Non-surgical treatment of tumors has always been a major focus of clinical research. Traditional chemotherapy methods often cause negative effects on healthy tissues due to their lack of specificity, leading to severe adverse consequences and significantly diminishing the treatment efficacy (1). In recent years, the role of immune evasion mechanisms in the initiation and progression of tumors has been increasingly elucidated, and the development of immune checkpoint inhibitors—including Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) inhibitors, Programmed Cell Death Protein 1 (PD-1) inhibitors, and Programmed Cell Death Ligand 1 (PD-L1) inhibitors—has offered novel therapeutic options for patients (2). The efficacy of immunotherapy in various solid tumors has been validated through multiple clinical trials (3–7). Blocking the PD-1/PD-L1 axis enhances T lymphocyte response to tumor cells, thus accelerating immune-mediated tumor cell destruction (8). Tislelizumab, an anti-PD-1 monoclonal antibody, exhibits stronger affinity for PD-1 compared to nivolumab and pembrolizumab (5). Its dissociation rate is 50 times slower than nivolumab and 100 times slower than pembrolizumab, and it has demonstrated significant clinical efficacy in the treatment of various tumors (3–7). On March 14, 2024, Tislelizumab received FDA approval for the treatment of esophageal and gastric cancer. Although short-term clinical studies show that Tislelizumab has manageable safety (3–5), these studies are limited by small sample sizes, making it difficult to comprehensively assess its adverse effects. Since immune checkpoint inhibitors (ICIs) may lead to excessive immune activation, triggering immune-related adverse events (irAEs) and causing organ damage (9), it is necessary to assess the occurrence of irAEs during Tislelizumab treatment. The FDA Adverse Event Reporting System (FAERS) is a publicly accessible voluntary reporting system that contains a large number of drug-related adverse reaction records. As the largest pharmacovigilance database globally, FAERS is an important resource for identifying drug-related adverse reactions. This study aims to evaluate the safety profile of Tislelizumab and reveal adverse reactions not mentioned in the drug label. Additionally, we focus on comparing the differences in irAEs between Tislelizumab and other ICIs.

Previous clinical studies have demonstrated that Tislelizumab shows favorable progression-free survival (PFS) and objective response rates (ORR) in the treatment of non-small cell lung cancer (5). In China, Tislelizumab has been approved for the treatment of advanced squamous and non-squamous (NSCLCs), hepatocellular carcinoma (HCC), esophageal squamous cell carcinoma (ESCC), urothelial carcinoma(UC), classical Hodgkin’s lymphoma (cHL) (11, 12). Among the medication records included in this study, the most common indications were not the FDA-approved esophageal cancer and gastric cancer, with lung cancer being the most frequent indication, accounting for about one-third of the reported cases. This is primarily due to the fact that most of the reports included in this study originated from China. Tislelizumab combined with chemotherapy has shown promising clinical results in the treatment of various cancer types. For instance, tislelizumab combined with gemcitabine plus cisplatin has demonstrated excellent clinical efficacy in the treatment of urothelial carcinoma(UC) (4). To minimize outcome bias caused by common clinical combination therapies, we excluded records involving combinations with Cisplatin, Oxaliplatin, Docetaxel, Gemcitabine, Pemetrexed. Through the analysis of the FAERS database, we identified several adverse reactions that are already listed in the Tislelizumab drug label, such as myelosuppression, hepatic function abnormalities, pruritus, rash, and exfoliative dermatitis. Additionally, we discovered some novel adverse reactions that are not listed in the drug label, including palmar-plantar erythrodysaesthesia syndrome, immune-mediated cystitis, and renal cysts.

In previous studies, Chen et al. identified various hematological adverse events associated with the use of immune checkpoint inhibitors (ICIs) through the analysis of the FAERS database (10). A systematic review of clinical trials suggested that the most common adverse reactions in the Tislelizumab treatment group were hematological parameter reductions (anemia, neutropenia, thrombocytopenia, and leukopenia), which is consistent with our findings (5). The exact mechanism of hematological adverse events related to Tislelizumab remains unclear; Excessive T cell activation and the potential removal of immune checkpoints may partially explain the mechanism underlying the occurrence of these adverse events (13). Comprehensive hematological monitoring should be performed for patients, including bone marrow biopsy if necessary. In terms of treatment, 1-2 mg/kg of prednisone daily may be used as needed, and blood transfusion support should be provided if necessary (13). The standard treatment regimen for Tislelizumab-related hematological disorders still requires further investigation.

Another notable adverse reaction is hepatic dysfunction. A phase III clinical study comparing the efficacy and safety of Tislelizumab and sorafenib in the treatment of hepatocellular carcinoma reported that elevated ALT, AST, and serum bilirubin levels were the most common adverse reactions in the Tislelizumab group, which is consistent with our analysis (7). The non-specific activation of the immune system related to Tislelizumab not only enhances immune-mediated tumor cell destruction but may also cause immune-related damage to hepatocytes and other normal tissues. The hemi-antigen hypothesis suggests that reactive metabolites bind to cellular proteins to form novel antigens called “haptens.” These “haptens” are presented to major histocompatibility complex molecules on antigen-presenting cells, activating cytotoxic T lymphocytes, B cells, and natural killer cells, which can lead to immune damage to hepatocytes (14, 15). Regular monitoring of liver function in patients receiving Tislelizumab treatment should be conducted, and immune-mediated hepatotoxicity should be managed with dose reduction, discontinuation, or immunosuppressive therapy when necessary (16).

Consistent with the drug label, our analysis identified dermatological adverse reactions such as pruritus, rash, and exfoliative dermatitis. In a clinical study by Qin et al., 35 out of 338 patients treated with Tislelizumab experienced pruritus (10.4%), and 34 experienced a rash (10.1%) (7). Dermatological adverse reactions can cause significant physical and psychological distress, leading to an increased risk of treatment discontinuation. Early diagnosis and timely management of these skin reactions may help patients continue receiving Tislelizumab treatment, resulting in better clinical outcomes. For example, topical corticosteroids can be used to alleviate pruritus (17). Notably, we identified a dermatological adverse reaction not listed on the drug label—Palmar-Plantar Erythrodysaesthesia Syndrome (PPES). Consistent with our findings, Qin et al. reported one case of PPES in the Tislelizumab treatment group (7). The mechanism underlying Tislelizumab-related PPES remains unclear, but the effectiveness of dexamethasone in treating PPES suggests that excessive immune system activation may be part of its pathogenesis (18). Although it is rarely life-threatening, it significantly affects the patient’s quality of life. Dose adjustment is effective in treating PPES. Additionally, some preventive strategies, such as the use of urea-based creams twice daily, have been shown in a randomized controlled study to effectively prevent PPES (18). Further research is needed to understand the pathogenesis and management of Tislelizumab-related PPES.

Our analysis found that the highest signal value for an adverse reaction was immune-mediated cystitis, which is not listed on the Tislelizumab drug label. Previous case studies have reported that Tislelizumab may induce immune-related ureteritis/cystitis (19, 20). High levels of PD-L1 expression were found in the bladder tissue of patients with severe cystitis (21). Therefore, Tislelizumab-induced cytotoxic T cell activation may not only target cancer cells but also attack normal urothelial cells expressing PD-L1. Clinically, immune-mediated ureteritis/cystitis may present as paroxysmal lower abdominal pain or bladder irritation symptoms. Urine analysis often shows elevated red blood cell and white blood cell counts, proteinuria, and negative urine cultures repeatly. Cystoscopy may reveal revealed diffused redness of the bladder mucosa, while CT scans can show ureteral dilation and bladder wall thickening. During Tislelizumab treatment, any new urinary symptoms or abnormal urine analysis should raise a high suspicion for immune-mediated ureteritis/cystitis. Regular urine analysis, renal function tests, and urinary imaging are helpful for early identification of immune-mediated ureteritis/cystitis, allowing effective relief of urinary symptoms and immune-related urinary tract damage through glucocorticoid treatment while avoiding unnecessary antibiotic use (19, 20). Furthermore, we identified a potential adverse reaction of Tislelizumab—renal cysts—which had not been previously reported. The potential mechanism by which Tislelizumab causes renal cysts remains unclear. Previous studies suggest that kidney injury can accelerate the growth of renal cysts (22), and we hypothesize that renal cysts may fall under the category of immune-mediated renal Toxicities, which requires further investigation to reveal its mechanism.

We further investigated the profile of immune-related adverse events associated with Tislelizumab. Compared to Anti-PD-1 (Nivolumab: OR 2.21; Pembrolizumab: OR 2.35; Cemiplimab: OR 2.42), Anti-PD-L1 (Atezolizumab: OR 2.27; Durvalumab: OR 3.84), Anti-CTLA-4 (Ipilimumab: OR 3.01; Tremelimumab: OR 4.52), and Combination therapy (Ipilimumab + Nivolumab: OR 4.80; Ipilimumab + Pembrolizumab: OR 7.77; Durvalumab + Tremelimumab: OR 7.03) (10), Tislelizumab exhibited a lower signal for irAEs (ROR 1.69). Our findings suggest that Tislelizumab offers better safety compared to other immune checkpoint inhibitors (ICIs) (23). For patient populations at high risk of immune-related adverse events, an immune therapy regimen based on Tislelizumab may be superior to other ICIs and could become the preferred option. Combining immune checkpoint inhibitors (ICIs) may help overcome resistance pathways and improve sensitivity to PD-1/PD-L1 therapy (24, 25). Furthermore, this combination could enhance efficacy while minimizing drug toxicity by reducing dosages and shortening the treatment duration. In a previous phase 1/2 clinical study, BGB-A333 (a novel PD-L1 inhibitor) combined with Tislelizumab demonstrated promising antitumor effects without increasing the risk of irAEs (26). Further research is urgently needed to explore immune checkpoint inhibitor (ICI) combination regimens based on Tislelizumab. We also conducted a temporal analysis of adverse events, which highlighted the importance of early detection and management of related adverse events by clinicians during the first month of Tislelizumab treatment.

This study has several limitations. Firstly, the FAERS is a spontaneous reporting system that compiles data from multiple countries and various professionals, which may sometimes be incomplete or inaccurate. Secondly, certain confounding factors, such as drug dosage, duration of use, and combination therapies, may introduce bias into the analysis. Fortunately, we excluded cases involving the five most common combination drugs with Tislelizumab. Moreover, the majority of the study data was sourced from China, which may lead to reporting bias. Future research should incorporate data from multiple countries to enhance the generalizability of the findings. Lastly, disproportionality analysis can only assess signal strength, and thus, this study could not establish a causal relationship between the target drug and adverse events. Further experimental research is needed to validate these risks.

In this study, we conducted a comprehensive analysis of Tislelizumab-related adverse events using the FAERS database. We identified adverse events that are already listed on the drug label, and notably, we also uncovered potential adverse events not mentioned on the label, such as palmar-plantar erythrodysaesthesia syndrome, renal cysts, immune-mediated cystitis. This study overcomes the limitation of insufficient sample size in clinical trials, providing clinicians with essential safety information when prescribing Tislelizumab. It also emphasizes the need for close monitoring of potential adverse reactions in patients. Further validation is required through the collection of hospital data or the use of other adverse drug reaction databases, and prospective clinical studies are needed to clarify the causal relationship between Tislelizumab and these adverse events. Furthermore, we highlighted the lower immune-related adverse event signal associated with Tislelizumab compared to other ICIs. This large-scale real-world study systematically evaluated the overall safety of Tislelizumab, highlighting the urgent need to develop clinical predictive models for adverse reactions to further enhance medication safety and promote personalized treatment. The relatively low risk of irAEs associated with Tislelizumab makes it a potential candidate for combination therapy with other ICIs. Therefore, novel ICI combination strategies based on Tislelizumab are expected to provide new therapeutic hope for patients burdened by irAEs. Further clinical trials are warranted to systematically evaluate the efficacy and safety of such combination therapies.