Immunotherapy has transformed the outlook for many people with advanced cancer, but a remarkable case report from clinicians in Shanghai shows just how sharply that power can cut both ways. A 64-year-old man with stage IV lung adenocarcinoma received a single cycle of the anti-PD-L1 antibody atezolizumab combined with tiragolumab, an experimental antibody targeting the TIGIT checkpoint molecule, as part of a phase I clinical trial. Within weeks, his immune system had turned on four different organ systems at once, producing the first reported case of multisystemic immune-related adverse events tied to this drug combination.

The story began in February 2022, when the patient was admitted to a hospital with hoarseness and coughing up blood. Imaging and pathology confirmed left lung adenocarcinoma with brain metastases, classified as stage IV under the American Joint Committee on Cancer TNM staging system, eighth edition. His tumor biology was aggressive: immunohistochemistry revealed a Ki-67 proliferation index of 70 percent and a PD-L1 tumor proportion score of 90 percent, while genetic testing showed wild-type EGFR and ALK. Because his tumor expressed PD-L1 so strongly, he was enrolled in a randomized, double-blind, placebo-controlled trial testing an anti-TIGIT antibody alongside atezolizumab for advanced non-small cell lung cancer. On March 21, 2022, he completed one cycle of atezolizumab at 1,200 milligrams plus the anti-TIGIT antibody or placebo at 600 milligrams, both intravenously, without immediate complications.

Less than a month later, the trouble started. The patient developed fatigue, facial swelling, and a rash. Laboratory tests on April 18, 2022 revealed elevated liver enzymes, with alanine aminotransferase at 71.9 units per liter and aspartate aminotransferase at 193.1 units per liter, along with abnormal cardiac markers including cardiac troponin T at 0.036 nanograms per milliliter, creatine kinase-MB at 41.8, and myoglobin at 1,371 nanograms per milliliter. Doctors at the first hospital suspected immune-related myocarditis, hepatitis, and secondary adrenal insufficiency, stopped the immunotherapy, and started methylprednisolone at 60 milligrams twice daily, later escalating the dose. Follow-up was disrupted by the COVID-19 pandemic, and by late May the patient had worsening chest discomfort, severe facial and neck edema, and a widespread rash. Neck computed tomography showed tonsillitis and inflammation of the parotid and submandibular glands compressing the trachea enough to require intubation. His platelet count then crashed to 15 times 10 to the ninth per liter, and his liver function deteriorated further.

When the patient reached the team at Zhongshan Hospital, Fudan University, the physicians conducted a systematic re-evaluation of each suspected immune-related adverse event. Cardiac magnetic resonance imaging with enhancement revealed scattered patchy enhancement in the left ventricular lateral wall and linear delayed enhancement in the subepicardium of the inferoposterior wall, findings strongly suggestive of grade 3 checkpoint inhibitor myocarditis, with a left ventricular ejection fraction of 50 percent. Pulmonary embolism and worsening of pre-existing cardiovascular disease were ruled out. A liver biopsy showed mild sinusoidal congestion, subtle inflammatory infiltration, bile stasis, hepatocyte swelling, and focal necrosis, consistent with grade 2 immune-related hepatic injury in the absence of liver metastases, viral hepatitis, or autoimmune disease. A bone marrow biopsy demonstrated poor maturation of megakaryocytes without tumor invasion, supporting grade 4 immune-mediated thrombocytopenia. Finally, the combination of widespread muscle soreness, facial and periorbital swelling, elevated creatine kinase dominated by the skeletal muscle fraction, and impaired self-care pointed to grade 4 dermatomyositis, with the MDA5 antibody testing negative.

Treatment was aggressive and multidisciplinary. The patient received intravenous methylprednisolone at 160 milligrams daily for five days, together with intravenous immunoglobulin at 20 grams daily for seven days, plus hepatoprotective, gastric-protective, anti-infective, and nutritional support. Cardiac troponin stabilized and platelet counts rose significantly, but liver enzymes and bilirubin continued climbing, prompting the addition of tofacitinib, a Janus kinase inhibitor, at 5 milligrams per day starting June 11, 2022. Liver function and the rash gradually improved, allowing tapering of the methylprednisolone from June 19 onward. After discharge, steroids were tapered weekly, and tofacitinib was stopped when the oral dose reached 30 milligrams per day. Yet each attempt to withdraw immunosuppression backfired: at 10 milligrams of methylprednisolone, pruritic rashes reappeared on the right lower limb with rising creatine kinase-MB, requiring a five-day course of intravenous methylprednisolone at 40 milligrams. A second taper attempt triggered worsening rashes and elevations in troponin, creatine kinase, and creatine kinase-MB, and tofacitinib was reintroduced.

Because the dermatomyositis persisted and multiple organ systems remained involved, steroid withdrawal proved impossible. The team settled on a long-term maintenance regimen of low-dose methylprednisolone, 5 milligrams every other day, plus tofacitinib 5 milligrams twice daily. To date, the patient has improved markedly, with rashes substantially alleviated, normal liver function, and normalization of most cytokines and cardiac markers. In a striking twist, he has received no anti-tumor therapy since the adverse events began, yet his tumor remained stable for a long period, a phenomenon the authors note with interest, before follow-up chest computed tomography on December 13, 2024 showed localized recurrence.

The clinical course illustrates why checkpoint inhibitor myocarditis demands such vigilance. Although cardiac involvement is among the rarer immune-related adverse events, it carries a mortality rate of 25 to 50 percent, with rapid onset, atypical symptoms, and swift progression. Risk factors include combination checkpoint blockade, concurrent cardiotoxic cancer drugs, and pre-existing cardiovascular disease. High-dose corticosteroids are the cornerstone of treatment, and guidelines such as those from the National Comprehensive Cancer Network recommend permanent discontinuation of checkpoint inhibitors, electrocardiographic and echocardiographic monitoring, and pulsed methylprednisolone for three to five days in grade 3 cases, followed by tapering over four to six weeks. When patients resist steroid pulse therapy, guidelines suggest adding a chemotherapeutic or biological agent plus immunoglobulins, with antithymocyte globulin or alemtuzumab offering potential advantages. In this case, the combination of immunoglobulin and tofacitinib alongside steroids appeared to play a critical role in achieving disease control.

The hepatic and hematological complications add further lessons. Immune-related liver injury typically emerges six to fourteen weeks after starting checkpoint inhibitors, with an incidence around 8.4 percent in one cited cohort, and patients receiving dual immune therapy are more susceptible to hepatotoxicity. Steroid dosing for hepatitis is generally lower than for myocarditis, scaled to the grade of liver dysfunction, and the pathological basis, autoimmune cells attacking normal hepatocytes, mirrors that of cardiac injury. The authors also raise an unresolved question: when patients are already on high-dose steroids and immunoglobulins, should standard hepatoprotective drugs be continued? Current guidelines offer little guidance on this point. Immune thrombocytopenia, meanwhile, occurs in fewer than 1 percent of checkpoint inhibitor recipients, usually within the first twelve weeks, and remains a diagnosis of exclusion. Because thrombocytopenia is common in cancer patients, clinicians must systematically rule out infection, tumor progression, and drug effects before attributing it to immunotherapy, as the team did here through bone marrow biopsy and careful history-taking.

What makes this case scientifically valuable is its rarity and its implications for the next generation of immunotherapy. TIGIT, a co-inhibitory receptor expressed on T cells and natural killer cells that competes with the costimulatory molecule CD226 for the ligands CD155 and CD112, has shown synergistic anti-tumor effects with PD-1 and PD-L1 blockade in preclinical studies, and trials of tiragolumab combinations have generally reported acceptable safety profiles. Yet this patient experienced four simultaneous, severe immune-related adverse events after a single treatment cycle, underscoring that combining checkpoints acting on different pathways can amplify loss of immune tolerance in unpredictable ways. The authors emphasize that multisystemic immune-related adverse events tend to appear early and progress rapidly, that glucocorticoids remain the core therapy, and that severe cases may require intravenous immunoglobulin, plasma exchange, or additional immunomodulatory drugs such as tofacitinib. For oncologists deploying anti-TIGIT and anti-PD-L1 combinations in trials and clinics, the message is clear: early recognition, precise diagnosis across organ systems, and prompt multidisciplinary intervention can mean the difference between catastrophe and recovery.

Subject of Research: Multisystemic immune-related adverse events from anti-PD-L1 and anti-TIGIT combination immunotherapy in lung adenocarcinoma

Article Title: Management of multisystemic irAEs associated with atezolizumab/tiragolumab combination therapy in a patient with lung adenocarcinoma: case report and review

Article References: Zhang, S., Zhang, N., Lin, J., Zhao, L., Jin, H., Gao, D., Ji, Z., Liu, Q., Ai, L., & Yu, Y. (2025). Management of multisystemic irAEs associated with atezolizumab/tiragolumab combination therapy in a patient with lung adenocarcinoma: case report and review. Clinical Cancer Bulletin, 4(1), Article 6. https://doi.org/10.1007/s44272-025-00034-2

Image Credits: AI Generated

DOI: 10.1007/s44272-025-00034-2

Keywords: immune checkpoint inhibitors, atezolizumab, tiragolumab, TIGIT, PD-L1, myocarditis, immune-related adverse events, lung adenocarcinoma, dermatomyositis, thrombocytopenia, hepatitis, tofacitinib

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Tags: anti-PD-L1 and anti-TIGIT combination therapyatezolizumabcancer immunotherapy risksdermatomyositishepatitisimmune checkpoint blockade safetyimmune checkpoint inhibitor side effectsimmune checkpoint inhibitorsimmune system hyperactivationimmune-related adverse eventsimmune-related organ failurelung adenocarcinomalung adenocarcinoma with metastaseslung cancer immunotherapy adverse eventslung cancer treatment complicationsmultisystem immune-related toxicitymyocarditisnovel immunotherapy adverse event case reportPD-L1phase I lung cancer clinical trialthrombocytopeniaTIGITtiragolumabtofacitinib