced DRESS primarily follows the treatment strategies for classical DRESS, which involves the immediate discontinuation of potential causative agents and the administration of systemic corticosteroids as the first-line therapy. However, some patients may experience rapid tumor progression after discontinuing ICIs treatment, leading to worse survival. Clinical data showed that irAEs are associated with better clinical outcomes, indirectly suggesting that continuing ICIs treatment may provide better overall benefit for patients with rapid tumor progression (Martini et al., 2021; Socinski et al., 2023; Wongvibulsin et al., 2022) . Therefore, it is essential to consider not only DRESS itself but also the overall goals of cancer treatment in these ICIs-induced DRESS patients. Under strict medical supervision, switching to an alternative therapeutic regimen can be considered to alleviate symptoms while continuing ICIs therapy (Maximova et al., 2020) . Amazingly, anti-IL-6 and anti-TNF-α targeted therapies showed promising potential in alleviating ICIs-induced DRESS (Maximova et al., 2020; Chu et al., 2024) . Moreover, limited data indicated immunosuppressants (such as cyclophosphamide, mycophenolate mofetil, and rituximab) or plasma exchange may be administered in refractory cases (Gottlieb et al., 2022) . These findings may present a strategy for treating DRESS without discontinuing ICIs therapy. However, particular attention is warranted when combining ICIs with other antibody-based therapies such as antiangiogenic agents (e.g., bevacizumab) or IL-6 receptor antagonists (e.g., tocilizumab), due to their potential to induce or exacerbate DRESS, especially from the perspective of IgG4-related immune dysregulation (Hong et al., 2022; Daoudlarian et al., 2025) . Previous studies showed that patients with pre-existing IgG4-RLAD exhibit a predisposition toward Th2 skewing and Tfh cell–mediated B-cell class switching to IgG4, thus ICIs therapy may further disrupt immune homeostasis, enhance Tfh activity, and promote the production of IgG4 autoantibodies, thereby aggravating tissue inflammation and immune complex deposition (Wöhner & Nimmerjahn, 2025; Qin et al., 2025) . Furthermore, concomitant use of other immunomodulatory antibodies (e.g., anti-VEGF or anti–IL-6R agents) could further alter cytokine networks, influence T-cell function, or enhance B-cell activation, potentially synergizing to trigger or worsen a DRESS-like immunoreaction (Trehan et al., 2025; Shao et al., 2025; Becker et al., 2024; Onalan et al., 2025) . Altogether, in patients with elevated IgG4 levels or pre-existing IgG4-RLAD, a thorough assessment of immune status is recommended before initiating combination therapy, accompanied by close monitoring of IgG4 titers, lymphocyte subsets, and inflammatory markers during treatment. Importantly, for the management of ICIs-induced DRESS, corticosteroids should be tapered gradually (by 10-20% every 3-5 days) until symptom alleviation, with a total treatment duration of ≥6-8 weeks to prevent recurrence (Raschi et al., 2019; Wei et al., 2024b; Xu et al., 2024) . It is necessary to screening for the levels of HHV-6, EBV, and CMV-DNA in patients with ICIs-induced DRESS. And these positive patients initially should be received antiviral therapy. As for these patients refractory to corticosteroids, immunosuppressants (e.g., cyclophosphamide, mycophenolate mofetil) or anti-IL-6/anti-TNF-α antibody may be administered (Maximova et al., 2020; Chu et al., 2024) . Additionally, patients with rapid tumor progression post-ICI cessation may be received the tailored treatment, switching to another alternative ICIs (e.g., from PD-1 to CTLA-4 inhibitors) or other targeted/antiangiogenic agents. When switching between different ICIs or combining them with antiangiogenic drugs, vigilance against DRESS induction is crucial. Immunomodulators with distinct mechanisms may have additive or synergistic effects, further breaking immune tolerance (Kumagai et al., 2024; Xie et al., 2024a; Xie et al., 2025) . For instance, CTLA-4 inhibitors predominantly affect early T-cell activation and the accumulation of auto-reactive B cells, whereas antiangiogenic agents may modulate immune cell infiltration and cytokine release within the tumor microenvironment, thereby influencing immune responses (Çakan et al., 2025; Dings et al., 2011) . Mechanistically, these agents could enhance Th2/Th17 skewing, promote eosinophil activation, or trigger viral reactivation, potentially precipitating DRESS in susceptible individuals (Ai et al., 2021; Wei et al., 2024b; Miyagawa & Asada, 2021) . Thus, before altering therapeutic regimens, a comprehensive immune evaluation including IgG4 levels, lymphocyte subsets, and cytokine profiles, is advised, along with intensified clinical and laboratory monitoring during the initial treatment phase. Additionally, in our view, clinical decisions should balance DRESS resolution and oncologic outcome, and individualized strategies are performed as follows：(1) For mild ICIs-induced DRESS, if corticosteroids stabilize the condition but tumor progression is imminent, transitioning to a different ICIs agent may be considered. (2) In moderate cases, corticosteroids combined with immunosuppressants or anti-IL-6/anti-TNF-α antibody are recommended, and ICIs discontinuation strongly advised. In conclusion, continuation or substitution of ICIs treatment requires rigorous risk-benefit balance. (3) Severe DRESS mandates immediate ICIs withdrawal and aggressive immunosuppressive therapy (e.g., high-dose corticosteroids, IVIG, or anti-IL-6/anti-TNF-α antibody) to alleviate systemic inflammation and organ dysfunction ( Table 5 ). 5.3 | Predicting optimal beneficiaries Nowadays, only a few ICIs-induced DRESS cases have been reported (Table 3). However, the pathogenesis of ICIs-induced DRESS remains unclear, and there are no definitive biomarkers to absolutely predict the risk of disease onset or therapeutic benefits. Based on previous findings, several potential indicators have been proposed for clinical identification of DRESS risk and optimal treatment beneficiaries. For instance, HLA-A*31:01-negative patients exhibit a significantly reduced risk of developing DRESS, and this population is more likely to benefit from ICIs therapy with improved safety (Ai et al., 2021) . Thus, HLA genotyping may help identify high-risk patients and guide treatment adjustments. Moreover, Th2/Th17 cell hyperactivation and elevated cytokines (e.g., IL-5, IL-6) are hallmarks of DRESS, and baseline assessments using flow cytometry and serological assays may identify patients with hyperactive immune states (Ai et al., 2021) . Importantly, in order to mitigate risks avoiding high-risk drug combinations, such as concurrent use of allopurinol, and minimizing ICIs combined with chemotherapy or targeted therapies, which may increase DRESS risk, are critical. Meanwhile, timely adjustment of dosing regimens is also recommended. For high-risk patients, prolonging ICIs dosing intervals or combining low-dose ICIs with immunomodulators may balance efficacy and safety. In summary, while these strategies seem very promising, more study is essential to confirm their efficacy and safety. 6 | CONCLUSIONS ICIs-induced DRESS is a severe and distinct drug hypersensitivity reaction, driven by immune checkpoint blockade that disrupts T-cell tolerance and leads to synergistic Th2/Th17 inflammation, cytotoxic CD8 + T-cell hyperactivation, and frequent viral reactivation. It is characterized by prolonged latency, atypical skin manifestations, heightened organ injury, and increased glucocorticoid resistance, distinguishing it from classical DRESS. Notably, pre-existing IgG4-RLAD and elevated IgG4 levels may synergize with checkpoint inhibition to amplify autoimmune-like pathology, underscoring the importance of pre-therapeutic screening for risk stratification. While corticosteroids remain first-line, tailored strategies—including potential continuation of anticancer therapy in select cases—should be considered. Future efforts should prioritize the validation of biomarkers (including IgG4), standardized diagnostic protocols, and immunomodulatory strategies to improve management outcomes and enhance the safety of cancer immunotherapy. AUTHOR CONTRIBUTIONS Ziheng Wu: Methodology，Software，Writing-review & editing, Writing-original draft, Resources. Huan Tian: Funding acquisition, Writing-review & editing. Qiang Tao: Writing–review & editing. Xiaoying Wu: Writing–review & editing. Li Wang: Writing–review & editing. Min Deng: Writing– review & editing. Liu Li: Funding acquisition, Writing–review & editing. Kaiwen Zhong: Writing–review & editing. Chenya Zhuo: Funding acquisition, Writing–review & editing. Wei Qin: Writing–original draft, Writing–review & editing，Visualization, Supervision, Project administration, Resources, Conceptualization. Songlin Peng: Writing–original draft, Project administration, Supervision, Conceptualization. ACKNOWLEDGEMENTS This work was supported by the Shenzhen Fundamental Research Program (JCYJ20220530145200001, JCYJ20240813150252047), the Medical Scientific Research Foundation of Guangzhou City (20241A011091), Guangdong Basic and Applied Basic Research Foundation (2023A1515220088, 2022A1515110893), the Shenzhen Postdoctoral Research Fund, the National Natural Science Foundation of China (32301121), and 2024 Basic and Applied Basic Research Topic of Guangzhou Science and Technology Project (2024A04J4710). CONFLICT OF INTEREST STATEMENT All authors declare no conflict of interest for this article. DATA AVAILABILITY STATEMENT Data sharing does not apply to this article as no data-sets were generated or analyzed during the current study. REFERENCES Ai L, Gao J, Zhao S, Li Q, Cui YH, Liu Q, et al. Nivolumab-associated DRESS in a genetic susceptible individual. 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ICI-mediated blockade of PD-1 or CTLA-4 disrupts peripheral T-cell tolerance, triggering hyperactivation of cytotoxic CD8⁺ T cells, aberrant Th2 responses (elevating IL-5), and Th17 polarization (increasing IL-17). Genetic susceptibility enhances cross-reactive T-cell responses to self/tumor antigens. Concurrent reactivation of latent viruses amplifies systemic inflammation via cytokine storms. Pre-existing IgG4-related lymphadenopathy (IgG4-RLAD) may exacerbate dysregulation through Tfh cell-driven B-cell class switching to pathogenic IgG4. Synergistic effects of eosinophilic tissue infiltration, direct CD8⁺ T-cell cytotoxicity, and cytokine-mediated damage culminate in multiorgan injury. In contrast to classical DRESS, ICI-induced pathogenesis is characterized by combined Th2/Th17 inflammation, higher severity of organ damages (particularly renal tubular injury), and greater dependence on checkpoint inhibitor-specific immune dysregulation. Fig. 2. ICIs-induced DRESS clinical features. Clinically, ICI-DRESS demonstrates a prolonged latency period, atypical cutaneous manifestations, higher-grade organ involvement, increased virus reactivation, and greater glucocorticoid resistance. FIGURE 1 FIGURE 2 Planck-Scale Periodicity C. R. Gimarelli (December 25, 2025) \affiliation Independent Researcher Tables TABLE 1. The relationship between HLA genotypes and the genetic susceptibility to DRESS HLA-A*31:01 Carbamazepine, Nivolumab (ICI) Europeans, Han Chinese, Japanese, Africans Strong [Hsiao et al., 2014; Ai et al., 2021] HLA-B*58:01 Allopurinol Han Chinese, Vietnamese, Korean, Malay, Portuguese Strong [Liu et al., 2022; Cramer et al., 2024; Nguyen et al., 2022; Mifsud et al., 2023; Kim et al., 2022] HLA-B*13:01 Dapsone, Trimethoprim-sulfamethoxazole, Trichloroethylene Han Chinese, Thai Strong [Su et al., 2019; Satapornpong et al., 2021] HLA-A*32:01 Vancomycin, Teicoplanin, Telavancin European-descent Americans Strong [Nakkam et al., 2021; Asif et al., 2024] HLA-B*56:02 Aromatic anticonvulsants (e.g., phenytoin) Indigenous Australians, Thai Moderate [Somogyi et al., 2019] HLA-C*14:02 Phenytoin Thai children Moderate [Manuyakorn et al., 2020] HLA-B*62 Piperacillin-tazobactam UK White Europeans Reporter [Rutkowski et al., 2017] HLA-B*15:13 Phenytoin South Indian Tamil Reporter [Chang et al., 2017] TABLE 2 Clinical characteristics of ICIs-induced DRESS and classical DRESS Latency Period Longer (median 40 days) 2-8 weeks Severity of Organ Damages Higher (primarily liver/kidney) Multiple organs but generally milder Glucocorticoid Resistance More common Less common TABLE 3 Summary of the reports on ICIs-induced DRESS Planck-Scale Periodicity C. R. Gimarelli (December 25, 2025) \affiliation Independent Researcher [Ai et al., 2021] Nivolumab 1 Gastric cancer DRESS syndrome: Rash (generalized),eosinophilia (peak4.21×10⁹/L), pneumonitis, myocarditis (subclinical), acute kidney injury (ATN), herpes zoster activation Elevated cytokines (IL-5, IL-17, IFN-γ, IL-6), high IgE (9071 IU/mL), HLA-A*31:01 risk allele, CD8+ T-cell infiltration (GrB+, TIA-1+) Steroids (methylprednisolone), discontinuation of nivolumab. Complete resolution of rash and renal function; sustained complete antitumor response during follow-up. [Ingen-Housz-Oro et al., 2023] Pembrolizumab 6 Melanoma (4 cases); Lung cancer (2 cases) Fever (100%); >50% BSA rash (100%); Facial edema (83%); Lymph node enlargement (50%); Oral mucosal inflammation (17%) Abnormal liver function (100%); Viral replication (67%); Kidney damage (33%); Stop ICI+systemic hormones 2 cases switched to Nivolumab (1 case recurred) 4 cases survived; 2 cases of tumor death Nivolumab 1 Lung cancer Fever; Purpura; Abnormal liver function;Viral replication; Kidney damage Stop ICI+systemic hormones Survived Ipilimumab +Nivolumab 4 Melanoma (3 cases); Urothelial (1 case) Fever (100%); >50% BSA rash (75%); Facial edema (75%); Lymph node enlargement (50%); Purpura (25%); Blisters (25%) Abnormal liver function (75%); Kidney damage (25%); Stop ICI+systemic hormones; Replace Nivo monotherapy successfully (1 case) 3cases survived; 1 case died Atezolizumab 1 Breast cancer Fever ;>50% BSA rash; Facial edema; Lymph node enlargement; Purpura; Blisters; Oral mucosal inflammation Abnormal liver function Stop ICI+systemic hormones Survived Cemiplimab 1 Squamous cell carcinoma Fever; >50% BSA rash; Oral mucosal inflammation Abnormal liver function Stop ICI+systemic hormones Died [Qin et al., 2025] Tislelizumab (PD-1) 1 Advanced intrahepatic cholangiocarcinoma Fever (37.2-38.6°C), cutaneous pruritus, nasal congestion, lymphadenopathy, face edema, coagulopathy, acute liver injury, hepatomegaly, intrahepatic Glisson’s sheath edema, lymph nodes swelling, pyoperitoneum/pelvic/pleural effusion, pneumonia, skin rashes, eosinophilia, elevated IgE, increased ESR, and EBV infection. Eosinophilia (peak 5.16×10^9/L, 46.3% of WBC), elevated IgE (398 kU/L), elevated ESR (87 mm/h), elevated IgG4 (5.05 g/L), high EBV-DNA load (1.12×10^6 copies/mL), HLA-B*13:01 allele, FGFR3 p.P774L mutation (1.96% in tumor). Discontinuation of Tislelizumab; intravenous methylprednisolone (0.5 mg/kg/day for 1 week, then tapered to 8 mg/day); IVIG (10g/day for 5 days); antiviral therapy (ganciclovir, 5 mg/kg). EBV infection decreased; Liver function normalized; Proteinuria disappeared; Resolution of hepatomegaly/edema on CT; Stable condition with low-dose steroids; Partial response to prior cancer therapy [Maximova et al., 2020] Nivolumab (anti-PD-1 antibody) 1 Metastatic melanoma DRESS syndrome: Rash (>80% body surface), fever (39.7°C), respiratory/circulatory failure, lymphadenopathy, edema, hepatitis. Elevated cytokines (IL-6, TNF-α, IFN-γ, IP-10/CXCL10), profound lymphopenia (210/mm³), hypocomplementemia (C3/C4). Tocilizumab (single dose), infliximab (single dose), steroids (prednisone), discontinuation of vemurafenib/cobimetinib. Rapid recovery of symptoms within hours; renal and hepatic function normalized. Later switched to dabrafenib without recurrence. TABLE 4 Optimized diagnostic workflow for ICI-induced DRESS syndrome Initial Assessment Viral Serology (HHV-6/CMV/EBV PCR) • Positive results indicate active viral reactivation, correlating with disease severity and poor prognosis. • Detection rate: 38.5% in ICI-DRESS cohorts. [Ingen-Housz-Oro et al., 2023; Di Palma-Grisi et al., 2019] Serum Immune Biomarkers: • TARC/CCL17 • IL-5, IL-17, IFN-γ • TARC/CCL17: Superior to eosinophil count for early diagnosis. • Cytokines: Th2/Th17 skewing (IL-5 high /IL-17 high ) and CD8+ T-cell activation (IFN-γ high ) predict systemic involvement. [Ai et al., 2021; Miyagawa and Asada, 2021] Tissue Confirmation Histopathology: • Skin biopsy • Visceral organ biopsy (if involved) •Skin: Mixed lymphocytic-eosinophilic infiltrates with interface dermatitis. •Organs: Rules out GVHD/ infections. [Hama et al., 2022; Ai et al., 2021;Ingen-Housz-Oro et al., 2023; Di Palma-Grisi et al., 2019] Genetic Risk Stratification HLA Genotyping • HLA-A31:01: Strongly associated with nivolumab-induced DRESS. • Guides pre-ICI screening for high-risk patients. [Ai et al., 2021] TABLE 5 Graded treatment strategy for ICIs-induced DRESS Mild Localized rash (<30% body surface area) Low-grade fever (<38.5°C) No or mild organ dysfunction (e.g., mild elevation of liver enzymes ALT/AST) Local Treatment: Topical corticosteroids (e.g., betamethasone ointment) Systemic Treatment: Low-dose oral prednisone (0.5-1 mg/kg/day) Supportive Care: Antihistamines (e.g., cetirizine), hydration Monitoring: Regular follow-up with blood tests, liver and kidney function tests Moderate Widespread rash (≥30% body surface area) High fever (≥38.5°C) Multi-organ involvement (e.g., significant elevation of liver enzymes, mild renal impairment) First-line Treatment: High-dose systemic corticosteroids (prednisone 1-2 mg/kg/day or equivalent methylprednisolone) Adjunctive Therapy: Antiviral medications (e.g., ganciclovir if HHV-6 positive) Symptomatic Support: Hepatoprotective agents, nutritional support Monitoring: Daily assessment of disease progression. Severe Generalized erythema/exfoliative dermatitis Persistent high fever (>39°C) Multi-organ failure (e.g., acute tubulointerstitial nephritis, liver failure, pulmonary infiltration) Intensive Immunosuppression: Intravenous methylprednisolone pulse therapy (500-1000 mg/day ×3 days) Second-line Treatment: Intravenous immunoglobulin (IVIG 2 g/kg ×3-5 days) Targeted biologics (e.g., tocilizumab, infliximab) Plasmapheresis: For refractory cases Critical Support: Hemodialysis, respiratory support Information & Authors Information Version history V1 Version 1 10 February 2026 Copyright This work is licensed under a Non Exclusive No Reuse License. Authors Affiliations Ziheng Wu The Seventh Affiliated Hospital Sun Yat-sen University View all articles by this author Huan Tian The Third Affiliated Hospital of Guangzhou Medical University View all articles by this author Qiang Tao The Eighth Affiliated Hospital of Sun Yat-Sen University View all articles by this author Xiaoying Wu The Seventh Affiliated Hospital Sun Yat-sen University View all articles by this author Li Wang The Seventh Affiliated Hospital Sun Yat-sen University View all articles by this author Min Deng The Seventh Affiliated Hospital Sun Yat-sen University View all articles by this author Li Liu The Seventh Affiliated Hospital Sun Yat-sen University View all articles by this author Kaiwen Zhong The Seventh Affiliated Hospital Sun Yat-sen University View all articles by this author Chenya Zhuo The Seventh Affiliated Hospital Sun Yat-sen University View all articles by this author Wei Qin The Seventh Affiliated Hospital Sun Yat-sen University View all articles by this author Songlin Peng [email protected] The Seventh Affiliated Hospital Sun Yat-sen University View all articles by this author Metrics & Citations Metrics Article Usage 112 views 62 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Ziheng Wu, Huan Tian, Qiang Tao, et al. Immune checkpoint inhibitors (ICIs)-induced Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) in cancer treatment. Authorea . 10 February 2026. DOI: https://doi.org/10.22541/au.177071065.57520748/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu . 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