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. 2025 Jul 1;23:718. doi: 10.1186/s12967-025-06768-w

Cardiotoxicity in cancer immunotherapy: a systematic review and global meta-analysis

Fanlin Zhou 1, Guangyue Liu 2, Shunhong Zhang 3, Chenchen Luo 4, Saidi Hu 5, Siran Wan 6, Weixi Xiong 7, Linyong Zhao 8,9,✉
PMCID: PMC12220369  PMID: 40598522

Abstract

Objective

Cancer immunotherapy enhances the prognosis of cancer patients; however, it has been shown to be associated with potentially fatal cardiac risks, which requires further confirmation. This study aimed to explore the cardiotoxicity of immune checkpoint inhibitors (ICIs) in solid tumors.

Methods

A systematic review and meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and registered in the PROSPERO database, CRD42024614721. All randomized controlled trials (RCTs) comparing ICI with placebo and reporting complete adverse events in solid tumors were included. The primary outcome is the relative risk (RR) of cardiotoxicity for the purpose of discerning the disparities between the two groups. Data were pooled using random-effects model.

Results

A total of 101 RCTs involving 58,698 patients were included. The incidence of all-grade cardiotoxicity was 3.0% in the ICI group and 2.3% in the placebo group. The pooled relative risk for cardiotoxicity was higher with ICI compared with placebo (RR = 1.31, 95% CI = 1.17–1.48, P<0.001). Regarding individual cardiac adverse event, the pooled relative risks for myocarditis (RR = 1.79, 95%CI = 1.11–2.91, p = 0.018) and arrhythmia (RR = 1.22, 95%CI = 1.04–1.44, p = 0.016) were also higher with ICI compared with placebo. Sensitivity analysis demonstrated consistency in the overall estimate.

Conclusions

Our study illustrated an increased cardiotoxicity of the use of ICI as single or combination regimens including myocarditis and arrhythmia based on a large number of the latest RCTs. More cautious attention should be paid on the ICIs-induced cardiotoxicities during cancer immunotherapy, especially for myocarditis and arrhythmia.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12967-025-06768-w.

Keywords: Immune checkpoint inhibitors, Immunotherapy, Solid tumor, Cardiotoxicity

Introduction

Apart from conventional surgery, chemotherapy, radiotherapy and Chinese medicines [1], the utilization of immunotherapy among cancer patients has been witnessing a gradual upward trend and has remarkably enhanced the prognosis of cancer patients [2–5], as shown in a recent report that the proportion of stage IV non-small cell lung cancer patients receiving immunotherapy escalated from 12% in 2016 to 33% in 2018 [6]. As the most commonly used reagents in immunotherapy, immune checkpoint inhibitors (ICIs) nowadays include PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors, and some new ICIs including LAG-3, TIGIT, TIM3 are also under study [7, 8]. ICIs mainly play an anti-tumor role by suppressing immune checkpoint to restore T cell activation, yet dysregulated T-cell activation are also prone to cause immune-mediated adverse reactions, which are manifested in gastrointestinal tract, lung, dermatology and heart in real-world [9–12]. The mechanisms underlying ICI-induced cardiotoxicity remain incompletely elucidated. Preclinical murine models revealed profound PD-L1 expression in cardiac tissue. Following anti-PD-1 treatment, PD-L1 levels were upregulated with concomitant infiltration of CD4+ and CD8+ T cells in the myocardium. Mice subjected to anti-PD-1 therapy combined with antibody-based CD8+ T cell depletion protocols showed preserved cardiac function, indicating that myocardial T-cell accumulation influences ICI-related cardiotoxicity [13, 14]. Similarly, myocarditis-prone mice with CTLA-4 deficiency exhibit dense infiltration of CD3+CD8+, CD4+ T cells, increased CD68+ macrophages and expansion of a population of CCR2 macrophages (Cxcl9Cxcl10 macrophages) [15], accompanied by cardiomyocyte necrosis. These mice also commonly display elevated serum troponin—biomarkers of cardiac injury [16]. Another hypothesis propose that T-cell infiltration is results from immune responses triggered by autoantigens such as myosin [14, 17], troponin I [18].

It is commonly recommended that cancer treatment should be discontinued when patients experience severe cardiotoxicity, and the cancer treatment plan can be reconsidered after corresponding heart diseases are stabilized, yet whether it is advisable to re-challenge with the same treatment regimen remains controversial and many cancer patients with cardiovascular diseases received conservative treatment resulting in poorer clinical outcomes [19–23]. In addition, the mortality burden caused by ICI treatment-induced cardiotoxicity is substantial, especially myocarditis, whose fatality rate can reach 50% [24].

However, whether ICI therapy itself is strongly associated with cardiotoxicity requires further confirmation, as most previous studies involved combination regimens with chemotherapy or other treatments that are inherently cardiotoxic. Here, to address this gap and isolate the specific impact of ICI therapy, we performed a systematic review and meta-analysis focusing on placebo-controlled randomized controlled trials (RCTs) of ICI-based therapy to assess ICI-induced cardiotoxicity in order to provide a State-of-the-Art review of ICI-related cardiotoxicity, and to increase clinical awareness of cardiotoxicity and prompt intervention.

Methods

Study objectives and outcome

The objective of this research is to assess the cardiotoxicity engendered by ICI treatment, as manifested by cardiac adverse events. For every individual trial, receiving ICI treatment is designated as the experimental group, and the one receiving placebo treatment is regarded as the control group. The primary endpoint is to evaluate the relative risk (RR) of cardiotoxicity for the purpose of discerning the disparities between the two groups.

Subgroup analyses were stratified by tumor type, the type of ICI and type of ICI combination used in the randomized, controlled trial. The trial designs which comparing ICI monotherapy or dual ICI therapy with placebo were classified as type 1 of ICI combination (type 1: ICI(s) vs. placebo), while the designs which comparing ICI with placebo, in combination with other systemic therapy were grouped as type 2 of ICI combination (type 2: ICI + others vs. placebo + others). Given that lung cancer and melanoma are the tumor types in which ICIs are most frequently used, the trials were generally divided into three group: (1) lung cancer; (2) melanoma; (3) non-lung non-melanoma cancers.

Search strategy and selection process

This systematic review and meta-analysis are consistent with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. It was registered in the PROSPERO database, CRD42024614721, and a protocol was not prepared. There are no amendments regarding the information provided at registration.

We searched PubMed, Embase, Web of Science from inception to January 10, 2025. The search strategy can be found at supplementary material 1. Records classification, duplicate and selection were performed by two independent investigators (ZFL and XWX). The selection criteria were as follows: (1) RCTs published before January 10, 2025; (2) participants diagnosed with solid tumor received at least one ICI in experimental group and placebo in control group; (3) RCTs report cardiac adverse events, including zero event; (4) the recent and comprehensive article when multiple publications of the same trial were reported; (5) meeting abstracts with specific data. The following exclusive criteria were used: (1) papers in languages other than English; (2) RCTs in phase I.

Data extraction and risk of bias assessment

For each eligibility study, data were extracted by two independent investigators (ZFL and XWX), and data with disagreements were analyzed by a third person (ZLY). First author, title, year, phase, cancer type, study name, number of NCT, type of ICI, type of ICI combination, type of treatment in control arm, number of patients in each group, number of cardiac adverse events (AEs) in each group were collected from each study. The number of myocarditis, arrhythmia and pericardial diseases, including pericarditis, pericardial effusion and cardiac tamponade was specially extracted. The cardiac AEs were graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events (NCI-CTCAE). The extracted characteristics of individual studies will be presented in the form of a table.

The risk of bias for each study was assessed by two independent investigators (ZFL and XWX) using the Cochrane Risk of Bias tool v.2. Random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, other bias were assessed. Each study was assessed as having a high, low, or an unclear risk of bias.

Statistical analysis

Pooled relative risks (RRs) and 95% confidence intervals (95% CIs) were utilized to indicate the risk of cardiotoxicity, while pooled RRs and 95% CIs of cardiotoxicity were calculated using the random effects model. And the pooled results will be displayed in the form of forest plot. The RRs were considered statistically significant when the 95% CIs did not include 1.0 and the P value<0.05. Sensitivity analysis was also performed by recalculating the RRs and 95% CIs after excluding each study. Statistical heterogeneity between the trials included in the meta-analysis was evaluated using the Ι2 statistic, and subgroup analysis was used to explore the possible existence of heterogeneity. Egger’s test and funnel plot were performed to exclude the potential publication bias.

All the data were collected using Microsoft Office Excel 2019, and the statistical analyses were performed using the STATA software version 18.

Result

Eligible studies and characteristics

The initial search revealed a total of 282,369 relevant records, and 858 full text articles were assessed after screening. After eligibility assessment, 101 studies and a total of 58,698 patients were included in the analysis. The study selection process is reported in Fig. 1.

Fig. 1.

Fig. 1

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Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) flowchart for study selection

Characteristics of the included studies are reported in supplementary material 2. The most frequent tumor type is lung cancer (31 studies included), followed by melanoma (11 studies), gastric cancer (9 studies). 76 studies compared ICI with placebo in combination other drugs including chemotherapy, targeted drugs and so on, and 5 studies compared ICI with placebo in combination with another ICI. 20 studies compared ICI alone with placebo.

Risk of bias in studies

Risk of bias assessment for 101 studies are reported in eFigure 1. Overall, most of the studies had a low risk of bias due to our selection of RCTs. Only 29 studies may have led to some concerns in the blinded part due to medicine administration and the trial involving surgery which does not affect the results.

Incidence and RR of cardiotoxicity with ICI

For cardiotoxicity of any grade, the incidence in experimental arms was 3.0% (95% CI, 2.6-3.5%) compared with 2.3% (95% CI, 1.9-2.7%) of control arms. The specific incidence of anti-PD-1 was 3.0% (95% CI, 2.4-3.6%), anti-PD-L1 was 2.0% (95% CI, 1.4-2.7%), and anti-CTLA-4 was 4.9% (95% CI, 3.4-6.5%), while the incidence of control arms was reported in the eTable 1 (Supplementary material S3). Risk of all grades of cardiotoxicity was higher among patients that received ICI compared with placebo (RR = 1.31, 95% CI = 1.17–1.48, P<0.001; Fig. 2) with low heterogeneity (Ι2 = 13.6%, p = 0.151). Subgroup analyses on type of ICI and type of ICI combination revealed significantly elevated cardiotoxicity risk for anti-PD-1 (RR = 1.32, 95% CI = 1.16–1.50, P<0.001), anti-PD-L1 (RR = 1.36, 95% CI = 1.05–1.75, P<0.001), type 1 of ICI combination(RR = 1.54, 95% CI = 1.20–1.98, P = 0.001) and type 2 of ICI combination(RR = 1.24, 95% CI = 1.10–1.40, P<0.001) while no statistically differences were observed between the two groups in anti-CTLA-4 and anti-TIGIT (Fig. 3). In the subgroup analysis on tumor type, the non-lung non-melanoma cancers group showed a higher risk cardiotoxicity associated with ICI (RR = 1.42, 95% CI = 1.21–1.65, P<0.001) while no statistically differences were observed in lung cancer and melanoma groups (eFigure 2, Supplementary material S3). In the overall sensitivity analysis, the pooled RR was stable with little fluctuation and consistent with our primary outcome when each study was sequentially excluded (eTable 2, Supplementary material S3).

Fig. 2.

Fig. 2

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Forest plot for all grades of cardiac adverse events in immune checkpoint inhibitor (ICIs) compared with placebo group, grouped according to ICI type

Fig. 3.

Fig. 3

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Forest plot for all grades of cardiac adverse events in immune checkpoint inhibitor (ICIs) compared with placebo group, grouped according to type of ICI combination

Other analyses were performed to estimate the RRs of single cardiac AEs, including myocarditis, pericardial events and arrhythmia. Comparing ICI to placebo, ICI treatment significantly increased the risk of myocarditis (RR = 1.79, 95%CI = 1.11–2.91, p = 0.018) and arrhythmia (RR = 1.22, 95%CI = 1.04–1.44, p = 0.016) (Figs. 4 and 5) while the pericardial events showed no significant difference (RR = 1.07, 95%CI = 0.72–1.58, p = 0.748). In subgroup analyses of myocarditis, statistically differences were observed between the two groups in anti-PD-1(RR = 1.91, 95% CI = 1.09–3.34, P = 0.023), type 1 of ICI combination (RR = 2.27, 95% CI = 1.02–5.04, P = 0.044) while no statistically differences were observed between the two groups in other subgroups (eFigs. 3 and 4, Supplementary material S3). In subgroup analyses of pericardial events, no statistically differences were observed between the two groups in each subgroup (eFigs. 5, 6 and 7, Supplementary material S3). Regarding subgroup analyses of arrhythmia (eFigs. 8 and 9, Supplementary material S3), statistically differences were observed just in non-lung non-melanoma cancers group (RR = 1.41, 95% CI = 1.06–1.88, P = 0.02). In the sensitivity analyses, the pooled RRs of myocarditis and pericardial event were stable, with little fluctuation when each study was sequentially excluded (eTable 3–4, Supplementary material S3). However, the pooled RR of arrhythmia has changed (eTable 5, Supplementary material S3). When two studies were excluded one by one, the direction of the pooled result was opposite (RR = 1.175, 95% CI = 0.996–1.387, P = 0.056 and RR = 1.184, 95% CI = 0.999–1.407, P = 0.052).

Fig. 4.

Fig. 4

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Forest plot for myocarditis events in immune checkpoint inhibitor (ICIs) compared with placebo group, grouped according to ICI type

Fig. 5.

Fig. 5

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Forest plot for arrhythmia events in immune checkpoint inhibitor (ICIs) compared with placebo group, grouped according to ICI type

Publication bias

No publication bias was observed for all cardiotoxicity (Egger’s test p = 0.146), myocarditis (Egger’s test p = 0.205), pericardial events (Egger’s test p = 0.066), and arrhythmia (Egger’s test p = 0.902) and funnel plots with 95% CI were reported in the supplementary material 3 (eFigure 10, Supplementary material S3).

Discussion

To our knowledge, our results report a more comprehensive, larger and the most recent analysis of ICI-induced cardiotoxicity risk, which including 101 studies. In our analysis of RCTs with placebo controls, ICIs are associated with increased cardiotoxicity, which was consistent with those of previous studies [24–30]. In this analysis, we included more standardized and up-to date RCTs, which resulted in less heterogeneity and more reliable pooled results. One study suggest that anti-PD-1 has a better survival advantage than anti-PD-L1 due to differences in their mechanisms [31]. However, from the results of this study, there is no significant difference in their cardiotoxicity (RR 1.32 vs. 1.36). In the past, some studies have suggested that ICI does not increase cardiotoxicity [32–34], and the difference can be attributed to the design of the studies we included. We included only randomized controlled trials with a placebo control group to avoid the influence of other effective treatments and to better reflect the cardiotoxic effects of ICIs. In addition, compared with past studies, our research includes more patients and more types of tumors. Interestingly, as the tumor types with the highest use of ICI, lung cancer and melanoma showed no statistically significant association between ICI and increased cardiotoxicity, which appears to suggest a favorable safety profile of ICI on heart. For non-lung non-melanoma cancers, however, it is not appropriate to generalize the cardiotoxicity of ICI, as this observation may be confounded by general tumor types and limited clinical experience.

In this study, we also analyzed three cardiac adverse events with a relatively high incidence to clarify the impact of ICIs on them, among which myocarditis was the most common. While we identified a significant myocarditis risk increase, particular with anti-PD-1 agents, these findings contrasts with a previous study [35] reporting no increased risk with PD-1/PD-l1 group, possibly due to differences in the size of the ICI type selected for enrollment and increased reporting of cardiac AEs. Bayesian meta-analysis accounting for sparse myocarditis data demonstrated that ICIs remained associated with a significantly increased risk of myocarditis (RR = 3.02, 95% CI = 1.54–6.14), indicating robust evidence for this association. Pericardial disease remains an underrecognized toxicity of ICIs, although a large retrospective cohort study reported higher risk of pericardial diseases in ICI-treated (HR = 4.37, 95%CI = 2.09–9.14, p<0.001) [36], whereas our results showed ICIs are not associated with pericardial events. While some pharmacovigilance studies [24, 37] have suggested that ICIs may increase the incidence of pericardial diseases, they also indicated a potential for overrepresentation of these events since pericardial diseases are common complications of malignant tumors. Therefore, whether ICIs truly increase the incidence of pericardial diseases requires further verification through more RCTs or real-world studies that specifically focus on ICI-induced pericardial events (distinguishing them from tumor complications). Additionally, while the risk of arrhythmia was higher in the ICI group, sensitivity on arrhythmia was not robust. The two trials (NCT numbers: NCT01844505 and NCT03629925) that caused changes in the sensitivity analysis were both high-quality studies with large sample sizes (including 626 and 357 patients, respectively). The types of ICIs used were anti-CTLA-4 and anti-PD-1, and adverse events were strictly defined according to CTCAE criteria. The reason for this change may be attributed to the large sample sizes and high weights of these two studies. The change of sensitivity result suggested caution is required when judging the arrhythmia caused by ICIs, and more research is still needed.

For the incidence rate, we found the low pooled incidence of all grades cardiotoxicity, which was consistent with previous studies (3%) [25, 32, 38]. However, according to previous studies of cardiotoxicity due to ICI, cardiotoxicities are more severe and associated with higher mortality, especially myocarditis, which can be as high as 50% [11, 24]. Among different types of ICIs, the incidence of cardiotoxicity also varies. We can see the incidence rate of anti-CTLA-4 group is higher than of anti-PD-1/PD-L1 group, which is somewhat different from previous studies [25, 29]. This may be related to the types of studies selected. In previous studies on incidence rates, data from retrospective studies were included. We performed meta-regression analysis to evaluate whether ICI class independently predicts cardiac risk (etable 6, Supplementary material S3). Although descriptive data indicated a higher cardiotoxicity incidence with anti-CTLA-4 versus anti-PD-1/PD-L1, meta-regression demonstrated no significant cardiotoxicity difference between ICI classes: anti-CTLA-4 vs. anti-PD-1 (p = 0.660) and anti-CTLA-4 vs. anti-PD-L1 (p = 0.758). The observed numerical differences likely stem from confounding factors rather than a drug-class effect. Therefore, more trials are needed to be consider the differences among different ICI types.

The present meta-analysis incorporated a robust dataset comprising 101 rigorously conducted placebo-controlled RCTs, demonstrating low risk of bias and no heterogeneity across studies, thereby ensuring the high reliability of our findings. Regarding the heterogeneity observed in the anti-CTLA-4 subgroup analysis, one article [39] was identified as a source of heterogeneity. The reasons for the heterogeneity may be attributed to the different intervention regimens and the dosage of ipilimumab. However, the heterogeneity does not affect our results, due to the low weight of this study and the fact that its results, after chi-square testing, show a statistically significant association between the occurrence of cardiotoxicity and the use of ICIs (eTable 7, Supplementary material S3).

The mechanism of ICI-mediated cardiotoxicity remain unclear, and the main view is that it is related to abnormal T cell immunity [40]. Histologic analysis of patients and animal models of ICI-related myocarditis revealed substantial T-cell infiltration [41–43]. PD-1 is an inhibitory receptor expressed on T cells. Upon binding to its ligand PD-L1, it inhibits signal transduction from the T-cell receptor (TCR) and CD28. In contrast, CTLA-4 is a receptor for the co-stimulatory proteins B7-1 and B7-2 expressed on antigen-presenting cells (APCs). Binding of CTLA-4 to B7-1/B7-2 prevents their interaction with CD28 on T cells. Additionally, CTLA-4 is also expressed on regulatory T cells (Tregs) to block its binding to B7, thereby exerting an inhibitory effect. ICIs can block these inhibitory signals, thereby restore T-cell activation and anti-tumor response [44–47]. In case reports [41, 48, 49] derived from both clinical trials and routine practice, endomyocardial biopsy revealed patchy lymphocytic infiltrates within the myocardium. Immunophenotyping demonstrated predominantly CD3⁺ T cells, with a high proportion of CD8⁺ cytotoxic T lymphocytes. TCR sequencing revealed that cardiac muscle, skeletal muscle, and tumors shared identical high-frequency TCR sequences. Additionally, following ICI treatment, a single immunodominant clone (rather than non-specific expansion) emerged in cardiac tissue, which may be associated with causing cardiac immune injury. Meanwhile, high PD-L1 expression was observed in the injured cardiac tissue. A retrospective case-control study presented consistent findings [12]. In mouse models, knockout of PDL1 or PD1 makes mice more susceptible to fulminant myocarditis [50, 51]. In addition, in some cases with a history of heart disease or risk factors [25, 52] such as acute myocardial infarction, heart failure [53], cardiac damage may be amplified by the use of ICI. Furthermore, other possible mechanisms include the secretion of autoantibodies, such as anti-troponin and anti-myosin [17, 54, 55] after ICI treatment, and the killing of cardiomyocytes by NK cells mediated by monoclonal antibodies through the ADCC pathway [56, 57]. Dual ICI therapy has been shown to increase cardiotoxicity [25], which may be associated with dual ICI inhibiting both signaling pathways [44], enhancing T cell-mediated immune responses, and causing cardiac inflammation. Previous autoimmune diseases and genetic factors have also been proposed as possible risk factors for cardiotoxicity [58]. Several new ICIs are under investigation, including TIM-3, TIGIT, LAG-3, and they need more randomized controlled trials to observe its efficacy and safety.

While this study specifically examines ICIs, it is important to recognize that immunotherapies encompass a broader spectrum, including cytokines, chimeric antigen receptor (CAR) T-cell therapy, bispecific T-cell engaging antibodies. CAR-T is a cell immunotherapy that uses gene technology to modify the T lymphocytes, then the lymphocytes can target specific tumor antigens resulting in apoptosis of tumor cells [59]. A pharmacovigilance data reported mortality of 30.9% in patients with cardiovascular and pulmonary events, and 17.4% in patients with CRS after CAR-T treatment [60]. High dose cytokines have anti-neoplastic and pro-apoptotic effects, and they are associated with cardiovascular toxicities [61, 62]. The mechanism of bispecific T-cell engaging antibodies is similar to that of CAR-T therapy and data regarding the incidence of cardiotoxicity with BiTE therapy are limited [63]. At present this CAR-T therapy and TiBE therapy, cytokines are mostly used in hematologic tumors.

Although this study included more comprehensive and standardized placebo-controlled RCTs, there are still some limitations. One is that the individual patient data such as baseline conditions and underlying diseases were absent, and there are still potential differences between real-world and RCT data. Another limitation is that irAEs are described without graded data, due to the rarity of cardiac AEs, resulting in reported events predominantly emphasizing severe adverse events. Thus, our findings primarily reflect serious adverse events in this context. Finally, we only classified medicines as ICI, non-ICI medicines, and placebo, and did not further identify medicines of ICI combination. Notably, heterogeneity across trials remained within acceptable thresholds during subgroup analyses.

Although there is currently no consensus on standardized monitoring protocols for ICI-induced cardiotoxicity, guidelines [64] indicate that no clear evidence supports the efficacy or value of routine baseline or serial electrocardiograms (ECGs) or troponin measurements in patients receiving ICI therapy. However, several studies suggest that baseline troponin may be useful for predicting cardiotoxicity or diagnosing it through dynamic changes [52, 65]. Meanwhile, identifying patients at high risk of ICI-related myocarditis has been emphasized in literature, warranting consideration of cardiovascular screening [24, 66] (e.g., ECG or cardiac biomarkers) for susceptible populations. If cardiac biomarkers become elevated during follow-up, consultation with a cardiologist and performance of an echocardiogram are recommended. Based on current research and this study, monitoring for cardiotoxicity during ICI therapy is recommended. Prior to initiating ICI treatment, patients should undergo baseline assessment of cardiovascular symptoms/signs, electrocardiogram (ECG), and troponin levels. However, the development of a specific standardized monitoring protocol requires further validation through future large-scale clinical trials and real-world data. Enhanced collaboration among oncologists, cardiologists and immunologists is essential, alongside increased multidisciplinary communication and integration of cross-disciplinary research [67–69] efforts to address this gap. For example, future research could prioritize multi-omics profiling [70] (e.g., single-cell sequencing of cardiac-infiltrating immune cells) to facilitate the discovery of intervention targets. Additionally, focusing on baseline values or dynamic changes in troponin or N-terminal pro-brain natriuretic peptide (NT-pro BNP) levels may aid in predicting and detecting early cardiotoxicity. Other parameters, such as left ventricular global longitudinal strain (GLS) and inflammatory biomarkers (e.g., neutrophil-to-lymphocyte ratio [NLR], C-reactive protein [CRP]), also require further investigation to clarify their associations with cardiotoxicities like myocarditis.

Conclusion

In monotherapy or combination therapy settings, our results show that the use of ICIs can increase the risk of cardiotoxicity with myocarditis and arrhythmia being particularly identified, although the incidence is low, most of the cardiotoxicity are fatal, which suggests that the use of ICIs should be cautious. Additionally, the basic condition of patients, especially their cardiac history should also be considered, and the process of use should be strictly monitored under multi-disciplinary integration to identify the occurrence of cardiotoxicity in time.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Material 1 (23.3KB, docx)
Supplementary Material 2 (419KB, docx)
Supplementary Material 3 (2.3MB, docx)
Supplementary Material 4 (32.1KB, docx)

Acknowledgements

This work was supported by Sichuan Science and Technology Program, [grant number No.2025ZNSFSC0715].

Abbreviations

ICI

Immune checkpoint inhibitor

PRISMA

Preferred Reporting Items for Systematic Reviews and Meta-Analyses

RCTs

Randomized controlled trials

RR

Relative risk

AEs

Adverse events

NCI-CTCAE

National Cancer Institute’s Common Terminology Criteria for Adverse Events

CI

Confidence intervals

CRS

Cytokine release syndrome

GLS

Global longitudinal strain

NLR

Neutrophil-to-lymphocyte ratio

CRP

C-reactive protein

Author contributions

ZFL: Conceptualization, methodology, formal analysis, data curation, writing original draft. LGY: Conceptualization, formal analysis, data curation, writing original draft. ZSH: Formal analysis, data curation, writing original draft LCC: Formal analysis, data curation, writing original draft HSD: Data curation, writing original draft WSR: Data curation, writing original draft XWX: Data curation, writing original draft. ZLY: Conceptualization, methodology, formal analysis, data curation, writing original draft, supervision, funding acquisition. All authors contributed to and approved the final version of the manuscript.

Funding

This work was supported by Sichuan Science and Technology Program, [grant number No.2025ZNSFSC0715].

Data availability

Not applicable.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

  • 1.Liao K, Gong L, Yang Y, He Y, Wang F, Huang Y, et al. A comprehensive review of research progress in Chinese medicines for primary liver cancer treatment. Tradit Med Res. 2022;7:10–8. [Google Scholar]
  • 2.Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint Blockade. Science. 2018;359(6382):1350–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Kraehenbuehl L, Weng C-H, Eghbali S, Wolchok JD, Merghoub T. Enhancing immunotherapy in cancer by targeting emerging Immunomodulatory pathways. Nat Reviews Clin Oncol. 2022;19(1):37–50. [DOI] [PubMed] [Google Scholar]
  • 4.Guo Z, Saw PE, Jon S. Non-Invasive physical stimulation to modulate the tumor microenvironment: unveiling a new frontier in Cancer therapy. BIO Integr. 2024;5(1):1–14. [Google Scholar]
  • 5.Luo Z, Mei J, Wang X, Wang R, He Z, Geffen Y, et al. Voluntary exercise sensitizes cancer immunotherapy via the collagen inhibition-orchestrated inflammatory tumor immune microenvironment. Cell Rep. 2024;43(9):114697. [DOI] [PubMed] [Google Scholar]
  • 6.Miller KD, Nogueira L, Devasia T, Mariotto AB, Yabroff KR, Jemal A, et al. Cancer treatment and survivorship statistics, 2022. CA Cancer J Clin. 2022;72(5):409–36. [DOI] [PubMed] [Google Scholar]
  • 7.Cai L, Li Y, Tan J, Xu L, Li Y. Targeting LAG-3, TIM-3, and TIGIT for cancer immunotherapy. J Hematol Oncol. 2023;16(1):101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Qin S, Xu L, Yi M, Yu S, Wu K, Luo S. Novel immune checkpoint targets: moving beyond PD-1 and CTLA-4. Mol Cancer. 2019;18(1):155. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Postow Michael A, Sidlow R, Hellmann Matthew D. Immune-Related adverse events associated with immune checkpoint Blockade. N Engl J Med. 2018;378(2):158–68. [DOI] [PubMed] [Google Scholar]
  • 10.Johnson DB, Chandra S, Sosman JA. Immune checkpoint inhibitor toxicity in 2018. JAMA. 2018;320(16):1702–3. [DOI] [PubMed] [Google Scholar]
  • 11.Moslehi JJ, Salem JE, Sosman JA, Lebrun-Vignes B, Johnson DB. Increased reporting of fatal immune checkpoint inhibitor-associated myocarditis. Lancet. 2018;391(10124):933. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Mahmood SS, Fradley MG, Cohen JV, Nohria A, Reynolds KL, Heinzerling LM, et al. Myocarditis in patients treated with immune checkpoint inhibitors. J Am Coll Cardiol. 2018;71(16):1755–64. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Michel L, Helfrich I, Hendgen-Cotta UB, Mincu R-I, Korste S, Mrotzek SM, et al. Targeting early stages of cardiotoxicity from anti-PD1 immune checkpoint inhibitor therapy. Eur Heart J. 2022;43(4):316–29. [DOI] [PubMed] [Google Scholar]
  • 14.Axelrod ML, Meijers WC, Screever EM, Qin J, Carroll MG, Sun X, et al. T cells specific for α-myosin drive immunotherapy-related myocarditis. Nature. 2022;611(7937):818–26. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Ma P, Liu J, Qin J, Lai L, Heo GS, Luehmann H, et al. Expansion of pathogenic cardiac macrophages in immune checkpoint inhibitor myocarditis. Circulation. 2024;149(1):48–66. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Wei SC, Meijers WC, Axelrod ML, Anang N-AAS, Screever EM, Wescott EC, et al. A genetic mouse model recapitulates immune checkpoint Inhibitor–Associated myocarditis and supports a Mechanism-Based therapeutic intervention. Cancer Discov. 2021;11(3):614–25. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Won T, Kalinoski HM, Wood MK, Hughes DM, Jaime CM, Delgado P, et al. Cardiac myosin-specific autoimmune T cells contribute to immune-checkpoint-inhibitor-associated myocarditis. Cell Rep. 2022;41(6):111611. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Bockstahler M, Fischer A, Goetzke CC, Neumaier HL, Sauter M, Kespohl M, et al. Heart-Specific immune responses in an animal model of Autoimmune-Related myocarditis mitigated by an Immunoproteasome inhibitor and genetic ablation. Circulation. 2020;141(23):1885–902. [DOI] [PubMed] [Google Scholar]
  • 19.López-Fernández T, Marco I, Aznar MC, Barac A, Bergler-Klein J, Meattini I, et al. Breast cancer and cardiovascular health. Eur Heart J. 2024;45(41):4366–82. [DOI] [PubMed] [Google Scholar]
  • 20.Lyon AR, López-Fernández T, Couch LS, Asteggiano R, Aznar MC, Bergler-Klein J, et al. 2022 ESC guidelines on cardio-oncology developed in collaboration with the European hematology association (EHA), the European society for therapeutic radiology and oncology (ESTRO) and the international Cardio-Oncology society (IC-OS): developed by the task force on cardio-oncology of the European society of cardiology (ESC). Eur Heart J. 2022;43(41):4229–361. [DOI] [PubMed] [Google Scholar]
  • 21.Gevaert SA, Halvorsen S, Sinnaeve PR, Sambola A, Gulati G, Lancellotti P, et al. Evaluation and management of cancer patients presenting with acute cardiovascular disease: a consensus document of the acute cardiovascular care (ACVC) association and the ESC Council of Cardio-Oncology—Part 1: acute coronary syndromes and acute pericardial diseases. Eur Heart J Acute Cardiovasc Care. 2021;10(8):947–59. [DOI] [PubMed] [Google Scholar]
  • 22.Gevaert SA, Halvorsen S, Sinnaeve PR, Sambola A, Gulati G, Lancellotti P, et al. Evaluation and management of cancer patients presenting with acute cardiovascular disease: a clinical consensus statement of the acute cardiovascular care association (ACVC) and the ESC Council of Cardio-Oncology—part 2: acute heart failure, acute myocardial diseases, acute venous thromboembolic diseases, and acute arrhythmias. Eur Heart J Acute Cardiovasc Care. 2022;11(11):865–74. [DOI] [PubMed] [Google Scholar]
  • 23.Simonaggio A, Michot JM, Voisin AL, Le Pavec J, Collins M, Lallart A, et al. Evaluation of readministration of immune checkpoint inhibitors after immune-Related adverse events in patients with Cancer. JAMA Oncol. 2019;5(9):1310–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Salem JE, Manouchehri A, Moey M, Lebrun-Vignes B, Bastarache L, Pariente A, et al. Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study. Lancet Oncol. 2018;19(12):1579–89. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Rubio-Infante N, Ramírez-Flores YA, Castillo EC, Lozano O, García-Rivas G, Torre-Amione G. Cardiotoxicity associated with immune checkpoint inhibitor therapy: a meta-analysis. Eur J Heart Fail. 2021;23(10):1739–47. [DOI] [PubMed] [Google Scholar]
  • 26.Dolladille C, Akroun J, Morice P-M, Dompmartin A, Ezine E, Sassier M, et al. Cardiovascular immunotoxicities associated with immune checkpoint inhibitors: a safety meta-analysis. Eur Heart J. 2021;42(48):4964–77. [DOI] [PubMed] [Google Scholar]
  • 27.Zhang C, Wei F, Ma W, Zhang J. Immune-related cardiovascular toxicities of PD-1/PD-L1 inhibitors in solid tumors: an updated systematic review and meta-analysis. Front Immunol. 2024;15:1255825. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Xavier CB, Lopes CDH, Harada G, Peres EDB, Katz A, Jardim DL. Cardiovascular toxicity following immune checkpoint inhibitors: A systematic review and meta-analysis. Translational Oncol. 2022;19:101383. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Nielsen DL, Juhl CB, Nielsen OH, Chen IM, Herrmann J. Immune checkpoint Inhibitor–Induced cardiotoxicity: A systematic review and Meta-Analysis. JAMA Oncol. 2024;10(10):1390–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Cone EB, Haeuser L, Reese SW, Marchese M, Nguyen DD, Nabi J, et al. Immune checkpoint inhibitor monotherapy is associated with less cardiac toxicity than combination therapy. PLoS ONE. 2022;17(11):e0272022. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Duan J, Cui L, Zhao X, Bai H, Cai S, Wang G, et al. Use of immunotherapy with programmed cell death 1 vs programmed cell death ligand 1 inhibitors in patients with cancer: A systematic review and Meta-analysis. JAMA Oncol. 2020;6(3):375–84. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Agostinetto E, Eiger D, Lambertini M, Ceppi M, Bruzzone M, Pondé N, et al. Cardiotoxicity of immune checkpoint inhibitors: A systematic review and meta-analysis of randomised clinical trials. Eur J Cancer. 2021;148:76–91. [DOI] [PubMed] [Google Scholar]
  • 33.Zhang X-T, Ge N, Xiang Z-J, Liu T. Immune checkpoint inhibitor-related adverse cardiac events in patients with lung cancer: a systematic review and meta-analysis. Cancer Cell Int. 2022;22(1):363. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Rahouma M, Karim NA, Baudo M, Yahia M, Kamel M, Eldessouki I, et al. Cardiotoxicity with immune system targeting drugs: A Meta-Analysis of Anti-PD/PD-L1 immunotherapy randomized clinical trials. Immunotherapy. 2019;11(8):725–35. [DOI] [PubMed] [Google Scholar]
  • 35.Liu S, Gao W, Ning Y, Zou X, Zhang W, Zeng L, et al. Cardiovascular toxicity with PD-1/PD-L1 inhibitors in Cancer patients: A systematic review and Meta-Analysis. Front Immunol. 2022;13:908173. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Gong J, Drobni ZD, Zafar A, Quinaglia T, Hartmann S, Gilman HK, et al. Pericardial disease in patients treated with immune checkpoint inhibitors. J Immunother Cancer. 2021;9(6):e002771. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Ma Z, Pei J, Sun X, Liu L, Lu W, Guo Q et al. Pericardial toxicities associated with immune checkpoint inhibitors: A pharmacovigilance analysis of the FDA adverse event reporting system (FAERS) database. Front Pharmacol. 2021;12:663088 10.3389/fphar.2021.663088 [DOI] [PMC free article] [PubMed]
  • 38.Liu M, Cheng X, Ni R, Zheng B, Huang S, Yang J. Cardiotoxicity of immune checkpoint inhibitors: A frequency network meta-analysis. Front Immunol. 2022;13:1006860. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Hodi FS, Chiarion-Sileni V, Gonzalez R, Grob J-J, Rutkowski P, Cowey CL, et al. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018;19(11):1480–92. [DOI] [PubMed] [Google Scholar]
  • 40.Grabie N, Lichtman AH, Padera R. T cell checkpoint regulators in the heart. Cardiovascular Res. 2019;115(5):869–77. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Johnson Douglas B, Balko Justin M, Compton Margaret L, Chalkias S, Gorham J, Xu Y et al. Fulminant myocarditis with combination immune checkpoint Blockade. N Engl J Med. 2016;375(18):1749–55. [DOI] [PMC free article] [PubMed]
  • 42.Love VA, Grabie N, Duramad P, Stavrakis G, Sharpe A, Lichtman A. CTLA-4 ablation and Interleukin-12–Driven differentiation synergistically augment cardiac pathogenicity of cytotoxic T lymphocytes. Circul Res. 2007;101(3):248–57. [DOI] [PubMed] [Google Scholar]
  • 43.Ji C, Roy MD, Golas J, Vitsky A, Ram S, Kumpf SW, et al. Myocarditis in Cynomolgus monkeys following treatment with immune checkpoint inhibitors. Clin Cancer Res. 2019;25(15):4735–48. [DOI] [PubMed] [Google Scholar]
  • 44.Wei SC, Meijers WC, Axelrod ML, Anang NAS, Screever EM, Wescott EC, et al. A genetic mouse model recapitulates immune checkpoint Inhibitor-Associated myocarditis and supports a Mechanism-Based therapeutic intervention. Cancer Discov. 2021;11(3):614–25. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Bagchi S, Yuan R, Engleman EG. Immune checkpoint inhibitors for the treatment of cancer: clinical impact and mechanisms of response and resistance. Annu Rev Pathol. 2021;16:223–49. [DOI] [PubMed] [Google Scholar]
  • 46.Tan S, Day D, Nicholls SJ, Segelov E. Immune checkpoint inhibitor therapy in oncology: current uses and future directions: JACC: cardiooncology State-of-the-Art review. JACC: CardioOncology. 2022;4(5):579–97. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Wang SJ, Dougan SK, Dougan M. Immune mechanisms of toxicity from checkpoint inhibitors. Trends Cancer. 2023;9(7):543–53. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Guiney Timothy E, Lopes Mathew S, Kalra Mannudeep K, Mooradian Meghan J, Neilan Tomas G, Stone James R. Case 30-2019: A 65-Year-Old woman with lung Cancer and chest pain. N Engl J Med. 2019;381(13):1268–77. [DOI] [PubMed] [Google Scholar]
  • 49.Cavalcante L, Chandana S, Lakhani N, Enstrom A, LeBlanc H, Schmalz J, et al. Case report of fatal immune-mediated myocarditis following treatment with davoceticept (ALPN-202), a PD-L1-dependent CD28 costimulator and dual PD-L1/CTLA-4 checkpoint inhibitor, in combination with pembrolizumab. J Immunother Cancer. 2024;12(8):e009475. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Lucas JA, Menke J, Rabacal WA, Schoen FJ, Sharpe AH, Kelley VR. Programmed death ligand 1 regulates a critical checkpoint for autoimmune myocarditis and pneumonitis in MRL mice. J Immunol. 2008;181(4):2513–21. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.Wang J, Okazaki I-m, Yoshida T, Chikuma S, Kato Y, Nakaki F, et al. PD-1 deficiency results in the development of fatal myocarditis in MRL mice. Int Immunol. 2010;22(6):443–52. [DOI] [PubMed] [Google Scholar]
  • 52.Chitturi KR, Xu J, Araujo-Gutierrez R, Bhimaraj A, Guha A, Hussain I, et al. Immune checkpoint Inhibitor-Related adverse cardiovascular events in patients with lung Cancer. JACC: CardioOncology. 2019;1(2):182–92. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Gröschel C, Sasse A, Röhrborn C, Monecke S, Didié M, Elsner L, et al. T helper cells with specificity for an antigen in cardiomyocytes promote pressure overload-induced progression from hypertrophy to heart failure. Sci Rep. 2017;7(1):15998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54.Balanescu DV, Donisan T, Palaskas N, Lopez-Mattei J, Kim PY, Buja LM, et al. Immunomodulatory treatment of immune checkpoint inhibitor-induced myocarditis: pathway toward precision-based therapy. Cardiovasc Pathol. 2020;47:107211. [DOI] [PubMed] [Google Scholar]
  • 55.Nishimura H, Okazaki T, Tanaka Y, Nakatani K, Hara M, Matsumori A, et al. Autoimmune dilated cardiomyopathy in PD-1 Receptor-Deficient mice. Science. 2001;291(5502):319–22. [DOI] [PubMed] [Google Scholar]
  • 56.Fujii R, Friedman ER, Richards J, Tsang KY, Heery CR, Schlom J, et al. Enhanced killing of Chordoma cells by antibody-dependent cell-mediated cytotoxicity employing the novel anti-PD-L1 antibody avelumab. Oncotarget. 2016;7(23):33498–511. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57.Khanna S, Thomas A, Abate-Daga D, Zhang J, Morrow B, Steinberg SM, et al. Malignant mesothelioma effusions are infiltrated by CD3(+) T cells highly expressing PD-L1 and the PD-L1(+) tumor cells within these effusions are susceptible to ADCC by the Anti-PD-L1 antibody avelumab. J Thorac Oncol. 2016;11(11):1993–2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.Lyon AR, Yousaf N, Battisti NML, Moslehi J, Larkin J. Immune checkpoint inhibitors and cardiovascular toxicity. Lancet Oncol. 2018;19(9):e447–58. [DOI] [PubMed] [Google Scholar]
  • 59.June Carl H, Sadelain M. Chimeric antigen receptor therapy. N Engl J Med. 2018;379(1):64–73. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60.Goldman A, Maor E, Bomze D, Liu JE, Herrmann J, Fein J, et al. Adverse cardiovascular and pulmonary events associated with chimeric antigen receptor T-Cell therapy. J Am Coll Cardiol. 2021;78(18):1800–13. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61.Prabhu SD. Cytokine-Induced modulation of cardiac function. Circul Res. 2004;95(12):1140–53. [DOI] [PubMed] [Google Scholar]
  • 62.Guo L, Liu MF, Huang JN, Li JM, Jiang J, Wang JA. Role of interleukin-15 in cardiovascular diseases. J Cell Mol Med. 2020;24(13):7094–101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63.Ganatra S, Dani SS, Yang EH, Zaha VG, Nohria A. Cardiotoxicity of T-Cell antineoplastic therapies: JACC: cardiooncology primer. JACC: CardioOncology. 2022;4(5):616–23. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64.Brahmer JR, Lacchetti C, Schneider BJ, Atkins MB, Brassil KJ, Caterino JM, et al. Management of immune-Related adverse events in patients treated with immune checkpoint inhibitor therapy: American society of clinical oncology clinical practice guideline. J Clin Oncol. 2018;36(17):1714–68. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 65.Rini BI, Moslehi JJ, Bonaca M, Schmidinger M, Albiges L, Choueiri TK, et al. Prospective cardiovascular surveillance of immune checkpoint Inhibitor–Based combination therapy in patients with advanced renal cell cancer: data from the phase III JAVELIN renal 101 trial. J Clin Oncol. 2022;40(17):1929–38. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 66.Wang DY, Okoye GD, Neilan TG, Johnson DB, Moslehi JJ. Cardiovascular toxicities associated with Cancer immunotherapies. Curr Cardiol Rep. 2017;19(3):21. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 67.Ji X, Tian X, Feng S, Zhang L, Wang J, Guo R, et al. Intermittent F-actin perturbations by magnetic fields inhibit breast Cancer metastasis. Research. 2023;6:0080. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 68.Xu Y, Zeng Y, Xiao X, Liu H, Zhou B, Luo B, et al. Targeted imaging of tumor associated macrophages in breast Cancer. BIO Integr. 2023;4(3):114–24. [Google Scholar]
  • 69.Xu H, Guo Z, Li M, Chaves HV, Pinto VPT, Filho GC, et al. Copper-Based nanomaterials for Image-Guided Cancer therapy. BIO Integr. 2024;5(1):1–14. [Google Scholar]
  • 70.Tang J, He J, Guo H, Lin H, Li M, Yang T, et al. PTBP2-Mediated alternative splicing of IRF9 controls Tumor-Associated monocyte/macrophage chemotaxis and repolarization in neuroblastoma progression. Research. 2023;6:0033. [DOI] [PMC free article] [PubMed] [Google Scholar]

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