Neuromuscular complications associated with cancer immunotherapy

Abstract

Immune checkpoint inhibitors (ICIs) and cellular immunotherapy have revolutionized cancer treatment. Although these therapies have significantly improved cancer patients’ survival, they are associated with a range of immune-related adverse events (irAEs) that can affect patients' quality of life. Neuromuscular complications related to cancer immunotherapy are rare (<5 % with monotherapy and up to 14 % with combination therapy), but they can be fatal if not addressed promptly. Early diagnosis and intervention are crucial to improving the quality of life and survival of cancer patients affected by neuromuscular complications associated with immunotherapy. However, symptoms can be diverse and nonspecific, including weakness, numbness, imbalance, dysarthria, dysphagia, and even difficulty in breathing, which presents significant challenges for diagnosis and management. This review summarizes the current understanding of the mechanisms, clinical features, diagnostic challenges, and management strategies for neuromuscular complications related to cancer immunotherapy. Understanding the complex interplay between T cells, B cells, and cytokines in the pathogenesis of neuromuscular irAEs is essential for guiding their management. It is important for healthcare providers, including oncologists, neurologists, primary care physicians, and other practitioners, to be familiar with the multidisciplinary clinical management of neuromuscular irAEs. This knowledge will help reduce the mortality and morbidity associated with these complications.

1. Introduction

Cancer immunotherapy is a milestone breakthrough in the field of cancer treatments, offering hope for a cure and significantly improved survival rates for various types of cancer, including melanoma, lung cancer, other solid tumors, and some hematological malignancies. The most applied immunotherapies are immune checkpoint inhibitors (ICIs) and cellular immunotherapy.^1,2 Cellular immunotherapy, also known as adoptive cell therapy (ACT), uses the cells from the body's immune system to eliminate cancer. ACT includes engineered T Cell receptor (TCR) therapy, Chimeric Antigen Receptor (CAR) T cell therapy, Tumor-Infiltrating Lymphocyte (TIL) therapy, and Natural Killer (NK) cell therapy. However, cancer immunotherapy is not without its challenges. These treatments can also lead to immunotherapy-related or immune-related adverse events (irAEs) from unleased immune responses, which may range from mild to severe and can affect various organs and systems in the body. It was estimated that 70 % of patients receiving ICIs developed various grades and types of irAEs.^3,4 Multiple organs and systems could be affected by irAEs, including the central nervous system (CNS) and peripheral nervous system (peripheral nerves, muscles, and neuromuscular junctions). Multiple reviews have discussed CNS complications, such as encephalitis/encephalopathy, in detail, which is more common than peripheral nervous system irAEs.5, 6, 7 Neuromuscular complications, including polymyositis, dermatomyositis, myasthenia gravis (MG), Guillain Barre syndrome (GBS), and chronic inflammatory demyelinating neuropathy (CIDP), are rare but could be potentially fatal. Although there are many case reports and series published, the incidence of neuromuscular complications associated with ICIs varied significantly, from <5 % for monotherapy and up to 14 % for combined therapy.6, 7, 8, 9, 10, 11 The risk factors for developing neuromuscular complications remain unclear. Some cases presenting with musculoskeletal or eye symptoms were not initially recognized as neuromuscular complications associated with ICIs, as noted in previously published review articles and retrospective studies.^12,13 As a result, the true incidence of neuromuscular complications is likely underestimated. While the symptoms of neuromuscular complications are usually nonspecific and mild at first, they can progress rapidly, potentially leading to severe disability or even death.¹⁴ Neuromuscular complications associated with cellular immunotherapy or ACT have been rarely reported in the literature.¹⁵ However, we observed that patients undergoing ACT frequently report significant fatigue, which tends to improve with rehabilitation and physical therapy. Therefore, it is important for healthcare providers to recognize and manage neuromuscular complications associated with cancer immunotherapy, in order to improve patient outcomes. In this review, we summarize the current understanding of the potential mechanisms, clinical presentation, diagnosis, and management of NM irAEs.

2. Potential mechanisms of neuromuscular irAEs associated with ICIs

ICIs exert their therapeutic effect by blocking the inhibitory regulation pathways of the immune system, thereby enhancing the immune response against cancer cells. However, this disruption of immune regulation can lead to irAEs resulting from tissue- or organ-specific autoimmune attacks. These immune attacks, targeting peripheral nerves and muscles, can cause acute abnormalities and may also result in chronic functional deficits. Although neuromuscular irAEs are recognized as immune-mediated diseases, the exact underlying etiology remains only partially understood. Currently, three potential mechanisms have been proposed for the development of neuromuscular irAEs (Fig. 1), which will be discussed in detail below.

Fig. 1.

Summary of the proposed etiologies of neurological complications associated with cancer immunotherapy. The proposed mechanisms of neurological complications associated with cancer immunotherapy involve complex interactions between the immune system and both cancer and normal tissues. Cancer cells and normal tissues often express surface antigens or receptor peptides that share similar sequences, making them susceptible to recognition by corresponding antibodies or ligands. ICIs activate B cells to increase the production of autoantibodies and activate cytotoxic T cells, both can target normal tissues in the nervous system, leading to neuromuscular complications. Furthermore, ICIs trigger other immune effector cells to release inflammatory cytokines and activate complements, amplifying the immune response and exacerbating tissue damage. This overactive immune response not only targets cancer cells but also affects normal tissues, contributing to the development of neurological and neuromuscular disorders. ICI, immune checkpoint inhibitors.

2.1. Antigen simulation associated with cytotoxic T cell activation

ICIs increase the activity of cytotoxic T cells by promoting cell apoptosis and necrosis in both cancer and potentially healthy tissues. Studies suggest that shared antigens are expressed in both cancer cells and normal cells. It is well known that paraneoplastic syndromes are immune-mediated diseases, often associated with surface epitopes that are similar or identical to antigens found in both cancer and normal tissues.¹⁶ There are also similar antigen sequences between TCRs and other molecules on the surface of healthy cells.^17,18 These shared or similar peptides are recognized by the same group of T cells, which stimulate cytotoxic T cells to target both cancer cells and healthy cells, leading to tumor cell death and the development of irAEs, respectively. Thus, it is relatively common for patients undergoing treatment with ICIs to develop various types and grades of irAEs, since the activated T cells target normal cells in addition to cancer cells.

Wang et al. compared T cells in patients with ICI-induced arthritis, rheumatoid arthritis, and psoriatic arthritis. Their study demonstrated that clonal CD38^hiCD127^- CD8 T cells uniquely infiltrated the joints and blood of patients with ICI-induced arthritis, a phenomenon not observed in rheumatoid arthritis or psoriatic arthritis. In vitro experiments showed CD8 T cells acquired the CD38^hi phenotype with increased cytotoxicity through type I interferon signaling.¹⁹ The MD Anderson group performed single-cell RNA sequencing on muscle biopsies of 11 patients with ICI-induced myocarditis and/or myositis. Cytotoxic CD8⁺ T cells with activation/exhaustion markers were detected in both myocarditis and myositis.²⁰ These findings suggest that cytotoxic T-cell activation plays an important role in various irAEs, including neuromuscular complications.

2.2. Proinflammatory cytokine and macrophage activation

ICIs increase the levels of proinflammatory cytokines and activate the complement system. Cytokines are essential molecules that regulate immune system functions, and multiple cytokines are involved in the regulation, cytotoxicity, and survival of both T and B cells. Proinflammatory cytokines can trigger systemic inflammatory responses, potentially leading to an inflammatory storm. These inflammatory responses can target not only tumor cells but also healthy tissues/organs, including peripheral nerves, muscles, or neuromuscular junctions, causing neuromuscular complications. Studies show that IL-6 activity is increased in nivolumab-associated psoriasiform dermatitis.^21,22 IL-6 induces inflammatory responses by increasing the production of acute-phase proteins such as amyloid A, fibrinogen, and C-reactive protein (CRP). It also promotes the differentiation of T cells involved in antibody production regulation, effector T cell proliferation, angiogenesis, and fibrosis through multiple signaling pathways, including transforming growth factor (TGF) beta and vascular endothelial growth factor (VEGF). The IL-6 monoclonal antibody tocilizumab has been used to treat irAEs. Holmstroem et al. performed an open-label clinical study using tocilizumab to treat ICI-induced colitis and arthritis. Although this was a small clinical study with only 19 patients, it demonstrated that 79 % of patients receiving tocilizumab showed clinical improvements within 8 weeks.²³ In a murine ICI myocarditis model (Ctla4^±Pdcd1^-/- mice), it was discovered that CCR2 (C—C chemokine receptor type 2)⁺ monocyte-derived macrophages and CD8⁺ T cells were significantly increased. These macrophages showed high expression of molecules involved in IFN-γ signaling pathways, including Cxcl9 (chemokine [C-X-C motif] ligand 9), Cxcl10 (chemokine [C-X-C motif] ligand 10), Gbp2b (interferon-induced guanylate-binding protein 2b), and Fcgr4 (Fc receptor, IgG, low affinity IV). Depleting CD8⁺ T cells or macrophages, or blocking IFN-γ signaling, blunted the expansion of Cxcl9⁺Cxcl10⁺ macrophages in the heart and attenuated myocarditis. Therefore, this research in a murine model of ICI myocarditis suggests that macrophages and IFN-γ signaling pathways may play important roles in ICI-induced myocarditis.²⁴

2.3. Autoantibody production

Detection of autoantibodies in patients with ICI-associated neuromuscular complications provides evidence of immune dysregulation following ICI treatment. The breakdown of self-tolerance due to ICIs leads to an increased production of autoantibodies. For example, acetylcholine receptor (AchR) antibodies have been detected in patients with ICI-associated MG or overlap syndromes,^25,26 highlighting a specific immune target in neuromuscular irAEs. Additionally, high-titer tropomyosin IgA and IgG autoantibodies have been detected in patients with ICI-associated myositis.²⁷ Moreover, patients with pre-existing autoimmune diseases, such as rheumatoid arthritis, may experience exacerbation of their underlying conditions after receiving ICI treatments.²⁸ Studies have shown that ICIs not only affect T cells but also modulate B cell function. Both CTLA-4 and PD-1 have been implicated in immune tolerance through B cells.^29,30 Changes in B cell populations, including a decrease in circulating B cells and an increase in plasmablasts, have been observed in patients treated with ICIs.^31,32 Laboratory studies demonstrate that blocking CTLA-4 in murine B cells leads to increased B cell responses, defective suppression of antigen-specific antibody responses, and the development of autoantibodies. This suggests that the inhibition of the CTLA-4 pathway may enhance B cell activity, promoting the production of autoantibodies through the modulation of T helper cells.^33,34 In a study by Siddiqui et al., muscle biopsies were performed in patients with ICI-induced myocarditis and/or myositis. Immunohistochemistry stain showed increased expression of all subclasses of IgG and the complement product C4d. These findings were correlated with higher titers of serum antibodies against muscle antigens.²⁰

In addition to the above three main proposed mechanisms of neuromuscular irAEs, our group also hypothesized that complement activation could potentially be involved in neuromuscular irAEs. There was very little research done to investigate the role of complement activation in these complications. In 2024, German physicians reported a woman with a past medical history of thymoma and positive acetylcholine receptor antibody MG developed tetraparesis after she was treated with pembrolizumab, paclitaxel, and epirubicin/cyclophosphamide. She did not respond to standard therapies, including high-dose steroids, immunoadsorption, and pyridostigmine. She was found to have elevated creatine kinase and troponin T. Finally, she was diagnosed with ICI-induced overlap syndrome of MG-myositis-myocarditis after cardiac MRI and muscle biopsy. Her muscle biopsy demonstrated not only CD8 T-cell infiltration in necrotizing muscle fibers but also positive immunostaining of complement protein C5b 9 in the muscle fibers and capillaries. Immunosuppressant Eculizumab is a humanized monoclonal antibody against complement protein C5 that was approved by the US Food and Drug Administration (FDA) for the treatment of anti-AchR antibody-positive generalized MG in October 2017.³⁵ It binds to the complement protein C5, preventing its cleavage into C5a and C5b and the formation of the membrane attack complex. The patient received Eculizumab treatment, and both muscle strength and cardiac function improved significantly. This case indicated that complement activation likely played an essential role in patients with ICI induced myositis given the complement deposit findings in muscle biopsy.³⁶ Fioda et al. also reported a similar case with colorectal cancer in Italy who had a good response to Eculizumab for MG crisis during the treatment of pembrolizumab.³⁷ Based on our clinical practice and communications with other neuromuscular specialists in the USA, we noted that the patients with severe ICI-induced MG responded to Eculizumab. Therefore, complement activation could be a potential underlying mechanism of neuromuscular irAEs.

In summary, these findings highlight the complex roles of both T and B cells, as well as cytokines, in the pathogenesis of neuromuscular irAEs. Further investigation is needed to fully elucidate the complex interplay of immune response, genetic factors, and treatment-related variables involved. Neuromuscular irAEs are more likely to lead to chronic sequelae, which could be attributed to either T-cell-mediated damage that leads to the burnout of nerve or muscle tissues, or to persistent inflammation and immune disturbance that continually attacks these tissues. Conditions like Guillain-Barré syndrome (GBS) or chronic inflammatory demyelinating polyneuropathy (CIDP), often present with persistent symptoms like numbness and weakness, even after ICIs have been discontinued for weeks or months.³⁸ Similarly, MG and myositis are chronic immune-mediated neuromuscular diseases known to be triggered or exacerbated by ICIs.

3. Potential mechanisms of ACT cell therapy-related toxicity involving the peripheral nervous system

ACT, especially CAR T cell therapy, specifically targets tumor cells that express unique antigens. While CAR-T therapy has revolutionized cancer treatment, particularly for hematologic malignancies, it is associated with several unique complications, including central nervous system (CNS) neurotoxicity. The underlying pathophysiology of CAR-T cell-associated CNS neurotoxicity is not fully understood, but it is often referred to as immune effector cell-associated neurotoxicity syndrome (ICANS). Current understanding suggests that ICANS may result from blood-brain barrier (BBB) disruption and the release of proinflammatory cytokines, which contribute to neuroinflammation and neuronal dysfunction (Fig. 2). Clinical manifestations of ICANS can include headaches, altered mental status, seizures, encephalitis, transverse myelitis, tremors, and other neurological symptoms.39, 40, 41 Although neuromuscular complications associated with CAR-T therapy are rarely reported, there are a few documented cases suggesting that CAR-T treatment may lead to elevated creatine kinase levels, myalgia, and weakness. In our own clinical practice, we have identified several instances of cranial nerve palsy occurring shortly after CAR-T therapy. These findings indicate that, while uncommon, neuromuscular complications can indeed occur following CAR-T treatment. CAR-T cells produce a variety of proinflammatory cytokines and express corresponding receptors that trigger a systemic inflammatory response. This inflammatory cascade can potentially affect not only the CNS but also peripheral nerves and muscles, contributing to neuromuscular dysfunction. Further research is needed to better understand the full spectrum of neuromuscular complications in CAR-T therapy and the mechanisms underlying these rare but significant side effects.

Fig. 2.

CAR-T cell therapy-associated neurotoxicity syndrome (ICANS). After CAR-T cell infusion, the engineered T cells recognize cancer cells through their surface antigens, leading to the activation of the CAR-T cells. This activation triggers the release of multiple proinflammatory cytokines, including IL-6, TNF-α, and IFN-γ, among others. These cytokines stimulate myeloid cells, such as macrophages and monocytes, which further amplify the cytokine release and activate additional immune effector cells. The destruction of cancer cells leads to the release of damage-associated molecular patterns (DAMPs), which further promote myeloid cell activation. The heightened immune response, including the release of cytokines, disrupts endothelial cell function, causing vascular leakage and damage to the blood-brain barrier (BBB). This damage allows the infiltration of cytokines and activated immune cells into the central nervous system, resulting in the neurotoxic effects of ICANS. The disruption of normal neural function, including cognitive and motor impairments, is characteristic of ICANS. Additionally, while less commonly reported, the proinflammatory cytokines and activated immune effector cells may also attack peripheral nerves and muscle tissues, leading to neuromuscular abnormalities. These neuromuscular effects, though rare, underscore the broader impact of CAR-T cell therapy-associated immune responses on both the central and peripheral nervous systems. BBB, blood-brain barrier; CAR-T, chimeric antigen receptor- T; DAMPs, damage-associated molecular patterns; IFN-γ, interferon-gamma; IL-6, interleukin-6; TNF-α, tumor necrosis factor-alpha.

3.1. Endothelial cell dysfunction leading to vascular leaking

Endothelial cell dysfunction leading to vascular leakage is a critical component of irAEs associated with cancer immunotherapies. Endothelial cells, which line the blood vessels, play a crucial role in maintaining the integrity of the BBB and regulating vascular permeability. When these cells become dysfunctional, their ability to form tight junctions and control the flow of fluids and immune cells across the vessel walls is compromised.^42,43 In the context of cancer immunotherapy, immune effector cells, including T cells and cytokines, can activate endothelial cells and trigger an inflammatory response. This inflammation disrupts the endothelial barrier, leading to increased vascular permeability or "vascular leaking.'' As a result, immune cells, cytokines, and other inflammatory mediators can infiltrate tissues, including the CNS, contributing to neurotoxicity and other systemic effects (Fig. 2). Gust et al. found that the concentration of von Willebrand Factor (VWF) was significantly higher in patients with severe neurotoxicity after CAR-T cell therapy compared to healthy donors. VWF is a glycoprotein involved in hemostasis that is stored in endothelial Weibel-Palade bodies and released on endothelial cell activation. In addition to VWF, they also evaluated functional changes in angiopoietin (Ang) levels. Ang1 is a potent angiogenic growth factor, whereas Ang-2 is identified as a vascular disruptive agent. Ang-2 is released upon endothelial activation and leads to increased microvascular permeability. They found that the concentration of Ang-2 was higher in patients with grade ≥4 neurotoxicity compared to those with grade ≤3 neurotoxicity.⁴⁴

3.2. Inflammatory cytokines release

The binding of CAR-T cells to the CD19 molecule on the surface of tumor cells triggers the activation of monocytes/macrophages, leading to the systemic release of granulocyte-monocyte colony-stimulating factor (GM-CSF) and Ang-2. Stimulated monocytes increase the secretion of tumor necrosis factor-α (TNF-α), which causes BBB dysfunction with increased permeability.^45,46 Research has demonstrated that there were significantly increased CD14⁺ myeloid cells in the cerebrospinal fluid (CSF) of patients with severe ICANS compared to those with low-grade neurotoxicity.⁴⁷ These myeloid cells, including activated CAR-T cells, secrete multiple proinflammatory cytokines. Cytokines such as TNF-α, Interferon-γ (IFN-Ƴ), IL-6, and IL-15, among others, have been reported to be elevated in both the serum and CSF of patients with ICANS.⁴³ IFN-Ƴ promotes the expression and re-localization of adhesion molecules, including intercellular adhesion molecule 1 (ICAM-1) and platelet endothelial cell adhesion molecule 1 (PECAM-1), on endothelial cells. Both ICAM-1 and PECAM-1 are critical for leukocyte-endothelial cell adhesion and migration during immune responses. ICAM-1 primarily facilitates the initial adhesion of immune cells to the endothelial cell surface, while PECAM-1 is involved in the final steps of immune cell migration through the blood vessel walls into tissues. These molecules are upregulated during inflammatory conditions and are important for the recruitment of immune cells (such as CD4⁺T cells) to sites of infection, injury, or immune responses, such as those triggered by CAR-T therapy and other immune therapies.⁴⁸ Although elevated IL-6 levels have been observed in patients with ICANS, clinical practice has shown that IL-6 receptor blocker Tocilizumab did not improve ICANS symptoms.^49,50 IL-15 induces T cell proliferation and activation,⁵¹ and studies in mice have shown that IL-15 plays an important role in brain injury following intracerebral hemorrhage.⁵² IL-1 is well known for its important role in inflammation, particularly in autoimmune central nervous system diseases and neurodegenerative conditions.^53,54 In a mice model of cytokine release syndrome (CRS) and neurotoxicity induced by CAR-T cell therapy, the IL-1 receptor antagonist anakinra alleviated both CRS and neurotoxicity, indirectly suggesting that the IL-1 signaling pathway could be involved in CAR-T-related neurotoxicity.⁵⁵ In addition, immunotherapy causes tumor cell necrosis and generates damage-associated molecular patterns (DAMPs). These DAMPs may trigger inflammation to eliminate tumor cells which can also cause normal tissue damage.⁵⁶

4. Risk factors of neuromuscular irAEs

Preliminary data from UC Davis indicated older age (>60), male sex, and dual ICI therapy are risk factors for neuromuscular irAEs, which align with previously reported case series.57, 58, 59, 60 Many clinical trials combine chemotherapy with ICIs to achieve better tumor remission outcomes. One pooled case study on pancreatic cancer showed no significant difference in adverse events between the group receiving combined immunotherapy and the chemotherapy-alone group.⁶¹ There is also a growing trend to combine immunotherapy with radiation therapy, alongside other antineoplastic agents such as alkylating agents or antimitotic drugs, to maximize antitumor effects. Alkylating agents, antimitotic drugs, and radiation therapy, which target cell division, can interfere with B cell and T cell proliferation, potentially disrupting immune homeostasis. Previous research has shown that PD-1 inhibitors can activate T cells to enhance radiosensitivity,⁶² and more active T cells could increase the risk of irAEs.⁶³ However, there is currently no large-scale, systematic study investigating whether combined chemotherapy or radiation therapy serves as a risk factor for neuromuscular irAEs. Pre-existing autoimmune diseases are generally considered to increase the risk of irAEs. However, a study of non-small-cell lung cancer patients treated with PD-1 inhibitors found that the incidence of irAEs in patients with pre-existing autoimmune disorders was similar to that in patients without such conditions.⁶⁴ Further clinical research is needed to determine whether pre-existing autoimmune diseases genuinely increase the risk of neuromuscular irAEs. It has also been reported that different ICI medications may have varying incidences and profiles of irAEs. Some studies suggest that PD-1/PDL-1 inhibitors may have a higher incidence of neurological irAEs compared to CTLA-4 inhibitors.65, 66, 67 Prior studies have also suggested that the use of proton pump inhibitors (PPIs) and non-steroidal anti-inflammatory drugs (NSAIDs) is associated with an increased risk of kidney injury after ICI therapy.⁶⁸ Recent studies suggest that the use of statins improves the effect of ICIs.^69,70 Although statins, known to cause muscle toxicity, are commonly prescribed for cardiovascular comorbidities in cancer patients, there are conflicting data for whether concurrent statin use is a significant risk factor for irAEs, including neuromuscular irAEs.^71,72 Given that most cancer patients are older and may have comorbid cardiovascular conditions such as hyperlipidemia, which necessitates statin usage, further research with a larger sample size is essential to address the effect of statins on ICI treatment and neuromuscular irAEs.

5. Clinical features of ICI-associated neuromuscular complications

ICI-associated neuromuscular complications include myopathy, MG, peripheral neuropathy such as GBS and CIDP, and overlap syndrome. These complications can occur in a wide time window, ranging from a few days to up to 2 years from ICI treatment, even after ICIs have been discontinued for weeks or months.⁷³ However, most neurological irAEs occur within the first 3 months of ICI treatments. These neuromuscular irAEs are more likely to lead to chronic sequelae. National Comprehensive Cancer Network (NCCN) 2025 Guidelines classified the neuromuscular irAEs into mild (Grade 1), moderate (Grade 2), and severe (Grade 3–4). Mild irAE does not interfere with patients’ function. Patients with moderate irAE have some interferences with instrumental activities of daily living (ADLs). Severe neuromuscular irAE will limit the self-care of patients and cause significant functional decline, even respiratory deficiency.⁷⁴The clinical features of these neuromuscular complications are summarized below.

5.1. Myopathy or myositis

Myopathy or myositis is the most common ICI-associated neuromuscular complication. The incidences varied from 0.6–0.8 % in cancer patients receiving PD-1 treatment, based on the case series.7, 8^{, 68} The most common histopathology of myopathy is inflammatory myopathy, with subtypes including dermatomyositis, polymyositis, and necrotizing myopathy. In addition to inflammatory myopathy, nonspecific myopathic changes have also been found in muscle biopsies of patients undergoing ICI treatment. There are some interesting histopathological features in muscle biopsies that differentiate ICI-associated myopathy from idiopathic immune-mediated myopathy. These include necrotic muscle fibers usually arranged in clusters, increased frequency of mitochondrial abnormality, and decreased number of regenerating muscle fibers. The common symptoms of ICI-associated myopathy include progressive extremity weakness (mainly in proximal muscle groups), diplopia, ptosis, dysphagia, dysarthria, and muscle aches. In some cases, patients may be presented only with ocular bulbar symptoms (such as diplopia and ptosis) without extremity weakness, which can resemble MG. ICI associated myositis usually presented with painful rhabdomyolysis. Laboratory tests may show significantly elevated serum creatine kinase (CK) levels in ICI associated myositis. A few cases have demonstrated special myositis antibodies, such as anti-3‑hydroxy-3-methylglutaryl-coA reductase (anti-HMGCR) antibody, anti-signal recognition particle (anti-SRP) antibody, Jo-1, among others. However, some patients may present with normal CK levels and negative myositis antibody tests.^75,76 EMG will demonstrate myopathic changes and abnormal spontaneous activities including fibrillations and positive sharp waves could be seen in patients with ICI associated myositis.⁷⁷ Radiological abnormalities can be seen in some cases. Magnetic resonance image (MRI) may show intramuscular T2 hyperintensity with or without gadolinium enhancement, while increased fluorodeoxyglucose (FDG) uptake in muscle may be seen on positron emission tomography (PET).^78,79 However, a significant number of patients with ICI-induced myopathy may have normal radiographic studies. In atypical cases, muscle biopsy and imaging studies can be used to confirm the diagnosis of myopathy. Researchers from the Mayo Clinic have revealed that patients with ICI-associated necrotizing myopathy have several distinctive features in muscle biopsies: 1). necrotic fibers distributed in multifocal cluster pattern; 2). a lower number of regenerating fibers with a higher number of ragged-blue fiber and cytochrome c oxidase-negative fibers per low power field, compared to immune-medicated necrotizing myopathy; and 3). an increased ratio of interstitial histiocytes, over-reactive for acid phosphatase, in the perimysium, when compared to immune-mediated necrotizing myopathy.^75,76 ICI-associated myopathy often presents with visual abnormalities (such as diplopia and ptosis), which are more commonly seen in myasthenia gravies than in idiopathic inflammatory myopathy. Due to this unique feature, it is suspected that co-existing myositis and MG may be relatively common in patients with ICI-associated neuromuscular complications.

It has been reported that approximately 30 % of patients with ICI-associated myopathy may have cardiac muscle involvement, which could contribute significantly to mortality in these patients. Therefore, it is important to monitor troponin levels and perform an echocardiogram for baseline screening when there is a suspicion of ICI-associated myopathy. Cardiac MRI or PET is helpful to improve the diagnostic yield of myocarditis in ICI associated myositis cases with high concern of cardiac muscle involvement. When the clinical suspicion is high, cardiac MRI or PET should be performed even patients with ICI associated myositis had normal echocardiogram.⁷⁷

Severe ICI associated myositis could be fatal complications, as it could cause respiratory failure due to bulbar weakness and respiratory muscle weakness. In addition to the skeletal muscle weakness, concurrent myocarditis also increases the mortality rate of ICI associated myositis. It is very important to make prompt diagnosis of ICI associated myositis and screen for possible concurrent myocarditis to decrease the mortality and morbidity of neuromuscular irAEs.

5.2. Myasthenia gravis

Some patients developed post-neuromuscular junction disease, such as MG, after ICI treatments. The symptoms are similar to those of ICI-associated myopathy/myositis and include ptosis, diplopia, dysarthria, dysphagia, and extremity weakness. ICI induced MG demonstrates more severe ocular and bulbar weakness than extremity weakness. The ocular and facial symptoms are usually asymmetric in ICI induced MG, compared with ICI associated myositis. MG frequently affects the diaphragm with the potential for respiratory failure. Unlike myositis, the weakness is worse after continuous effort, leading to severe fatigue. Patients with ICI associated MG usually presented with fluctuating weakness without muscle ache or myalgia, which could be used to differentiate from myositis. Isolated ICI associated MG usually does not present with myalgia, which could be different from ICI induced myositis. However, it is not uncommon for patients to develop both myopathy and MG after ICI treatment. Compared to idiopathic MG, MG associated with ICI treatment typically presents with more severe clinical symptoms (based on MG Foundation of America (MGFA) classification: grade III-IV) and a more rapid progression. It has been reported that 45 % of cases may require mechanical ventilation. ICI associated MG may overlap with myositis or myocarditis. Idiopathic MG rarely has concurrent myopathy or cardiomyopathy. Given the severe functional impairment, early diagnosis and intervention of ICI-associated MG are crucial to decrease morbidity and mortality. The diagnosis can be challenging as fewer than 70 % of patients show positive antibodies (e.g., acetylcholine receptor antibodies, MUSK antibody, LRP4 antibody). Electrophysiological studies can aid in the diagnosis of patients with negative antibody tests, although the diagnostic yield is, similarly relatively low (41 %).^7,8,78

The majority of ICI induced MG cases usually required long term immunosuppression treatment after the initial recovery from acute exacerbation. Only a small number of patients presented with mild symptoms and pyridostigmine treatment is adequate for symptomatic managements after holding ICI therapies.

5.3. Neuropathy

Peripheral neuropathy is a very rare NM irAE. The common clinical symptoms include sensory abnormalities, such as neuropathic pain and paresthesia, and motor disturbance, such as weakness and muscle cramps. In some cases, patients present with cranial palsy, leading to ptosis, diplopia, dysarthria, and dysphagia. Chen et al. conducted a series of 23 cases of ICI- ICI-associated peripheral neuropathies and summarized the electrophysiological types of these neuropathies. The most common type was acute inflammatory demyelinating polyneuropathy (AIDP), followed by axonal sensorimotor polyneuropathy, sensory polyneuropathy, and mononeuropathy. Among these cases, 52 % required hospitalization. Interestingly, the electromyography (EMG) studies also showed coexisting myopathy or MG in a few cases. For some patients with ICI-associated peripheral neuropathy, cerebrospinal fluid (CSF) tests demonstrated both pleocytosis and elevated protein levels, which is not a typical feature of AIDP (albuminocytological dissociation).⁷⁹ ICI associated AIDP is a feared complication as it may cause respiratory failure due to diaphragm weakness and bulbar weakness. Early diagnosis is the key to initiate timely treatment of ICI associated with AIDP, including immunoglobulin (Ig) and plasma exchange, to decrease mortality and morbidity. A unique treatment is the steroids use for ICI associated AIDP, which is not indicated in idiopathic AIDP.

5.4. Overlap or coexistence syndromes of neuromuscular irAEs

As discussed above, it is quite common to detect coexisting neuromuscular conditions, such as myopathy, MG, and neuropathy, in patients receiving ICI treatment. In addition to overlap syndromes affecting two organs or systems, a few cases may present with triple syndrome, which includes myositis, MG, and myocarditis. The frequency of these coexisting neuromuscular complications has been estimated to be as high as 25–30 %.7, 8, 9^,80 The remarkable incidence of overlap syndromes may contribute to severe clinical symptoms, rapid progression, and high mortality and morbidity in patients with neuromuscular irAEs. Although it is hard to differentiate between myopathy and MG based on clinical symptoms, it is important to recognize overlapping myopathy in patients with ICI induced MG when the patients complained about pain/muscle ache/soreness and lab tests demonstrated elevated muscle enzymes (including CK, aldolase and transaminases), because patients with ICI associated myopathy/myositis have increased risk of myocarditis that is a fatal complication.

6. Challenges in the diagnosis of NM irAEs

Early diagnosis and intervention are crucial to improving lifespan and quality of life for cancer patients with neuromuscular irAEs. However, achieving an early diagnosis is challenging due to several factors. First, symptoms such as fatigue, weakness in the extremities, swallowing difficulty, and vision disturbance are relatively nonspecific in the early stages of neuromuscular irAEs. Fatigue and weakness are common chronic complaints in cancer patients, particularly among the elderly, making it difficult to differentiate them from symptoms of neuromuscular complications that develop after cancer immunotherapy. When symptoms are mild in the early stages, patients who are not aware of their significance may attribute them to cancer-related issues or aging. As a result, they might not report these symptoms to their oncologists. Additionally, certain symptoms overlap with chronic deficits related to cancer lesions. For instance, dysphagia and dysarthria are common in patients with laryngeal malignancy or gastrointestinal tract cancer, such as esophageal cancer. Healthcare providers may be misled by these chronic symptoms, even though they could be early clues of neuromuscular irAEs. Second, many cancer patients received other cancer treatments, including chemotherapy and radiation therapy, prior to the immunotherapy. These treatments can lead to residual symptoms, such as paresthesia and weakness, which may mask the symptoms of neuromuscular irAEs following immunotherapy.

Third, there are no reliable biomarkers with high sensitivity and specificity to aid in the early diagnosis of neuromuscular irAEs. For example, positive acetylcholine receptor antibody tests are detected in fewer than 70 % of patients with MG associated with ICIs. Even electrophysiological studies can be negative in some patients with neuromuscular irAEs. In our practice, we had one patient in whom an MRI showed paraspinal muscle edema, which helped establish the diagnosis of ICI-associated myositis, as muscle enzyme levels, antibody tests, and electrophysiological studies were all inconclusive. Due to these challenges, achieving an early diagnosis of neuromuscular irAEs is difficult. Our group previously found that a higher frequency of CD4-CD8- double-negative (DN) T cells was associated with a longer progression-free survival (PFS) without neuromuscular complications after ICI therapy.81, 82, 83 Unpublished data from our group has also found that increased B cells and CD4 central memory cell proportions, as well as elevated inflammatory cytokine levels, were observed in a small sample of patients with neuromuscular irAEs. Clonal expansion of CD8⁺ T cells in the systemic circulation was observed preceding the development of various ipilimumab-induced toxicities in a small case study.⁸⁴ All these findings suggest that there could be potential cellular biomarkers linked to autoimmune overactivity targeting nerves and muscles.

Fourth, some cancer patients present paraneoplastic neuromuscular syndromes, such as Lambert-Eaton syndrome. The clinical presentations of these paraneoplastic neuromuscular syndromes are very similar to the neuromuscular complications after cancer immunotherapy, making it difficult to differentiate between the two at an early stage. However, the time course differs for paraneoplastic neuromuscular syndromes, as syndromes typically appear before ICI treatments. Detailed baseline history and neurological exam are helpful in distinguishing these paraneoplastic syndromes from neuromuscular irAEs. We recently reported that the neurological symptoms of patients with paraneoplastic neuromuscular syndromes improve over time with combined IVIG and ICI treatments.⁸⁵

7. Managements

It is challenging to offer a standardized guideline for all cases with neuromuscular irAEs, as these patients are often complicated with multiple medical comorbidities. Therefore, it is important to follow the general principles of managing inflammatory myopathy, MG, and AIDP, an individual treatment regimen is necessary to achieve optimal therapeutic responses. The first and most important step in managing neuromuscular irAE is to stop cancer immunotherapy and conduct a comprehensive neurological evaluation to assess the severity. Given the potential for rapid progression, clinicians should consider MG and AIDP (or GBS) as moderate to severe complications that require close neurological monitoring and hospitalization to decrease mortality and morbidity. ICI associated myositis, MG and AIDP could cause bulbar weakness and respiratory muscle weakness, leading to severe respiratory failure. These complications are life threatening emergency irAEs.

Since overlap syndromes are common, even in patients with mild symptoms of myositis or MG, it is recommended to obtain serum troponin T, perform an EKG, and conduct an echocardiogram to evaluate potential cardiac muscle involvement. Whenever there is a suspicion of possible myocarditis, MRI or PET imaging could be obtained to confirm the diagnosis if the above routine laboratory tests and echocardiogram are normal. Immunomodulation therapy is the mainstream of treatment for neuromuscular irAEs. Commonly used therapies include steroids (IV or oral), IVIG, plasmapheresis, and rituximab. Based on published references and our own practice experience, we summarized the managements of neuromuscular irAEs including the above therapies in Table 1.^74,77,86,87

Table 1.

Suggested managements of neuromuscular irAEs.

Neuromuscular irAEs	Grade	Managements
		Medical treatments	Clinical processing
Myopathy/myositis	Mild (CK<1000 mg/L)	Consider decreasing or stopping ICIs	Close clinical monitoring and frequent lab tests (CK, Aldolase, CMP), baseline EKG, troponin, Echocardiogram
	Moderate	Stop ICIs, start prednisone 0.5 mg/kg/d for 2–4 weeks, if improving, taper down by 5 mg/week; if no improvements, go to management of severe myopathy/myositis; if relapse, slow prednisone taper and add nonsteroids immunosuppressant	Close clinical monitoring and frequent lab tests; Screen myocarditis and MG; Neurology/rheumatology consultation
	Severe	Stop ICIs, start IV methylprednisolone 1000 mg/d x 3 days followed by prednisone 1 mg/kg/d, tapering pending on response. Combined IVIG 2 g/kg (divided to 3–5 days) if there is bulbar weakness, respiratory insufficiency, rapid decline or life-threatening situations. If not improving, consider plasma exchange or Abatacept	Close clinical monitoring and frequent lab tests; Screen myocarditis and MG; Neurology/Rheumatology consultation
MG	Mild	Consider decreasing or stopping ICI, start pyridostigmine 30–60 mg TID	Close clinical monitoring and baseline lab tests (CK, Aldolase, CMP, troponin), EKG, Echocardiogram; Neurology consultation
	Moderate	Stop ICIs, start low dose prednisone 20 mg daily, slowly titrate up (no >1 mg/kg/d) pending on responses. Add pyridostigmine 30–60 mg TID, can titrate up to 120 mg QID pending on responses and tolerance. Consider inpatient care	Close clinical monitoring and bedside swallowing evaluation, PFT; repeat CK, Aldolase, CMP, troponin, EKG and Echocardiogram if no improvements or continuing decline; Neurology consultation
	Severe	Stop ICIs, start inpatient care (ideally ICU level). Combined IVIG 2 g/kg (divided to 5 days) or plasma exchange with IV methylprednisolone 1000 mg/d x 3–5 days, followed by prednisone 1 mg/kg/d, slow taper as outpatient; if no improvements, consider adding Rituximab; avoid medications that can exacerbate MG	Close clinical monitoring and frequent swallowing/PFT evaluation; repeat CK, Aldolase, CMP, troponin, EKG and Echocardiogram if no improvements or continuing decline; for highly suspected overlapping myositis/myocarditis cases, consider MRI or PET; Neurology consultation
Neuropathy	Mild	Consider decreasing or stopping ICIs, may start gabapentin (Neurontin)/Pregabalin for neuropathic pain, paresthesia	Close clinical monitoring, obtain common neuropathy labs (B12, B1, HgbA1c, SPEP with immunofixation, HIV, ANA and ANCA)
	Moderate	Stop ICIs, consider neuraxial imaging and EMG/NCS study per neurology; may start gabapentin (Neurontin)/Pregabalin for symptomatic care of neuropathic pain, paresthesia	Close clinical monitoring, obtain common neuropathy labs (B12, B1, HgbA1c, SPEP with immunofixation, HIV, ANA and ANCA); Neurology consultation; physical therapy
	Severe (GBS/AIDP)	Stop ICIs, start inpatient care (ideally ICU level), obtain neuroaxial imaging to rule out compressive lesion, start IVIG 2 g/kg (divided to 3–5 days) or plasma exchange or IV methylprednisolone 1000 mg/d x 3–5 days, followed by prednisone 1 mg/kg/d, or combined therapy pending on clinical judgements and multidisciplinary decision; gabapentin (Neurontin)/Pregabalin for symptomatic care of neuropathic pain, paresthesia	Close clinical monitoring and frequent swallowing/PFT evaluation. Monitor autonomic dysfunction. Neurology consultation; Ganglioside antibody test, in addition to common neuropathy labs. Lumbar puncture and EMG/NCS study (highly recommended but not mandatory)

Abbreviations: ANA, antinuclear antibody; ANCA, antineutrophil cytoplasmic antibody; CK, creatine kinase; CMP, comprehensive metabolic panel; EKG, electrocardiography; EMG, electromyography; ICI, immune checkpoint inhibitor; ICU, intensive care unit; irAE, immune related adverse effect; IV, intravenous; IG, immunoglobulin; MG, myasthenia gravis; MRI, magnetic resonance imaging; NCS, nerve conduction study; PFT, pulmonary function test; QID, quarter in die, four times daily; SPEP, serum protein electrophoresis; TID, three times daily.

Currently, the diagnosis of neuromuscular irAEs is heavily relied on detailed history and careful physical examination, rather than special laboratory tests or imaging studies. In our own clinical retrospective research at University of California at Davis, the estimated incidence of neuromuscular irAEs was relatively low (1 %). However, the real incidence could be much higher, given many patients undergoing cancer immunotherapy may experience mild and transient symptoms of neuromuscular irAEs. Patients with mild symptoms of neuromuscular irAEs usually will stop cancer immunotherapy to help resolve the symptoms. Symptomatic management including pain medications, physical therapy could be applied to improve function. These mild cases still need close clinical monitoring (Fig. 3), especially for the patients who decide to continue cancer immunotherapy while they have mild or transient symptoms. The decision of continuing cancer immunotherapy should be based on individual cases, as some cases may progress rapidly to grade 3 and 4 that need admission for urgent treatment. If the symptoms of mild cases of neuromuscular irAEs are resolved after stopping cancer immunotherapy, ICI rechallenging could be attempted with careful evaluation and close monitoring under the multidisciplinary team work. The decision should be based on individual cases, rather than a generalized standard.

Fig. 3.

A multidisciplinary approach for managing subjects with neuromuscular irAEs. A multidisciplinary approach is crucial for the effective management of patients at risk of developing neuromuscular immune-related adverse events (NM irAEs) during cancer immunotherapy. Before initiating treatment, patients will undergo a risk assessment to identify those at high risk for developing NM irAEs. High-risk patients will be instructed to download the MyChart app on their smartphones, enabling them to complete weekly surveys that facilitate close monitoring of potential symptoms. Additionally, all patients, their family members or caregivers, and healthcare providers, will receive comprehensive education on the signs and symptoms of neuromuscular irAEs associated with cancer immunotherapy treatments. To further support this process, alerts will be integrated into electronic medical record systems (such as Epic and MyChart) to notify healthcare providers when they access the charts of patients receiving ICIs. This system will act as a proactive reminder for clinicians to remain vigilant for any emerging NM irAEs. If symptoms and signs indicating neuromuscular complications arise, a multidisciplinary team will promptly evaluate the patient’s condition and assess the severity of the complications. Blood samples will be collected to assist in diagnosis and further understanding of the underlying mechanisms. Additionally, the patient’s information will be entered into a neuromuscular irAE database, which will be invaluable for future research aimed at improving the management and prevention of these adverse events. This proactive and collaborative approach ensures that potential neuromuscular complications are detected early, improving patient outcomes and contributing to ongoing clinical research. App, application; EMG, electromyography; EMR, electronic medical records; ICI, immune checkpoint inhibitor; irAEs, immune-related adverse events; IT, information technology; NCS, nerve conduction study; NM, neuromuscular.

7.1. Corticosteroids

Corticosteroids are the most commonly used immunomodulatory agent for treating NM irAEs, including ICANS. They can be administrated intravenously (IV) or orally. For severe neuromuscular irAEs, a common clinical practice is to start IV Methylprednisolone (1000 mg daily for 3–5 days), followed by a tapering regimen of oral prednisone. For patients with myositis/myocarditis and MG, oral prednisone may be started at a higher dose of 1 mg/kg daily, but no >100 mg daily. It is important to start vitamin D and calcium supplementation, as well as proton pump inhibitors, for patients on corticosteroids to mitigate potential side effects. This is particularly crucial as cancer patients are often elderly and have multiple medical comorbidities. For ICI-induced myositis/myocarditis and MG, the oral corticosteroid tapering process is relatively slow, often taking >4 weeks. Therefore, prophylaxis against Pneumocystis jirovecii pneumonia (PCP) is recommended for patients who need to be on relatively high-dose corticosteroids for >2 months. ICI-induced GBS usually is treated with IVIG or plasma exchange. For severe ICI-induced GBS, administration of short-term corticosteroids is a reasonable trial in addition to IVIG or plasma exchange.

7.2. Immunoglobulin

Intravenous immunoglobulin (IVIG) is a mixture of normal human serum immunoglobulins used to treat multiple medical conditions. It is a powerful immunomodulatory therapy for autoimmune diseases or inflammatory disorders. Given the multiple long-term side effects associated with corticosteroids, IVIG is often preferred for cancer patients with severe ICI-induced myositis/myocarditis and MG. Additionally, IVIG is the first-line treatment for both ICI-induced GBS and idiopathic GBS. However, IVIG has not been used to treat ICANS. IVIG is generally well tolerated, and premedication with acetaminophen, diphenhydramine, and IV methylprednisolone is recommended to reduce adverse effects, such as allergic reactions. Although the incidence of adverse reactions is low, it is important to watch for potential complications, including thromboembolic events, kidney injuries, and anaphylaxis during the IVIG administration.

7.3. Plasma exchange

Plasma exchange, or plasmapheresis, is a medical procedure to remove and return exchanged blood plasma to treat various disorders, including immune-mediated neuromuscular diseases such as GBS and MG. Prior studies in Japan and Egypt have shown that IVIG and plasma exchange were equivalent in therapeutic efficacy and long-term outcomes for idiopathic GBS.^88,89 Although IVIG and plasma exchange are considered to have similar effectiveness in managing idiopathic MG exacerbations, plasma exchange may be less costly.⁹⁰ However, this procedure requires an implanted catheter and a special machine, which makes it less commonly used as a first-line treatment for immune-mediated neuromuscular complications associated with cancer immunotherapy. Plasma exchange also carries an increased risk of multiple complications, including bleeding or hematoma at the catheter site, infection, hypotension, and transfusion reaction.

Plasma exchange was used for the ICANS management. In a 17-case study from multiple medical centers in China, plasma exchange significantly improved clinical outcomes and laboratory tests in patients with corticosteroid/Tocilizumab refractory cytokine release syndrome after CAR-T therapy.⁹¹

7.4. Rituximab

Rituximab is a monoclonal antibody that targets the protein CD 20, a surface molecule expressed on B lymphocytes. CD20 is lost when B cells mature into plasma cells. CD 20 plays a role in B cell receptor signaling and is considered a marker for B cell malignancies as well as some inflammatory diseases.⁹² Rituximab has been used to treat various cancers, such as lymphomas, and multiple immune-mediated disorders, including MG, vasculitis, and rheumatoid arthritis.^93,94 Rituximab has been reported to treat cancer patients with ICI-induced CNS complications, such as encephalitis.⁹⁵ Several case reports have also shown rituximab was used to treat ICI-induced vasculitis involving peripheral nerves and muscles, with varying therapeutic responses.^96,97

Rituximab is the first-line treatment for MG associated with anti-MUSK antibodies, but no case reports have shown positive MUSK antibodies in ICI-induced MG.^98,99 However, since the underlying etiology of ICI-induced neuromuscular complications may involve increased autoantibody production, it is reasonable to consider rituximab in patients with refractory ICI-induced MG or overlap syndrome.

7.5. Abatacept

Abatacept is a recombinant, soluble fusion protein consisting of the CTLA4 extracellular domain and IgG Fc fusion protein acting as a T cell co-stimulatory signal blocker through inhibition of the CD80/CD86-CD28 interaction. Abatacept inhibits proliferation and cytokine production in vitro, and reduces parameters of inflammation in vivo in patients with juvenile idiopathic arthritis.^100,101 It was used to treat rheumatological diseases such as rheumatoid arthritis. Wei et al. had shown that Abatacept attenuated myocarditis in a genetic mouse model of ICI myocarditis.¹⁰² In 2022, French physician reported a thymoma case with fulminant myocarditis after pembrolizumab treatment. The patient did not respond to mycophenolate mofetil (CellCept) but combined therapy of Abatacept and Roxolitinib reversed his myocarditis.¹⁰³ Abatacept with Ruxolitinib has also been reported for patients with concomitant myositis and myocarditis.¹⁰⁴ It is unclear if Abatacept could be applied to treat other neuromuscular irAEs.¹⁰⁵ Abatacept has been actively evaluated for treating other ICI associated adverse events and other autoimmune diseases (clinicaltrials.gov).

7.6. New immunomodulation agents

Recent developments have introduced new agents targeting the treatment of neuromuscular irAEs associated with ICI or ACT. CD24 is a cell adhesion molecule expressed on the surface of B cells, neutrophils, and neuroblasts. Siglec-10, the receptor for CD24, binds to CD24 and suppresses inflammation triggered by DAMPs released by damaged cells.106, 107, 108 Liu et al. demonstrated that CD24Fc ameliorated irAEs while preserving the anti-tumor therapeutic effect.¹⁰⁹ Clinical trials of CD24Fc for managing ICI-associated irAEs are highly anticipated.

Janus kinase inhibitor (JAK) Ruxolitinib was reported to be used to treat ICI associated transverse myelitis.¹¹⁰ The combined use of Roxolitinib and Abatabcept also successfully managed ICI induced myocarditis.¹⁰³ JAK signaling pathway activation is involved in cell proliferation/survival and invasiveness. It has been reported in multiple papers on the pathophysiology of autoimmune diseases and cancers. Many anti-tumor medications have been targeting JAK signaling pathway and the JAK inhibitors have shown the therapeutic effects on inflammatory diseases.^111,112 JAK inhibitors could potentially decrease the inflammation triggered by ICIs. Further laboratory research and large-scale clinical trials will be necessary to investigate the therapeutic effect of JAK inhibitors in the managements of ICI associated myocarditis.

As multiple proinflammatory cytokines are involved in ICANS, several treatments in clinical trials have explored cytokines blockage as a strategy to manage ICANS. Anakinra, a recombinant human IL-1 receptor antagonist, has been approved for the treatment of rheumatological diseases. A retrospective study examined 14 cases of steroid-refractory ICANS, with or without CRS after standard CAR-T treatment. It showed that there were statistically significant reductions in fever, inflammatory cytokines, and biomarkers associated with ICANS/CRS after anakinra treatment in this single-center cohort.¹¹³

As we mentioned earlier in this review, medications targeting complements, such as Eculizumab, could be potentially good choices for patients with ICI-induced MG or myositis, even overlap syndromes.^36,37 Large case serial studies or clinical trials in the future could be helpful to explore the efficacy of complement monoclonal antibodies in the treatment of neuromuscular irAEs.

Based on our experience, the combined use of multiple immunomodulatory therapies is often required to treat patients with high-grade neuromuscular irAEs or overlap syndromes. For mild cases with rapid progression, we recommend a low threshold to initiate IVIG or plasmapheresis in addition to steroids. Besides immunomodulatory therapies, symptomatic management and supportive multidisciplinary care are crucial for improving patients’ quality of life.^114,115 To decrease the mortality and morbidity of neuromuscular irAEs, our institution has established a multidisciplinary team that includes specialties along with an integrated technology platform, to ensure timely diagnosis and treatments (Fig. 3). Our recent practice has successfully applied this multidisciplinary approach to manage a patient with ICI-associated AIDP, who remains in remission from cancer and maintains high function in daily activities.

8. Summary and perspectives

With the increasing use of cancer immunotherapy, more patients are experiencing adverse events affecting the nerves and muscles, leading to significant acute and chronic disability or even death. Therefore, it is very important to recognize and manage the neuromuscular irAEs in a timely manner to improve the overall life quality of cancer patients. Current data highlights the complex and interactive roles of T cells, B cells, and cytokines in the pathogenesis of neuromuscular irAEs, which informs the current management strategies. However, further research is needed to fully elucidate the intricate interplay of immune responses, including the involvement of various immune cells, genetic factors, and treatment-related variables. This knowledge is critical for developing effective interventions that balance maintaining anti-tumor efficacy while minimizing the severity of neuromuscular irAEs caused by autoimmune overactivation.

Early diagnosis and effective management of neuromuscular irAEs remain challenging due to the barriers outlined in this review. To address these challenges, our institution has developed a multidisciplinary work algorithm aimed at improving the outcome of patients with neuromuscular irAEs. The optimization of this workflow, along with the identification of reliable biomarkers, will be key future directions. Additionally, further studies are needed to accurately determine the incidence, underlying mechanisms, and clinical features of neuromuscular complications associated with cancer immunotherapy.

Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:

Dr. Li reports personal fee from BMS for serving in a steering committee in 2023, grants from Amgen, Astellas, AstraZeneca, Bristol Myers Squibb (BMS), Chugai Pharma, Duality Biologics, Genentech/LaRoche, Jounce Therapeutics, LabyRx Immuno-Oncology, Merck, OncoC4/BioNTech, Novartis, RasCal Therapeutics, Tempus, Xilio Therapeutics, outside the submitted work. Dr. Xiong reports a clinical trial grant of multifocal motor neuropathy from Argenx that is not related to this research project and manuscript. Dr. Lomen-Hoerth reports no financial interests or personal relationships. Dr. Richman reports no competing financial or personal relationships.