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Immune-Related Adverse Events in Cancer Immunotherapy

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Immunology and Immunotherapy".

Deadline for manuscript submissions: 15 May 2026 | Viewed by 26141

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Special Issue Editors

Dr. Kate Young

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Guest Editor

The Royal Marsden NHS Foundation Trust, Royal Marsden Hospital, London, UK
Interests: medical oncology; immune checkpoint inhibitor toxicities; immunotherapy

Dr. Anna Olsson-Brown

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Guest Editor

Immunotherapy Team, The Clatterbridge Cancer Centre, Liverpool, UK
Interests: medical oncology; immune checkpoint inhibitor toxicities; immunotherapy

Special Issue Information

Dear Colleagues,

Over the last decade, immunotherapy treatments, particularly immune checkpoint inhibitors, have brought about a paradigm shift in the treatment of multiple solid tumors. These drugs are now used in many settings, from neoadjuvant through to advanced disease, across a wide variety of tumor types and in combination with other systemic anti-cancer therapies, including chemotherapy and tyrosine kinase inhibitors. While these checkpoint inhibitor drugs have revolutionized outcomes for some patients, understanding and treating their attendant side effects, or immune-related adverse events (irAEs), have provided new challenges for the oncology community. While we now know more about the spectrum of irAEs expected with ICIs, less is known about their long-term impact, how best to predict who may suffer from irAEs, how best to capture data on irAEs in clinical trials and in the real world, the mechanisms underlying the different irAEs, how best to treat them, particularly in steroid refractory cases or rarer irAEs, and how to educate our patients and the wider medical community about these very different side effects. Less is still known about the adverse events associated with some of the newer immunotherapies or combination treatments.

This Special Issue ‘Immune-Related Adverse Events in Cancer Immunotherapy’ aims to focus on these topics and more. In this Special Issue, original research articles and reviews are welcome.

We look forward to receiving your contributions.

Dr. Kate Young
Dr. Anna Olsson-Brown
Guest Editors

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Keywords

check point inhibitors (CPIs)
immunotherapy
irAEs
immune checkpoint inhibitors (ICIs)
survivorship
long-term toxicity
steroid refractory
biologics
CAR-T
TILs

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Published Papers (8 papers)

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Research

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19 pages, 1277 KB

Open AccessArticle

Clinical Characteristics and Predictive Factors of Immune-Mediated Cholangitis: A Large Single-Center Retrospective Observational Study

by Noriaki Iijima, Yasutaka Ishii, Shinya Nakamura, Juri Ikemoto, Masaru Furukawa, Yumiko Yamashita, Risa Nomura, Shin Ohtagaki, Yoshihiro Tanaka, Morihito Okada, Noboru Hattori, Sachio Takeno, Nobuyuki Hinata, Akio Tanaka, Wataru Okamoto, Hideki Ohdan, Souichi Yanamoto, Tomonao Aikawa, Ken Yamaguchi, Shinya Takahashi, Tatsuo Ichinohe, Yuji Murakami, Masataka Tsuge and Shiro Oka Show full author list Hide full author list

Cancers 2026, 18(4), 685; https://doi.org/10.3390/cancers18040685 - 19 Feb 2026

Viewed by 662

Abstract

Background: Immune-mediated cholangitis (IMC) is a rare complication of immune checkpoint inhibitor (ICI) therapy, and its clinical characteristics and prognostic implications remain unclear. This study aimed to clarify the characteristics, risk factors, and outcomes of IMC compared with non-cholangitis cases of immune-mediated hepatotoxicity (IMH). Methods: In this single-center retrospective study, 1332 patients who received ICIs between 2014 and 2023 were analyzed. IMH was diagnosed based on liver enzyme elevation and exclusion of other liver diseases, while IMC was identified through characteristic imaging findings. Baseline factors, clinical presentations, treatment responses, and overall survival (OS) were evaluated. Multivariate analysis identified IMC risk and IMH prognostic factors. Results: Among the cohort, 81 (6.1%) patients had IMH, including 10 (0.8%) with IMC. Baseline eosinophil count > 270/μL (odds ratio [OR] 10.33, p = 0.004) and C-reactive protein (CRP) levels > 0.8 mg/dL (OR 6.260, p = 0.027) were independent predictors of IMC. IMC was associated with delayed onset, cholestatic liver injury, abdominal pain, and neutrophil-predominant inflammation. In prognostic analysis, IMC was not associated with OS. However, cholestatic liver injury (hazard ratio [HR] 2.318, p = 0.023) and neutrophil-to-lymphocyte ratio (NLR) ≥ 4.0 (HR 3.622, p = 0.001) were independent predictors of poor OS. Bile duct imaging abnormalities before or after onset were common in patients with treatment-resistant IMC. Conclusions: Baseline eosinophil count and CRP may help predict IMC. While IMC was not a prognostic factor, cholestatic injury and high NLR were associated with worse outcomes. IMC exhibits distinct clinical features, and radiologic findings may support earlier diagnosis and management. Full article

(This article belongs to the Special Issue Immune-Related Adverse Events in Cancer Immunotherapy)

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13 pages, 263 KB

Open AccessArticle

Neoadjuvant Pembrolizumab Associated with Chemotherapy in Early Triple-Negative Breast Cancer Patients: Real-World Data from a French Single-Center Experience

by Ichrak Ben Abdallah, Severine Guiu, Xavier Quantin, William Jacot and Philine Witkowski

Cancers 2026, 18(3), 358; https://doi.org/10.3390/cancers18030358 - 23 Jan 2026

Viewed by 1187

Abstract

Introduction: The addition of immunotherapy to neoadjuvant treatment for early triple-negative breast cancer (TNBC) has been adopted in clinical practice in France since March 2022, with little real-world data published on the topic. The aim of this study was to evaluate real-world data on treatment feasibility, efficacy, and related toxicities, with a specific focus on immune-related adverse events (irAEs). Methods: We conducted a retrospective analysis of patients who completed at least the neoadjuvant sequence of pembrolizumab combined with chemotherapy for early-stage TNBC at Montpellier Cancer Institute from April 2022 to July 2024. Adverse events were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. The pathological complete response (pCR) was defined as the absence of residual invasive disease in the breast and axillary lymph nodes (ypT0/Tis ypN0). Results: We reviewed data from 92 patient records. The median age at diagnosis was 50 years (range: 27–76). The history of autoimmune disease was noted in 3.2% of patients. Grade 3–4 irAEs were observed in 20% of patients and included hepatitis (8.6%), colitis (3.3%), skin toxicity (2.1%), myocarditis (2%), arthralgia (1%), autoimmune hemolytic anemia (1%), hypothyroidism (1%), and adrenal insufficiency (1%). No treatment-related deaths were reported. Immunotherapy was discontinued due to irAEs in 29.3% of patients in the study population. The pCR rate was 61,1%, with no significant association between the number of neoadjuvant pembrolizumab cycles and the pCR rate (p = 0.7). Patients experiencing grade 3–4 irAEs had a pCR rate of 80%, compared to 56.7% in those without such toxicities (p = 0.079). Initial positivity of antinuclear antibodies (ANA) was not associated with an increased incidence of irAEs. Conclusions: The immune-related adverse events and efficacy data observed in our cohort were broadly comparable to those reported in the KEYNOTE-522 trial, with no treatment-related deaths. Patients with grade 3–4 irAEs tended to have higher pCR rates. Full article

(This article belongs to the Special Issue Immune-Related Adverse Events in Cancer Immunotherapy)

14 pages, 925 KB

Open AccessArticle

Late-Onset Immune-Related Adverse Events in Patients with Advanced Melanoma: The LATENT Study

by Javier Pozas, Sowmya Cheruvu, Poorni Priya Jaganathan, Priya Ganesan, Arjun Modi, James Larkin, Laura Cossar, Anna Olsson-Brown, Alexandra Johnson, Nicholas Garbutt, Rebecca Lee, James Jones, Aislinn Macklin-Doherty, Kate Young and LATENT Study Investigators

Cancers 2025, 17(15), 2461; https://doi.org/10.3390/cancers17152461 - 25 Jul 2025

Cited by 2 | Viewed by 3004

Abstract

Background/Objectives: Immune checkpoint inhibitors have significantly transformed the treatment paradigm of advanced melanoma, leading to substantial improvements in survival outcomes. However, this therapeutic success is accompanied by a spectrum of treatment-related adverse events, some of which are increasingly recognised as enduring and non-reversible. Whilst early-onset immune-related toxicities have been well characterized, late-onset toxicities, often emerging in patients with long-term disease control, remain understudied and are frequently overlooked. Methods: To address this knowledge gap, we conducted a retrospective multicentre study in three UK tertiary referral centres, exploring immune-related adverse events in 246 patients with melanoma who received immune checkpoint inhibitors in the advanced setting. We defined late-onset immune-related adverse events as those occurring at least 3 months after the last cycle of immune checkpoint inhibitors. Results: Although most patients experienced early-onset toxicity, almost 15% of patients developed late-onset immune-related adverse events, including skin rash, colitis, hepatitis, and arthritis, among others. These were often challenging to manage and necessitated the use of systemic steroids. Up to 2% of patients presented ultra-late-onset toxicities, defined as those events occurring at least 12 months after treatment completion. Conclusions: This study provides valuable insights into the characteristics of late-onset immune-related adverse events. To further advance our understanding of these late-onset toxicities, dedicated prospective studies are needed to assess risk factors associated with their development and their impact on quality of life. Additionally, translational research focused on finding predictive biomarkers is essential to identify patients at a higher risk of developing delayed adverse events and to understand how best to manage them. Full article

(This article belongs to the Special Issue Immune-Related Adverse Events in Cancer Immunotherapy)

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13 pages, 503 KB

Open AccessArticle

Neutrophil to Lymphocyte Ratio as a Biomarker for the Prediction of Cancer Outcomes and Immune-Related Adverse Events in a CTLA-4-Treated Population

by Michael M. Cunningham, Rachel Romero, Carolina Alvarez, Shruti Saxena Beem, Todd A. Schwartz and Rumey C. Ishizawar

Cancers 2025, 17(12), 2011; https://doi.org/10.3390/cancers17122011 - 17 Jun 2025

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Abstract

Background/Objectives: Immune-related adverse events (irAEs) triggered by immune checkpoint inhibitor therapy (ICI) have been paradoxically associated with both significant morbidity and improved cancer outcomes. While predictive markers for irAEs have been studied in the PD-1 blockade, less is known for their role in CTLA-4 inhibition. This study aims to fill this gap by evaluating NLR and irAE incidence in a CTLA-4-treated population. Methods: This study is a single-center retrospective cohort study investigating 111 patients treated with CTLA-4 inhibition (ipilimumab) to assess associations for baseline low NLR values with cancer outcomes and irAE type and incidence. Patient charts were manually reviewed by a single physician, and unclear clinical events were assessed by a second physician reviewer. Results: In this cohort, the occurrence of more than one irAE presentation was associated with an improved cancer outcome, OR 1.48 (1.02, 2.15). When stratified by organ-specific manifestation, only endocrinologic irAEs were associated with improved cancer outcome, OR 2.82 (1.19, 6.67). A low baseline NLR was statistically significantly associated with an increased incidence of irAEs of any type, OR 4.34 (1.73, 10.9). Conclusions: These data show that irAE occurrence in cancer patients treated with CTLA-4 inhibition is associated with improved cancer outcomes, similar to that previously seen with PD-1 inhibition. It also suggests that the NLR may serve as a practical peripheral biomarker to predict both cancer response and odds of irAEs in patients treated with CTLA-4 inhibition. This low-cost and widely available tool could provide additional information for modeling cancer outcomes. Full article

(This article belongs to the Special Issue Immune-Related Adverse Events in Cancer Immunotherapy)

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Review

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13 pages, 260 KB

Open AccessReview

by Alexandra M. Dunker, Neha Malik, Kathryn J. Krause, Emily Z. Keung, Jason B. Liu, Elise F. Nassif Haddad, Neeta Somaiah, Heather G. Lyu and Christina L. Roland

Cancers 2025, 17(24), 3917; https://doi.org/10.3390/cancers17243917 - 7 Dec 2025

Cited by 1 | Viewed by 1247

Abstract

Background: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment by providing durable survival gains, but understanding their effects on patient health-related quality of life (HRQL) is critical. Methods: We performed a narrative review of cross-sectional surveys, early-phase trials, and large-scale phase II and III randomized controlled clinical trials assessing FDA-approved ICIs, including programmed cell death protein 1 (PD-1) inhibitors, programmed death ligand 1 (PD-L1) inhibitors, and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) inhibitors, with emphasis on patient-reported HRQL. Validated HRQL instruments were summarized, and for pivotal trials, the positioning of HRQL outcomes as primary, secondary, or exploratory endpoints was taken from original protocols or primary manuscripts. Results: ICIs generally preserved or improved HRQL in patients with various malignancies compared with chemotherapy, targeted therapies, or observation. PD-1/PD-L1 inhibitors maintained global health and function and delayed symptom progression in patients with lung cancer, melanoma, and renal cell carcinoma. Regimens combining CTLA-4 blockade and PD-1/PD-L1 inhibition (e.g., nivolumab + ipilimumab, durvalumab + tremelimumab) are associated with HRQL outcomes similar or superior to those of targeted therapies. Overall, most immune-related adverse effects were short-term and did not diminish HRQL benefits. Conclusions: ICIs extend survival while preserving, and often enhancing, patient HRQL. These medications represent a shift in oncology, offering not just longer life but also better daily well-being. Continued long-term patient-reported outcome monitoring is essential to guide survivorship care in the immunotherapy era. Full article

(This article belongs to the Special Issue Immune-Related Adverse Events in Cancer Immunotherapy)

27 pages, 1142 KB

Open AccessReview

Hepatotoxicity in Cancer Immunotherapy: Diagnosis, Management, and Future Perspectives

by Alberto Savino, Alberto Rossi, Stefano Fagiuoli, Pietro Invernizzi, Alessio Gerussi and Mauro Viganò

Cancers 2025, 17(1), 76; https://doi.org/10.3390/cancers17010076 - 29 Dec 2024

Cited by 7 | Viewed by 9095

Abstract

Cancer immunotherapy, particularly immune checkpoint inhibitors, has positively impacted oncological treatments. Despite its effectiveness, immunotherapy is associated with immune-related adverse events (irAEs) that can affect any organ, including the liver. Hepatotoxicity primarily manifests as immune-related hepatitis and, less frequently, cholangitis. Several risk factors, such as pre-existing autoimmune and liver diseases, the type of immunotherapy, and combination regimens, play a role in immune-related hepatotoxicity (irH), although reliable predictive markers or models are still lacking. The severity of irH ranges from mild to severe cases, up to, in rare instances, acute liver failure. Management strategies require regular monitoring for early diagnosis and interventions, encompassing strict monitoring for mild cases to the permanent suspension of immunotherapy for severe forms. Corticosteroids are the backbone of treatment in moderate and high-grade damage, alone or in combination with additional immunosuppressive drugs for resistant or refractory cases. Given the relatively low number of events and the lack of dedicated prospective studies, much uncertainty remains about the optimal management of irH, especially in the most severe cases. This review presents the main features of irH, focusing on injury patterns and mechanisms, and provides an overview of the management landscape, from standard care to the latest evidence. Full article

(This article belongs to the Special Issue Immune-Related Adverse Events in Cancer Immunotherapy)

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Other

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22 pages, 4491 KB

Open AccessSystematic Review

Prognostic Significance of Endocrine-Related Adverse Events in Patients with Melanoma, Non-Small Cell Lung Cancer and Urothelial Cancer After Treatment with Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis

by Stylianos Kopanos, Charalampos Filippatos, Pantelis Rousakis, Ioannis V. Kostopoulos, Constantin N. Baxevanis, Anastasios Tentolouris, Maria Gavriatopoulou, Ourania Tsitsilonis and Ioannis Ntanasis-Stathopoulos

Cancers 2025, 17(22), 3675; https://doi.org/10.3390/cancers17223675 - 17 Nov 2025

Cited by 1 | Viewed by 1263

Abstract

Background/Objectives: Immune checkpoint inhibitors (ICIs) have revolutionized the management of several malignancies, including melanoma, non-small cell lung cancer, and urothelial carcinoma. However, these therapies frequently cause endocrine immune-related adverse events (irAEs), such as thyroid dysfunction, hypophysitis, or autoimmune diabetes, and may carry important prognostic implications. This systematic review and meta-analysis aimed to determine the incidence, spectrum, and clinical significance of endocrine irAEs across major tumor types. Methods: Following PRISMA guidelines and PROSPERO registration (CRD42025646504), we systematically searched PubMed, Embase, Cochrane CENTRAL, Web of Science, and Scopus for studies reporting endocrine irAEs in ICI-treated patients. Random-effects meta-analyses estimated pooled hazard ratios (HRs) for overall (OS) and progression-free survival (PFS) and odds ratios (ORs) for adverse events. Subgroup and meta-regression analyses explored associations by cancer type, ICI class, and event severity. Results: Forty-three studies comprising 17,399 patients were included. Endocrine irAEs occurred in 11–30% of patients and were associated with improved OS (HR: 0.60, 95% CI: 0.54–0.67; p < 0.001) and PFS (HR: 0.61, 95% CI: 0.54–0.68; p < 0.001). Severe events were most frequent with pembrolizumab in melanoma and non-small cell lung cancer and with anti-programmed death-ligand 1 therapy in urothelial carcinoma. In exploratory meta-regression analyses accounting for cancer type, ICI subclass, and irAE severity, no statistically significant correlation was observed between the occurrence of endocrine irAEs (OR) and survival benefit (PFS HR: 0.20, 95% CI −0.10 to 0.51; p = 0.19; OS HR: 0.14, p > 0.05). Conclusions: The development of endocrine irAEs coincides with favorable long-term survival outcomes but may represent surrogate markers of immune activation rather than direct predictors of ICI efficacy. However, the lack of consistent ≥ 3-year follow-up across studies warrants cautious interpretation. Routine endocrine monitoring and interdisciplinary management are essential to optimize the safety and effectiveness of immunotherapy. Full article

(This article belongs to the Special Issue Immune-Related Adverse Events in Cancer Immunotherapy)

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15 pages, 1444 KB

Open AccessSystematic Review

Management of Triple M Syndrome: A Narrative Review of Immune Checkpoint Inhibitor-Induced Myasthenia Gravis, Myositis and Myocarditis

by Martin Furlepa, Isabella Watts and Aisling S. Carr

Cancers 2025, 17(13), 2063; https://doi.org/10.3390/cancers17132063 - 20 Jun 2025

Cited by 4 | Viewed by 7318

Abstract

Background: The advent of immunotherapy has revolutionised cancer treatment by harnessing the immune system to target tumour cells. However, there is increasing awareness of immunotherapy-related adverse events, which can be severe and even fatal. While system-specific immune-related adverse events (ir-AEs) are well documented, growing evidence suggests the existence of overlap syndromes—distinct clusters of immune-mediated complications. One such syndrome is the overlap of myasthenia gravis, myositis and myocarditis, collectively known as Triple M (3M) syndrome. This syndrome is complex, varying in presentation and severity, with in-hospital mortality rates approaching 40%. Whilst there is consensus on the management of system-specific complications, there is no consensus guidance for the management of these overlap syndromes. Methods: In this paper, we conduct a review of the literature, analysing reported cases of 3M syndrome, focusing on treatment approaches and patient outcomes at an individual level. Conclusions: This review highlights the complexity of diagnosing and managing 3M syndrome due to inconsistent reporting, lack of standardised criteria for diagnosis, and treatment variability. While evidence remains limited, we offer broad clinical recommendations and underscore the urgent need for consensus definitions, prospective data collection, and structured treatment guidance. Full article

(This article belongs to the Special Issue Immune-Related Adverse Events in Cancer Immunotherapy)

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