64-year-old male with a history of hypertension and diabetes mellitus (DM); Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score = 1. Tumor Diagnosis: Adenocarcinoma in the right lung upper lobe diagnosed in March 2024, stage cT2N2M1c (with pleural and bone metastases), IVB stage. Pre-treatment Tests: Cardiac biomarkers (cardiac Troponin T [cTnT], myoglobin, N-terminal pro-B-type natriuretic peptide [NT-proBNP], creatine kinase [CK], creatine kinase MB [CK-MB], etc.) were all within normal ranges; electrocardiogram (ECG) showed sinus tachycardia with occasional atrial premature beats.

From April 8 to May 22, 2024, the patient completed three cycles of chemotherapy combined with immunotherapy. Chemotherapy: Pemetrexed 980 mg (Day 1) + Carboplatin 450 mg (Day 1), every 3 weeks; Immunotherapy: Pembrolizumab 200 mg (Day 1), every 3 weeks. After 2 cycles of treatment, tumor assessment revealed partial response (PR).

Nine weeks after anti-tumor treatment, the patient reported occasional palpitations, with other vital signs normal. Cardiac biomarkers showed significant elevation, including: cTnT 0.093 ng/mL (normal < 0.014 ng/mL), myoglobin 306.0 ng/mL (normal < 121.1 ng/mL), CK 509 U/L (normal 34–174 U/L), CK-MB 28 U/L (normal < 22 U/L), alanine transaminase (ALT) 65 U/L (normal 9–50 U/L), aspartate transaminase (AST) 53 U/L (normal 15–40 U/L). NT-proBNP and D-dimer levels remained within normal ranges. Electrocardiogram showed no significant changes compared with pre-treatment. Cardiac Magnetic Resonance Imaging (CMR) revealed suspected mild myocardial thickening in the lateral wall of the basal segment and suspected mild fibrosis in the same area. Coronary CT showed multiple coronary plaques with mild to moderate lumen narrowing.

Based on the history of immunotherapy, abnormal myocardial biomarkers, contrast-enhanced cardiac MRI, and coronary CT scans, ICIM was initially considered, with coronary artery disease as a secondary consideration. Antitumor therapy was temporarily suspended. On June 12, methylprednisolone (1 mg/kg/day) was administered for anti-inflammatory treatment. However, 5 days after the initiation of steroid therapy, cTnT levels showed no improvement (see Figure 1). The next day, clopidogrel, atorvastatin, and isosorbide dinitrate were added, and the dose of methylprednisolone was gradually reduced; yet, cTnT levels continued to rise. Following a multidisciplinary team (MDT) consultation involving specialists in cardiology, pulmonology, and rheumatology, the diagnosis was subclinical ICIM (suspected) with steroid resistance.

On July 5, the dose of methylprednisolone tablets was increased to 60 mg daily, and tofacitinib 5 mg twice daily (BID) was added. The dose of methylprednisolone was gradually tapered, and both methylprednisolone and tofacitinib were discontinued in mid-November.

Myocardial biomarkers progressively decreased to normal levels (see Figure 1). Follow-up chest CT scans on August 12 and October 14, 2024 showed the tumor remained in PR status. The original chemotherapy regimen was resumed on October 30, while immunotherapy was permanently discontinued.

72-year-old male with a history of hypertension; ECOG PS score = 0. Diagnosed with squamous cell carcinoma of the right lung in February 2024, stage cT1N1M0 (IIA). No abnormalities were detected in cardiac biomarkers or ECG prior to treatment.

Following multidisciplinary team consultation, preoperative neoadjuvant therapy was planned. The patient completed two cycles of chemotherapy combined with immunotherapy on March 8 and March 28, 2024. Chemotherapy regimen: Albumin-bound paclitaxel 500 mg (Day 1) + Carboplatin 400 mg (Day 1), every 3 weeks; Immunotherapy: Pembrolizumab 200 mg (Day 1), every 3 weeks. After 2 cycles of treatment chest CT showed PR.

Four weeks after anti-tumor treatment, the patient developed lower limb weakness with muscle soreness. Significant elevation of cardiac biomarkers was observed on April 18, 2024, including cTnT 0.090 ng/mL, CK 6,625 U/L, CK-MB 166 U/L, myoglobin > 3,000 ng/mL, ALT 133 U/L, AST 261 U/L; NT-proBNP and D-dimer were within normal ranges. Echocardiography showed left atrial enlargement and septal thickening at the basal segment; CMR revealed suspected mild enhancement foci in the inferior septum of the left ventricle, suggesting myocarditis.

Following MDT discussions, the diagnosis of immune-mediated myositis complicated with ICIM was confirmed based on the history of immunotherapy, myalgia symptoms, significantly elevated cardiac biomarkers, and cardiac MRI findings.

Immunotherapy was discontinued. Starting from April 22, methylprednisolone pulse therapy (500 mg daily for 3 consecutive days) was administered along with intravenous immunoglobulin (IVIG) (total dose 2 g/kg) for immune modulation. After one week of treatment, persistent elevation of cTnT levels suggested steroid resistance. Oral mycophenolate mofetil (0.75 g twice daily) was added, followed by IVIG 20 g once daily for three consecutive days. Trimethoprim-sulfamethoxazole (TMP-SMX) (160/800 mg/day) was also administered for Pneumocystis jirovecii pneumonia (PCP) prophylaxis.

Cardiac biomarkers gradually decreased (see Figure 2), with significant improvement in fatigue and myalgia. Following 4 weeks of anti-ICIM treatment, a follow-up chest CT scan showed persistent PR status. The chemotherapy regimen was resumed the next day, while immunotherapy was permanently discontinued. Corticosteroids were tapered and discontinued one month later, and the patient subsequently underwent radical lung cancer resection at the Department of Thoracic Surgery on the following day. Postoperative pathological examination revealed pathological Complete Response (pCR).

62-year-old male with a history of DM; ECOG PS score = 0. Diagnosed with squamous cell carcinoma of the right upper lobe of the lung in April 2024, stage cT4N2M0 (IIIB). Pre-treatment evaluations: ECG showed sinus tachycardia; cardiac biomarkers: cTnT 0.015 ng/mL, NT-proBNP 464 pg/mL, while CK, CK-MB, ALT, and AST levels were normal; echocardiography revealed left atrial enlargement.

The patient completed three cycles of chemotherapy combined with immunotherapy from April 25 to June 6, 2024, as follows: Chemotherapy regimen: Albumin-bound paclitaxel 500 mg (Day 1) + Carboplatin 550 mg (Day 1), every 3 weeks; Immunotherapy: Tislelizumab 200 mg (Day 1), every 3 weeks. After 2 cycles of treatment, chest CT assessment revealed PR.

Eight weeks after anti-tumor treatment, the patient developed chest tightness and generalized fatigue. Emergency examination on June 28 showed significantly elevated cardiac biomarkers: cTnT 2.890 ng/mL, CK 6,863 U/L, CK-MB 189 U/L, NT-proBNP 2,435 pg/mL (normal <300 pg/mL), ALT 290 U/L, AST 303 U/L, D-dimer 0.32 mg/L (normal <0.5 mg/L). ECG revealed atrial fibrillation with ST-segment elevation. Echocardiography showed reduced contractile activity in the anterior wall of the left ventricle and a left ventricular ejection fraction (LVEF) of 56%. Subsequent coronary CT angiography (CTA) demonstrated multiple coronary plaques [moderate-to-severe stenosis in the proximal segment of the left anterior descending artery (LAD), with mild to moderate stenosis in other segments]. CMR revealed mild global left ventricular systolic dysfunction, bilateral atrial enlargement, and right ventricular enlargement with an LVEF of 49%.

After cardiology consultation, myocardial injury [acute coronary syndrome (ACS)? ICIM?] was considered. The patient and his family refused emergency coronary angiography. Following antiplatelet therapy, anticoagulation, and coronary vasodilation treatment, myocardial biomarkers did not decrease, leading to a strong suspicion of ICIM.

On June 28, methylprednisolone was added at 2 mg/kg/day for anti-inflammatory therapy, combined with IVIG (total dose 2 g/kg) for immune modulation. Improvement in symptoms led to switching to oral prednisone for sequential therapy.

Chest tightness and fatigue improved; myocardial biomarkers gradually decreased toward normal levels (see Figure 3); ECG restored sinus rhythm with ST-segment normalization. Chemotherapy was resumed after 4 weeks of anti-ICIM treatment, and immunotherapy was permanently discontinued. Subsequent chest CT revealed no tumor progression, with the patient maintaining PR. The patient completed 6 cycles of chemotherapy followed by sequential radiotherapy on December 23, 2024. After chemotherapy and radiotherapy, the patient remained stable without significant abnormalities.

67-year-old female with no comorbidities; ECOG PS score = 1. Diagnosed with adenocarcinoma of the right upper lobe of the lung in June 2024, stage cT4N3M0 (III-C). Pre-treatment evaluations: ECG and cardiac biomarkers were within normal ranges.

The patient completed two cycles of chemotherapy combined with immunotherapy on June 21 and July 12, 2024. Chemotherapy regimen: Pemetrexed 740 mg (Day 1) + Carboplatin 380 mg (Day 1), every 3 weeks; Immunotherapy: Tislelizumab 200 mg (Day 1), every 3 weeks.

Four weeks after anti-tumor treatment, the patient developed fatigue, bilateral ptosis, and blurred vision. Follow-up on August 1 showed elevated cardiac biomarkers: cTnT 0.195 ng/mL, CK 3,989 U/L, CK-MB 119 U/L, ALT 116 U/L, AST 208 U/L; NT-proBNP was normal. ECG showed ST-segment depression; Enhanced MRI revealed slightly uneven signals in the extraocular muscles; Coronary CTA and cardiac CMR showed no significant abnormalities.

Based on the presence of ptosis, elevated cardiac biomarkers, and abnormal ECG findings following immunotherapy, a diagnosis of possible ICIM with concomitant myositis was established.

Consequently, immunotherapy was discontinued and methylprednisolone therapy (1 mg/kg/day) was initiated. One week later, serum cTnT levels continued to rise (see Figure 4). Methylprednisolone pulse therapy (500 mg/day for 3 days) combined with IVIG (2 g/kg) was administered, but cTnT remained elevated, confirming steroid-resistant ICIM. Subsequently, tofacitinib (11 mg/day) was added, followed by mycophenolate mofetil (0.75 g BID).

The addition of tofacitinib and mycophenolate mofetil significantly improved symptoms such as ptosis, with cTnT gradually decreasing. After 3 months of anti-ICIM treatment, the patient developed chest tightness and dyspnea. Chest CT revealed newly developed multiple pulmonary inflammatory lesions, and the patient was confirmed to have PCP by etiological examination. Mycophenolate mofetil and tofacitinib were discontinued, and anti-PCP treatment was initiated. Pulmonary inflammation gradually subsided, but myocardial markers elevated again. After pneumonia control, mycophenolate mofetil was resumed at 0.5 g BID, resulting in a gradual decrease in myocardial markers. After discontinuing anti-tumor therapy for 4 months, follow-up chest CT showed stable disease (SD). Since then, the patient and her family refused anti-tumor treatment, and tumor progression occurred 5 months later.

A 64-year-old male with no clear underlying diseases; ECOG PS score = 1. Diagnosed with lung adenocarcinoma at an external hospital in June 2024, staged cT2aN3M1b (with adrenal gland metastasis), stage IVA. Pre-treatment auxiliary examinations indicated that myocardial biomarkers and ECG were normal.

The patient previously received a chemotherapy regimen (pemetrexed 800 mg on Day 1 + carboplatin 450 mg on Day 1, once every 3 weeks) combined with bevacizumab (700 mg on Day 1, once every 3 weeks) for anti-angiogenic targeted therapy. Due to severe myelosuppression, the regimen was changed on August 27 to pembrolizumab immunotherapy (200 mg, once every 3 weeks).

Six weeks after ICI initiation, the patient was admitted to the emergency department due to chest tightness, shortness of breath, and fever (maximum body temperature 39 °C). Emergency Examination Results: Procalcitonin (PCT) 3.83 ng/mL, cTnT 0.041 ng/mL, NT-proBNP 4,362 pg/mL, D-dimer 6.83 mg/L, hemoglobin (Hb) 75 g/L, platelets (PLT) 75 × 10⁹/L, white blood cells (WBC) 3.84 × 10⁹/L, C-reactive protein (CRP) 90.0 mg/L; ECG showed sinus tachycardia, which later converted to atrial fibrillation; echocardiography indicated enlargement of both atria, moderate-to-severe mitral regurgitation (MR), and severe tricuspid regurgitation (TR). Chest CT revealed a right lung mass, bilateral pulmonary exudative lesions, and a small amount of bilateral pleural effusion; results of peripheral blood metagenomic next-generation sequencing (mNGS, including both DNA and RNA) and blood culture were all negative.

Based on clinical manifestations and examination findings, the patient was diagnosed with severe pneumonia, septic shock, and heart failure. Norepinephrine was administered to maintain blood pressure, meropenem for anti-infective therapy, and bilevel positive airway pressure (BiPAP) for respiratory support, along with diuretic therapy and myocardial nutritional support. Due to severe respiratory failure, endotracheal intubation was performed one week later. On treatment day 15, PCT was 0.42 ng/mL, serum creatinine (Scr) 173 μmol/L, WBC count 7.9 × 10⁹/L, and CRP 21.8 mg/L. The patient's body temperature decreased, but myocardial markers continued to rise (see Figure 5). Considering the patient's history of immunotherapy, cardiology consultation suggested possible ICIM. Consequently, intravenous methylprednisolone 4 mg/kg daily was initiated, combined with IVIG (total dose 2 g/kg) for immune modulation. On hospital day 15, the patient developed significant bradycardia and underwent temporary cardiac pacemaker implantation. On hospital day 17, ventricular tachycardia occurred and was treated with lidocaine and amiodarone. On hospital day 19, ventricular fibrillation occurred, which was successfully converted with electrical defibrillation. Reevaluation at this time showed: cTnT 0.047 ng/mL, NT-proBNP 30,664.0 pg/mL, PCT 0.81 ng/mL, WBC count 7.88 × 10⁹/mL, and CRP 31.1 mg/mL. Repeat echocardiography indicated biatrial enlargement, moderate-to-severe mitral regurgitation, severe tricuspid regurgitation, and a small amount of pericardial effusion, with no evidence of valvular vegetations. Repeated electrocardiograms showed no dynamic ST-T segment changes. Cardiology was consulted again, and given the diagnosis of fulminant ICIM, additional intravenous IVIG therapy was administered.

During treatment, cTnT and NT-proBNP continued to rise (see Figure 5), and malignant arrhythmias occurred repeatedly. On hospital day 21, ventricular fibrillation occurred again, and the patient died despite aggressive resuscitative efforts.

The symptoms of ICIM are diverse and may include chest pain, palpitations, dyspnea, fatigue, dizziness, and syncope. These symptoms may be masked by or coexist with other irAEs or pulmonary symptoms related to the underlying malignancy and comorbid conditions. Approximately 20% to 30% of patients with ICIM also exhibit manifestations of myositis or muscle weakness (6, 11), suggesting immune cross-reactions. The underlying mechanism may be related to the shared antigenicity of α-myosin in both cardiac and skeletal muscles (12). Among the five cases, in addition to cardiovascular symptoms, Case 2 also experienced limb soreness, while Case 4 presented with muscle weakness, including fatigue and eyelid ptosis (Table 1).

In the early stages of ICIM, some patients may have subtle symptoms, and the only indication of myocardial injury may be an increase in certain biomarkers. Among these markers, cTnT is the most important for diagnosing ICIM. According to prospective studies, cTnT has the highest positive rate (98%) within 72 h, which is significantly higher than that of cTnI (88%) and CK (75%) (13). Additionally, BNP can assist in the diagnosis of ICIM, with a positive rate of 66% (7). It can be used as a supplementary indicator to assess cardiac function. In addition to these myocardial markers, biomarkers related to the liver and skeletal muscles also have diagnostic value for ICIM. Studies have shown that at least three of the following biomarkers—AST, ALT, CK, and lactate dehydrogenase (LDH)—are elevated in 95% of ICIM patients (14).

In the five cases reported in this study, all patients showed varying degrees of cTnT elevation, accompanied by elevations in NT-proBNP (3/5), CK-MB (4/5), myoglobin (5/5), ALT (5/5), and AST (5/5). Therefore, when suspecting ICIM, monitoring cTnT and assessing changes in liver enzymes and skeletal muscle biomarkers are essential.

ECG abnormalities in patients with ICIM are highly diverse and may include supraventricular arrhythmias, ventricular arrhythmias, heart block, as well as new ST-T segment changes and T-wave abnormalities unrelated to coronary artery disease (15). Complete heart block, ventricular arrhythmias, and pathological Q-waves are associated with an increased 30-day all-cause mortality (16). However, the ECGs of some patients may show no abnormalities (16, 17).

In three out of the five cases in this study, different ECG changes were observed (see Table 2). Although these ECG changes are not specific, they still have certain auxiliary value for the early identification of ICIM and can provide valuable time for subsequent treatment. It is worth noting that in the early stages, the ECGs of some ICIM patients may be normal or show only mild abnormalities. As inflammation spreads from focal to diffuse, electrocardiogram conduction abnormalities can progress significantly within a short time (18). For example, in Case 5, the early-stage ECG only indicated sinus tachycardia, but it progressed to malignant arrhythmia rapidly, ultimately leading to the patient's demise.

Echocardiography is a valuable tool for evaluating changes in cardiac structure and function, such as reduced LVEF and abnormal myocardial motion. However, in some cases, even with normal LVEF, global longitudinal strain (GLS) may decrease (19). Notably, these changes may not be significant in the early stages of myocarditis, making it difficult to confirm the diagnosis using echocardiography alone.

Cardiac structural abnormalities were identified in 4 of the 5 cases in this cohort (Table 2), as follows: atrial and/or ventricular chamber enlargement in all 4 cases; interventricular septal thickening in 1 case; severe valvular regurgitation in 1 case. Notably, despite these structural alterations, none of the patients exhibited a clinically significant decline in LVEF.

According to the 2018 Lake Louise criteria (20), CMR is a core tool for the diagnosis of myocarditis, with high accuracy. It not only clearly demonstrates the typical features of myocardial inflammation, edema, and fibrosis but also identifies the specific location, extent, and severity of myocardial inflammation. However, it has clinical limitations: in the early disease stage, myocardial inflammation may not induce obvious CMR signal changes, and the prolonged examination duration poses risks for critically ill patients.

Among the five clinical cases summarized in Table 2, distinct cardiovascular manifestations were observed: Two cases exhibited suspected myocardial late gadolinium enhancement (LGE) on CMR imaging; one case presented both LGE and interventricular septal thickening; one case demonstrated reduced left ventricular systolic function with decreased EF; one case showed no significant structural or functional abnormalities; the remaining case was excluded from imaging analysis due to critical clinical instability. Notably, discrepancies in LVEF quantification were identified between CMR and echocardiography. Suboptimal acoustic windows during echocardiographic examination may lead to underestimation of left ventricular volume measurements, whereas CMR's three-dimensional reconstruction capability provides superior spatial resolution and volumetric accuracy, thereby serving as the gold standard for LVEF assessment. Nevertheless, echocardiography remains a pragmatic alternative for longitudinal monitoring of cardiac function in clinical practice, owing to its accessibility and non-invasiveness.

Myocardial biopsy is the gold standard for diagnosing myocarditis (10, 21). However, due to its invasive nature, it carries certain risks, such as bleeding and arrhythmia, which limit its widespread clinical practice. Given the low acceptance of myocardial biopsy among patients and the associated procedural risks, myocardial biopsies were not performed in the five cases described above.

In the treatment of ICIM, discontinuing ICIs is the initial step. Subsequently, based on the severity of the disease, glucocorticoids are selected for use, and decisions are made on regarding the combination with immunosuppressive agents. Due to the lack of high-quality clinical evidence, there is no unified guideline for the optimal dose of glucocorticoids. The 2022 NCCN guidelines recommend that for patients diagnosed with ICIM, methylprednisolone 1 g/d should be administered immediately for pulse therapy, followed by oral administration after 3–5 consecutive days (24). However, this guideline does not provide a clear graded treatment plan. In contrast, the 2021 ASCO guidelines suggest that patients with grade G1 can be closely observed. For patients with grade ≥ 2, it is recommended to use high-dose glucocorticoids (1–2 mg/kg/d of prednisone, administered orally or intravenously based on the symptoms) as early as possible within 24 h (10). For patients who do not show an immediate response, early use of glucocorticoids at the dose used for preventing heart transplant rejection (methylprednisolone 1 g/d) can be considered (10). Regarding the tapering of glucocorticoids in ICIM, it is currently believed that close follow-up of cTn is necessary (first follow-up 48–72 h after treatment initiation). If cTn levels decrease compared to the baseline and symptoms improve, glucocorticoids can be gradually tapered. Initially, all patients in this study were treated with the regimen of “ICI discontinuation combined with glucocorticoid administration”. With reference to the aforementioned guidelines, the dosage and tapering schedule of glucocorticoids were individually determined, but only one patient was sensitive to glucocorticoids (Table 3).

A striking finding of our study is the 80% glucocorticoid resistance rate (4 out of 5 patients), which is substantially higher than the 50% resistance rate reported in previous large-scale retrospective studies (8, 25). All four glucocorticoid-resistant patients initially received standard-dose glucocorticoids (1–2 mg/kg/day methylprednisolone); however, their cTnT levels failed to decrease by ≥50% within 3–7 days, and in two cases (Cases 1 and 4), cTnT even continued to rise—consistent with the definition of glucocorticoid-resistant ICIM (srICIM) (8). This high resistance rate in our NSCLC cohort warrants attention, as most prior data on srICIM were derived from mixed cancer types (26). Collectively, these findings may remind us of the underappreciated severity and treatment resistance of ICIM in NSCLC. They could challenge the management paradigm largely derived from broader oncology cohorts, underscoring the need for increased NSCLC-specific vigilance. Consequently, clinicians may benefit from proactively monitoring for steroid resistance in this subgroup, and lowering the threshold for prompt escalation to second-line immunosuppression to reduce the high risk of life-threatening complications.

Our case data underscore the critical role of prophylaxis during ICIM treatment. Case 2, who received combined high-dose glucocorticoids, one immunosuppressant and TMP-SMX prophylaxis as recommended, remained free of PCP. In contrast, Case 4, treated with high-dose glucocorticoids and two immunosuppressants but without prophylaxis, subsequently developed PCP. Although the patient recovered following anti-PCP therapy, cTnT levels rebounded, after which mycophenolate mofetil was safely reintroduced at a reduced dose. These observations highlight key clinical implications: in srICIM patients receiving combined immunosuppression, clinicians should closely monitor respiratory symptoms, implement tailored prophylaxis, and promptly differentiate between PCP co-infection, ICIM exacerbation, and tumor progression. Once PCP is confirmed, coordinated management of both conditions is essential to avoid compromising the outcome.

Against this high glucocorticoid resistance background, our case series provides real-world evidence for the efficacy of tofacitinib and mycophenolate mofetil as second-line agents—a critical gap in current guidelines, which lack specific recommendations for srICIM. Case 1, a 64-year-old male with probable ICIM, showed no response to 1 mg/kg/day methylprednisolone; after adding tofacitinib (5 mg twice daily), his cTnT levels progressively normalized, and tumor control (partial response, PR) was maintained. Case 4, a 67-year-old female with possible ICIM and immune-mediated myositis, failed both standard glucocorticoids and methylprednisolone pulse therapy (500 mg/day for 3 days); the combination of tofacitinib (11 mg once daily) and mycophenolate mofetil (0.75 g twice daily) led to rapid resolution of ptosis and a gradual decrease in cTnT. These outcomes align with the mechanistic rationale of tofacitinib (a JAK1/JAK2 inhibitor) in inhibiting excessive T-cell activation via the JAK-STAT pathway (27) and mycophenolate mofetil (a purine analog) in inhibiting lymphocyte proliferation (28). Notably, our data extend prior small case series (26, 29) by demonstrating efficacy in NSCLC-specific ICIM and supporting the use of combination second-line therapy for patients unresponsive to single-agent immunosuppression.

In the current treatment strategies, second-line therapies for srICIM include, in addition to the two aforementioned agents, other immunosuppressants such as tacrolimus, biological agents including infliximab, tocilizumab, and alemtuzumab, as well as antithymocyte globulin, abatacept, and IVIG (10, 25, 30–33). Another potential treatment is plasma exchange, which removes antigens and antibodies from the plasma and inhibits the excessive immune response. A retrospective analysis suggests that combining plasma exchange with glucocorticoid therapy may be more effective than glucocorticoids alone in patients with ICI-induced myocarditis (34).