The double-edged sword of tumor-targeted treatment: the influence of targeted therapy on the heart

Introduction

Most anti-tumor drugs exhibit non-selective effects, affecting cancer cells and non-cancer cells across most organs and tissues, including hepatorenal toxicity, cardiotoxicity, hematopoietic toxicity, etc., whereas targeted therapy disrupts core pathways of specific cancer growth and progression. In recent years, significant progress has been made in targeted treatment of many cancers, including lung, breast, and gastrointestinal cancers, with major advantages including the ability to specifically target cancer cells, thereby reducing damage to normal cells and improving treatment outcomes and patient survival rates.

However, targeted therapy is not perfect, as common problems include drug resistance and side effects. Moreover, the main targets of targeted therapy are angiogenesis and immunomodulation. The cellular composition and structural characteristics of the heart make it susceptible to these two influences, with recent studies indicating that targeted therapeutic agents can cause cardiac damage. For example, anthracyclines have been fully demonstrated to induce severe cardiac toxicity, mainly in cardiomyopathy and heart failure (HF) (1). Therefore, targeted therapy poses a challenge, requiring cooperation between oncologists and cardiologists, with close monitoring of patients’ cardiac function and the implementation of necessary preventive measures to minimize the risk of cardiovascular complications. Understanding the impact of targeted therapy on the heart and its potential mechanisms is crucial for providing more effective clinical guidance and treatment plans.

The present review aims to systematically summarize the common clinical types, potential mechanisms, and clinical monitoring and management strategies of cardiac toxicity induced by tumor-targeted therapy, with the purpose of providing scientific guidance for the rational clinical application of tumor-targeted therapy.

Overview of the core mechanisms of targeted therapy cardiotoxicity

The cardiotoxicity of targeted drugs generally arises from disruption of signaling networks, particularly those regulating angiogenesis, immune homeostasis, and cell metabolism. Mechanistically, targeted agents can induce injury through multiple overlapping pathways, including DNA damage, mitochondrial dysfunction, oxidative stress, ferroptosis, inflammation, and endothelial injury. The above processes impair contractility and trigger arrhythmias, thereby promoting hypertrophy, which may lead to HF (2).

Direct DNA damage-induced cardiotoxicity

Destroying the DNA of tumors is one of the main anti-cancer mechanisms of specific targeted drugs, such as doxorubicin, which selectively fuse with isoforms of topoisomerase II: Top2α in dividing cells and Top2β in myocardial cells, with fusion with Top2α enabling doxorubicin to form a ternary cleavage complex (Top2α-doxorubicin-DNA), thereby causing double-strand breaks and apoptosis in cancer cells (3). Conversely, in myocardial cells, interaction with Top2β causes double-strand breaks of DNA, which trigger apoptosis and cause cardiac toxicity (4).

Oxidative stress and mitochondrial dysfunction

Oxidative stress and inflammation are considered to be basic pathophysiological processes in cardiovascular diseases and cancer (5). While doxorubicin fuses with cardiolipin in the mitochondrial inner membrane, thereby promoting excessive reactive oxygen species (ROS)/reactive nitrogen species (RNS) generation, inhibiting oxidative phosphorylation, and damaging the membrane, it can also activate p53, disrupt myocardial metabolism, and further increase ROS/RNS, thus leading to cell apoptosis (6). Platinum drugs accumulate in mitochondria, damaging mitochondrial DNA, consuming glutathione, inhibiting oxidative phosphorylation, opening permeability transition pores to release cytochrome c, thereby activating apoptosis (7). Moreover, proteasome inhibitors such as bortezomib and carfilzomib can impair mitochondrial metabolism and reduce ATP synthesis, thereby limiting contractile function (8).

Ferroptosis in cardiomyocytes

Ferroptosis is a newly recognized, iron-dependent cell death mechanism, distinct from apoptosis, necrosis, and autophagy, characterized by accumulation of iron-dependent lipid peroxidation products, mainly driven by excessive ROS generation and oxidative stress (9). It can be triggered by inhibiting glutathione peroxidase 4 (GPX4) or impairing the cystine/glutamate antiporter system Xc⁻, thereby reducing glutathione synthesis and antioxidant capacity (10). While in cardiomyocytes, anthracyclines induce ferroptosis through the following ways: (I) glutathione depletion, GPX4 inhibition, and ROS-driven lipid peroxidation, and (II) disruption of iron homeostasis, thus increasing labile iron and oxidative damage. Evidence supports the notion that ferroptosis is a major mechanism of anthracycline cardiotoxicity, in which drugs such as Sorafenib also inhibit system Xc⁻, deplete glutathione, and increase ROS (11).

Additional mechanistic pathways

Other mechanisms encompass disruption of Ca²⁺ homeostasis, in which alterations in channel activity impair contraction and diastolic function, thereby increasing risk of arrhythmias (12). Moreover, endothelial dysfunction, such as cisplatin-induced vascular endothelial damage, increases the risk of atherosclerosis and ischemia, while some drugs can trigger systemic inflammation, leading to myocarditis or pericarditis. These mechanisms highlight the multifactorial nature of targeted therapy cardiotoxicity and the necessity of close monitoring and early intervention for high-risk.

The relationship between tumor-targeting therapy and heart disease

Targeted growth factor inhibitors

Growth factor receptors play dysregulated roles in many cancers, making them potential targets for chemotherapy, while specific growth factor inhibitors should exhibit high specificity, high potency, activity in intact cells, and therapeutic efficacy in vivo. Currently, growth factor receptors used for cancer treatment include vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), human epidermal growth factor receptor (HER2) and epidermal growth factor receptor (EGFR) (Table 1).

FGFR inhibitors

Therapeutic role and classification

FGFRs fuse with FGFs, thereby regulating cell proliferation, tissue proliferation, differentiation, vascular generation and metabolism, while the human FGFR family encompasses FGFR1 to FGFR5, with genomic analysis showing that FGFR1 to 4 have amplification in lung cancer, gastric cancer, bladder cancer, liver cancer and cholangiocarcinoma, while point mutations of FGFR2 are seen in endometrial cancer, which highlights the status of FGFRs as core targets of precision oncology. Currently, FGFR-targeted drugs include small-molecule receptor tyrosine kinase inhibitors, monoclonal antibodies, FGF ligand traps, and DNA/RNA aptamers, and representative inhibitors include AZD4547, BGJ398, Debio-1347, dovitinib, LY2874455, and ponatinib, which block FGFR activity at concentrations less than 20 nM. Among them, AZD4547, BGJ398, Debio-1347, and dovitinib mainly target FGFR1-3, while erdafitinib, LY2874455, and ponatinib are pan-FGFR inhibitors; BLU9931 shows selectivity for FGFR4, and FIIN-2 irreversibly inhibits multiple FGFR subtypes (29). These drugs exert anti-tumor effects by inhibiting FGFR kinase activity, thereby blocking downstream oncogenic signaling pathways, inhibiting vascular generation, and regulating the immune microenvironment.

Mechanism analysis—cardiovascular toxicity

FGFR inhibitors in clinical practice most commonly cause adverse events encompassing phosphate imbalance, diarrhea, fatigue, and skin or ocular toxicity (30). While hyperphosphatemia can cause phenotypic transformation of vascular smooth muscle, dysregulation of collagen metabolism, and a synergistic effect with inhibitory parathyroid hormone, leading to myocardial interstitial fibrosis, decreased myocardial perfusion, increased ventricular stiffness, and increased risk of arrhythmia (15). Moreover, ponatinib, a pan-FGFR multi-kinase inhibitor, has significant cardiovascular risk, with clinical data in chronic myeloid leukemia associating it with myocardial infarction, stroke and arterial occlusion, while in animal models, pan-FGFR inhibitors reduced heart rate and impaired cardiac function manifested as reduction in ejection fraction, stroke volume and early diastolic filling velocity, thus indicating acute diastolic dysfunction and reduced vascular compliance.

EGFR tyrosine kinase inhibitors (TKIs)

Therapeutic role and classification

EGFR is a transmembrane receptor with tyrosine kinase activity, and its dysregulated signaling drives tumorigenesis by promoting uncontrolled proliferation, angiogenesis, and metastasis, and by altering therapeutic response. Consequently, pharmacological targeting of EGFR has become an established therapeutic approach in oncology, particularly in non-small cell lung cancer. First-generation drugs (gefitinib, erlotinib) are oral ATP-competitive kinase inhibitors, while second-generation drugs (canertinib, EKB-569) irreversibly block EGFR and other ErbB members to bypass resistance, and third-generation inhibitor osimertinib targets sensitizing mutations and T790M mutation while also being selective for wild-type EGFR, thereby reducing off-target effects. Their clinical application depends on generation, mutation spectrum, and tumor type, thus making EGFR-TKIs the focal point of EGFR-driven cancer management.

Mechanism analysis—cardiovascular toxicity

EGFR-TKI-related cardiovascular toxicity originates from on-target and off-target effects, while different drugs have different characteristics, and in preclinical studies, gefitinib promotes cardiomyocyte hypertrophy by altering expression of hypertrophic/anti-hypertrophic genes [for example, B-type natriuretic peptide (BNP), α-MHC] and increasing apoptotic mediators (caspase-3, p53), thereby leading to cardiomyocyte apoptosis and remodeling (31). Whereas erlotinib in clinical observations is associated with acute coronary syndrome and venous thromboembolism, which is possibly caused by impairing endothelial function and promoting pro-thrombotic signal transduction secondary to EGFR blockade in vascular endothelium.

Osimertinib, although designed for minimizing wild-type EGFR inhibition, still has subtle clinically relevant cardiac toxicity, which, by inhibiting the HER2 receptor pathway, can cause myocardial cell damage and impaired contractile function, thereby leading to HF, and additionally, Osimertinib inhibits PI3K signal transduction, thus disrupting myocardial repolarization current and prolonging the QT interval (32,33).

Overall, cardiotoxicity caused by EGFR TKIs mainly stems from their inhibition of EGFR tyrosine kinase, as this therapeutic mechanism has off-target effects on normal physiological functions of the heart, including cardiomyocyte survival, repair, and electrical activity (34).

HER2-targeted therapy

Therapeutic role and classification

HER2, also called Neu or ErbB2, is a transmembrane tyrosine kinase receptor that belongs to the EGFR family and regulates cell growth, differentiation, and survival. HER2 overexpression or gene amplification occurs in multiple malignant tumors, including breast cancer, gastric cancer, prostate cancer, lung cancer, and bladder cancer. HER2-targeted drugs contain monoclonal antibodies and small-molecule TKIs. Trastuzumab is a humanized monoclonal antibody targeting the HER2 extracellular domain, which binds subdomain IV and blocks ligand-independent signaling, while pertuzumab targets subdomain II and prevents HER2/HER3 dimerization, thereby complementing trastuzumab’s mechanism and also showing synergistic clinical efficacy. Lapatinib is an oral, reversible dual TKI that can inhibit HER2 and HER1 signaling.

Mechanism analysis—cardiovascular toxicity

Cardiovascular toxicity associated with HER2-targeted therapy, especially trastuzumab, has long been a clinical concern, as HER2 signaling in cardiomyocytes is critical for cardiomyocyte growth, contractile function, and survival under physiological stress. Inhibition of HER2 in the heart downregulates important pro-survival pathways, including PI3K/AKT, mammalian target of rapamycin (mTOR), and the Ras/RAF/MEK/ERK cascade, thereby impairing cell metabolism, disrupting autophagy, and leading to mitochondrial dysfunction (35). While trastuzumab in clinical use generally induces cardiomyopathy, pertuzumab, although targeting different HER2 epitopes, when combined with trastuzumab, does not significantly increase the risk of cardiac toxicity, and lapatinib generally shows good cardiovascular safety (36). Clinically, combination use of HER2 inhibitors with anthracycline drugs will significantly amplify cardiac damage by blocking myocardial repair, thus causing synergistic toxicity, and mechanistically speaking, cardiac toxicity of HER2 inhibitors mainly involves interrupting important signaling pathways and is generally reversible, however, newly emerging connections with mitochondrial dysfunction and ferroptosis weaken mitochondrial antioxidant defense and increase sensitivity to ferroptosis, which is confirmed through GPX4 downregulation and increase of lipid peroxidation (37).

VEGF receptor TKIs

Therapeutic role and classification

VEGF, particularly VEGF-A, is the focus of tumor angiogenesis, which relies on fusion with VEGFR-1/2 on endothelial cells, and activates downstream pathways (PI3K/AKT, MAPK) to promote proliferation, migration, and survival of endothelial cells, thereby driving the formation of new, abnormal, leaky tumor blood vessels, supplying oxygen and nutrients, moreover, VEGF also promotes immune suppression and metastasis (38). Current anti-VEGF therapies include monoclonal antibodies (bevacizumab, aflibercept, ramucirumab) and TKIs (sunitinib, sorafenib, cabozantinib, axitinib), which are effective in renal cell carcinoma, hepatocellular carcinoma, and thyroid cancer.

Mechanism analysis—cardiovascular toxicity

Although having oncological benefits, VEGFR-TKIs are frequently associated with clinically significant cardiovascular toxicity, with the majority of patients experiencing an elevation of blood pressure when receiving VEGFR-TKIs in clinical trials. The mechanism involves reduced NO bioavailability, increased endothelin-1, and oxidative stress (39). The cardiac toxicity of VEGFR inhibitors encompasses HF, reduced left ventricular function, cardiomyopathy, and Takotsubo syndrome. They impair coronary microvascular function, reduce coronary flow reserve, damage endothelial cells, and promote thrombus formation. Additionally, VEGF-mediated angiogenesis is very important for myocardial adaptation to ischemia or load, while its inhibition impairs this response; Certain drugs (such as sunitinib) can simultaneously inhibit PDGFR-β, leading to loss of pericytes and vascular instability (36).

Targeted signaling pathway inhibitors

Advancements in molecular understanding of disease mechanisms have led to the recognition that many illnesses stem from dysfunctions in signaling pathways. This recognition has led to exhaustive research and the development of therapies that target the interception of cellular signaling in diseased cells.

Ras-targeted therapy

Therapeutic role and classification

Ras is a membrane-fused GTP-binding protein that functions as a molecular switch, transmitting extracellular signals to intracellular pathways, and mainly relies on the MAPK and PI3K signaling cascades to regulate proliferation, metabolism, apoptosis, and angiogenesis, thereby driving tumor development. Among its three subtypes, KRAS, HRAS, and NRAS, KRAS mutations dominate in pancreatic and colorectal cancers, while NRAS mutations are more common in melanoma, and HRAS mutations are relatively rare (40). KRAS-off inhibitors bind to mutant KRAS in the GDP-bound state, blocking its conversion to the active GTP-bound form, but have limited efficacy in tumors with high RAS-GTP levels. In contrast, RAS-on inhibitors target the active GTP-bound conformation, which remains effective even when RAS-GTP is elevated (41). Sotorasib selectively inhibits KRAS G12C, and is one of the few direct Ras inhibitors showing clinical efficacy, and indirect strategies remain the main approach for Ras inhibition, particularly through targeting farnesyltransferase, which is an enzyme required for post-translational farnesylation of Ras protein, with this modification promoting its membrane localization and activation, since farnesylation is crucial for Ras signaling, FTase inhibitors have become an important focus of anti-Ras drug development.

Mechanism analysis—cardiovascular toxicity

While direct KRAS allele-specific inhibitors such as sotorasib have not yet shown clinical cardiac toxicity, certain indirect Ras targeting strategies have been associated with cardiovascular risks due to off-target effects, where L778123, a dual farnesyltransferase inhibitor, caused QT prolongation during 7-day continuous infusion in early studies, possibly by altering cardiac ion channel conduction through off-target kinase effects and inducing conduction abnormalities. Other FTase inhibitors under investigation have not shown significant cardiac toxicity; However, extensive prenylation inhibition may disrupt small GTPases that are crucial for cardiomyocyte and endothelial function, thereby disturbing myocardial signal transduction, vascular tone, and electrophysiological stability, and may lead to subclinical myocardial dysfunction or adverse vascular events (42).

PI3K-targeted therapy

Therapeutic role and classification

PI3K pathway regulates multiple physiological processes, including glucose metabolism, cell proliferation and cell growth, while PI3K inhibitors are divided into pan-PI3K inhibitors, isoform-specific PI3K inhibitors and dual PI3K/mTOR inhibitors (43). It not only shows clinical benefits in solid tumors such as breast cancer, but also demonstrates efficacy in hematological malignancies, especially in selected B-cell neoplasms (44). Most clinically available PI3K inhibitors achieve potent inhibition by targeting highly conserved kinase active sites, with combined treatment regimens targeting PI3K and other oncogenic pathways, although these regimens improve tumor control and thereby increase cardiovascular risks.

Mechanism analysis—cardiovascular toxicity

Cardiotoxicity from PI3K inhibitors primarily arises from two interrelated mechanisms: direct targeted inhibition in cardiac tissue and indirect effects on parallel pathways, where the PI3K/AKT axis is critical for survival, metabolism, and adaptive contraction of cardiomyocytes. PI3K mediates adaptive myocardial growth and fibrosis, and its inhibition disrupts this process, thereby promoting hypertrophy and fibrosis (45). While PI3K inhibitors also alter the expression and function of cardiac ion channels, thereby reducing potassium, calcium, and sodium currents, prolonging action potential and repolarization, manifesting as QT interval prolongation. Besides, they induce electrical remodeling similar to chronic AV block, thereby prolonging the QT/JT interval and reducing repolarization reserve; PI3K inhibition further increases repolarization dispersion, thereby increasing the risk of metabolism (46).

mTOR-targeted therapy

Therapeutic role and classification

mTOR is a serine/threonine kinase that centrally regulates cell survival, proliferation, and metabolism in response to environmental signals, and its dysregulation is very common in human cancers. mTOR operates in two complexes: mTORC1 regulates protein synthesis and cell growth, while mTORC2 controls cytoskeletal organization, cell survival, and metabolic adaptation (47). Rapamycin is the first mTOR inhibitor to selectively inhibit mTORC1 and, with long-term use, mTORC2, and was initially used for rare tumors such as lymphangioleiomyomatosis. Temsirolimus is the first approved Rapalog for the treatment of advanced renal cell carcinoma, while Everolimus is approved for multiple cancers, including breast cancer, pancreatic cancer, and lung cancer, as well as subependymal giant cell astrocytoma.

Mechanism analysis—cardiovascular toxicity

mTOR inhibitors have shown cardiac protective effects in multiple preclinical models, although potential risks should not be ignored. Preclinical data indicate that sirolimus can inhibit myocardial hypertrophy and fibrosis. Mechanistically, sirolimus reduces the proliferation of cardiac fibroblasts and collagen production, as well as the expression of pro-fibrotic genes (such as BNIP3) and extracellular matrix-related genes (48). The mTOR inhibitor everolimus has not been associated with serious adverse reactions, but it can cause a series of metabolic syndromes related to cardiotoxicity, thus indirectly leading to cardiac toxicity (49).

Targeted protein modification (TPM) inhibitor

TPM is a general term that encompasses many tools and methods required for using bifunctional reagents to induce TPMs, where the most famous TPM mechanism is proteolysis-targeting chimera-mediated protein ubiquitination, and drug discovery has gone beyond traditional small molecule inhibition, expanding to multiple forms of TPM, including targeted acetylation (50). Although TPM inhibition provides new therapeutic pathways, potential cardiovascular adverse events should not be overlooked.

Therapeutic role and classification

The ubiquitin-proteasome system (UPS) is a major intracellular protein degradation pathway and is very important for maintaining cellular homeostasis by regulating core processes such as the cell cycle, apoptosis, and the stress response. Its dysregulation can lead to tumor formation (51). UPS-targeted drugs include inhibitors of E1 ubiquitin-activating, E2 ubiquitin-conjugating, and E3 ubiquitin-ligase enzymes, as well as proteasome inhibitors. Bortezomib (PS-341) is the first Food and Drug Administration (FDA)-approved proteasome inhibitor, used for relapsed multiple myeloma and mantle cell lymphoma, and is being explored for other hematological and solid tumors (52). Bortezomib exerts potent anti-tumor activity by inhibiting the 26S proteasome, thereby causing the accumulation of ubiquitinated proteins in cancer cells and triggering apoptosis. In addition to bortezomib, other proteasome inhibitors are under investigation, thus expanding therapeutic possibilities for UPS regulation in cancer treatment.

Mechanism analysis—cardiovascular toxicity

Clinically, bortezomib is associated with arrhythmia and chronic HF, especially in lung cancer and multiple myeloma, where arrhythmia may be indirectly generated through autonomic neuropathy, which involves sympathetic and parasympathetic nerve fibers, thereby resulting in conduction disorders such as AV block, while proteasome inhibition also induces ER stress, triggers compensatory autophagy, and proteotoxic stress disrupts metabolic and contractile functions of cardiomyocytes. Mitochondrial dysfunction is another core mechanism, just as bortezomib significantly causes mitochondrial dysfunction and reduces ATP production (53). Additionally, proteasome inhibition activates the calcineurin-NFAT pathway, promotes nuclear translocation of NFAT, and alters gene expression, which may drive cardiac remodeling, with Bortezomib further activating caspase-3/-7, thereby inducing apoptosis of cardiomyocytes (54).

Histone deacetylase (HDAC) inhibitors

Therapeutic role and classification

HDACs are evolutionarily conserved enzymes in plants, animals and fungi, which function as core epigenetic regulatory factors, thereby regulating structure of chromatin and gene expression, while in cancer, inhibition of HDAC induces histone hyperacetylation, and increases accessibility of chromatin, thus reactivating silenced tumor suppressor genes, resulting in cell cycle arrest, apoptosis, senescence, inhibition of differentiation, enhancement of immunogenicity and reduction of angiogenesis. HDAC inhibitors are divided into four major chemical categories: hydroxamic acids, short-chain fatty acids, benzamides and cyclic tetrapeptides (55). FDA-approved examples, including vorinostat, romidepsin and belinostat, which are used for certain hematological malignancies, particularly cutaneous and peripheral T-cell lymphomas, while combination therapy of HDAC with conventional drugs is a promising approach that can increase efficacy and overcome drug resistance.

Mechanism analysis—cardiovascular toxicity

HDAC inhibitors generally exhibit cardiac protective effects in preclinical models, where in animal models of diabetic cardiomyopathy, inhibition of HDAC can reduce myocardial fibrosis, while also inhibiting proliferation of cardiac fibroblasts, and reducing expression levels of type I collagen, type III collagen, α-SMA, and vimentin (56). HDAC inhibitors cause cardiac toxicity through multiple mechanisms, as they disrupt sodium/calcium channels and SERCA2a, thereby leading to arrhythmias, and promote hypertrophy/fibrosis through regulation of HDAC IIa and sirtuin, with them affecting survival/death of cardiomyocytes through regulation of p53, FOXO and NF-κB pathways, while mitochondrial dysfunction and elevation of ROS further trigger apoptosis and impair cardiac function, thus inducing inflammation, oxidative stress and endothelial dysfunction (57,58). In clinical practice, QT prolongation, arrhythmias, myocardial injury, and inflammatory responses remain important concerns.

Targeted cell cycle therapy

Aberrant cell cycle activity is observed in all tumor types. Cyclins can promote cell division and regulate cell function extensively. Given the clinical success of some cyclin inhibitors and related DNA-targeting drugs, targeting single-cell-cycle components may be an effective anticancer strategy. However, the risk of heart disease is not negligible.

Cyclin-dependent kinase (CDK) inhibitor

Therapeutic role and classification

CDKs are serine/threonine kinases that drive the progression of the cell cycle by phosphorylating core substrates. After CDK4/6 complexes with cyclin D, it phosphorylates the retinoblastoma protein (Rb) to facilitate the G1/S transition. In addition to regulation of the cell cycle, CDK4/6 inhibitors can also enhance anti-tumor immunity, including CD8⁺ T-cell mediated tumor killing (59). The FDA has approved three CDK4/6 inhibitors: palbociclib (first approved in 2015 for ER⁺/HER2⁻ advanced breast cancer), abemaciclib, and ribociclib. Cardiovascular adverse events are not common, but have clinical relevance, with ribociclib being associated with prolongation of the QT interval (60).

Mechanism analysis—cardiovascular toxicity

Although cardiovascular events are less common than in other targeted therapies, they still occur in CDK4/6 inhibitors, and a recent cohort study found cancer patients taking these drugs experienced adverse cardiovascular events, including hypertension, HF, atrial fibrillation, and atrial flutter. Compared with similar events in anthracycline-treated patients, such events are associated with worse overall survival (61). Mechanistically, cardiac toxicity may stem from CDK4/6 inhibition affecting cardiac stromal cells, such as fibroblasts, endothelial cells, and macrophages, with these cells maintaining proliferative activity and being very important for structure, vasculature, and immune homeostasis. Inhibiting their proliferation may impair cardiac repair, electrophysiological stability, and promote structural damage. While abemaciclib induces cardiomyocyte apoptosis by activating Hippo pathway (62). Moreover, CDK4/6 blockade also increases interferon production, amplifies T cell-macrophage/leukocyte crosstalk and chronic inflammation, thereby leading to hypertension, left ventricular hypertrophy/remodeling and HF (63).

DNA damage repair inhibitors

Therapeutic role and classification

DNA damage repair mechanism, also known as DNA damage response (DDR) mechanism, includes nucleotide excision repair, mismatch repair, homologous recombination repair, base excision repair and non-homologous end-joining, jointly maintaining stability of the genome (64). Targeting and inhibiting components of DDR can block repair of tumor DNA, which is an effective anti-cancer strategy, with core DDR targeted drugs including poly(ADP-ribose) polymerase (PARP), ataxia-telangiectasia mutated (ATM) and ataxia-telangiectasia and Rad3-related (ATR) inhibitors.

PARP inhibitors mainly rely on blocking PARP-1-mediated BER, preventing the repair of single-strand DNA, thereby increasing the accumulation of DNA damage to exert anti-tumor effects (65). They also leverage promoting recruitment of T cells and activation of immunity to enhance anti-tumor immunity, while ATM inhibitors rely on blocking transmission of ATM signals to impair G1/S checkpoint, subsequently preventing DNA repair, and inducing lethal genomic instability in tumor cells. Such drugs show substantial efficacy in solid tumors and hematological malignancies, although cardiovascular safety deserves attention (51).

Mechanism analysis—cardiovascular toxicity

Although overall tolerance is good, DDR inhibitors, especially PARP inhibitors, have been reported to have cardiovascular adverse reactions, with proposed mechanisms involving off-target effects, particularly neurotransmitter metabolism disorders and ion channel interference, thereby leading to arrhythmias (66). PARP inhibitors can block serotonin, dopamine, and norepinephrine transporters, as well as DYRK1A kinase, thus leading to enhanced cardiac contractility, vasoconstriction/remodeling, elevated blood pressure, and tachycardia (67). Similarly, some PARP inhibitors may cause off-target inhibition of the Kv1.11 (hERG) potassium channel, which leads to QT interval prolongation and increased risk of torsades de pointes ventricular tachycardia (68). Besides, DDR inhibitors can also cause thrombotic tendency and myocardial ischemia/reperfusion injury.

Therapy targeting the immune microenvironment

Development of cancer occurs simultaneously with alterations of surrounding stroma, while immune cells are important constituent elements of tumor microenvironment and also participate in this process, with cross-connections between cancer cells and adjacent immune cells ultimately promoting tumor growth and creating environment favorable for metastasis, where understanding nature of this type of connections will be beneficial to improving therapeutic approaches that simultaneously target multiple components of microenvironment, thereby increasing possibility of patients obtaining good prognosis.

Immune checkpoint inhibitors (ICIs)

Therapeutic role and classification

Immune checkpoints are inhibitory receptor-ligand pathways expressed on immune cells, playing key role in dynamically maintaining immune homeostasis and regulating T cell function, while in tumor microenvironment, cancer cells frequently utilize immune checkpoint signaling to evade immune surveillance, and by selectively blocking checkpoint pathways, ICIs restore T cell-mediated anti-tumor immunity, thereby enabling cytotoxic T cells to recognize and eliminate malignant cells. ICIs targeting programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) have now become the focus of immuno-oncology, which are approved for melanoma, non-small cell lung cancer, advanced renal cell carcinoma, and other malignant tumors (69). FDA-approved drugs, including nivolumab, pembrolizumab, cemiplimab, avelumab, atezolizumab, durvalumab, and ipilimumab, thus represent a paradigm shift that generates durable responses in selected patients.

Mechanism analysis—cardiovascular toxicity

Although effective, ICIs can induce immune-related cardiovascular toxicity, where acute fulminant myocarditis is a severe early complication, often manifesting as cardiac arrhythmias accompanied by myositis, with its pathophysiology involving T cell-driven myocardial infiltration, in which checkpoint blockade amplifies autoimmune recognition of cardiac antigens (70). While myocarditis is another relatively common manifestation, particularly in lung cancer patients receiving anti-PD-1/PD-L1 therapy, and most cases are mild, generally responsive to steroids, rarely requiring treatment interruption (71). Long-term use of ICI may also lead to chronic cardiovascular diseases, including coronary artery/vascular diseases, hypertension, and cardiomyopathy, possibly driven by sustained vascular inflammation and immune-mediated injury.

Bruton’s tyrosine kinase (BTK) inhibitors

Therapeutic role and classification

BTK is a non-receptor tyrosine kinase of the Tec family, which is very important for the development of B cells and the transduction of BCR signal, and after BCR fusion, signal cascade reaction involving Lyn, Syk, and BTK activates PLCγ2, thereby causing activation of downstream NF-κB and promoting survival, proliferation, and differentiation of B cells (72). Besides its normal function, BTK is also important in B-cell malignancies, such as chronic lymphocytic leukemia and various lymphomas, thereby supporting tumor survival, proliferation, chemokine receptor signaling, and integrin-mediated adhesion and migration of malignant cells (73). BTK inhibitors have changed the treatment of such malignant tumors, with ibrutinib as the first drug of its kind, irreversibly binding to cysteine-481 in BTK, thereby blocking abnormal BCR signaling and significantly improving survival in patients with chronic lymphocytic leukemia and mantle cell lymphoma.

Mechanism analysis—cardiovascular toxicity

Despite efficacy being significant, Ibrutinib is associated with a series of cardiovascular toxicities, with the most common being hypertension, and the most serious being cardiac toxicity (74). While documented adverse events include atrial fibrillation, HF, and ventricular arrhythmias, as well as myocarditis and cardiac fibrosis. Mechanistically, ibrutinib-induced cardiotoxicity is considered an off-target adverse reaction, where inhibition of kinases other than BTK, particularly kinases within PI3K/AKT signaling axis, may disrupt survival pathways of cardiomyocytes, thereby also impairing the regulation of ion channels and altering the electrophysiological stability of myocardium (75). While inhibition of PI3K/AKT pathway can increase susceptibility to arrhythmias, thus leading to adverse ventricular remodeling, and aggravating the inflammatory injury of the myocardium.

Antibody-drug conjugates (ADCs)

Therapeutic role and classification

ADCs are targeted biological agents that fuse monoclonal antibody with cytotoxic payload via linker, where the antibody binds tumor-specific antigens and delivers payload-typically potent chemotherapy agent-into interior of cancer cells, where its release disrupts DNA replication or microtubule assembly, thereby inducing apoptosis, and by combining specificity of antibody with potency of cytotoxic, ADCs increase efficacy while reducing systemic toxicity, with over 200 ADC candidates having been tested; as of December 2024, 13 have received FDA-approved for various tumors (76). Moreover, similar approvals in Europe, Japan and China. In China, 9 ADCs have been approved, including vidicitumab, lukansatuzumab and ruikangtrastuzumab, while data for elderly patients (>65 years) remains limited, thereby highlighting the necessity of conducting targeted assessments.

Mechanism analysis—cardiovascular toxicity

Although ADCs have tumor targeting precision, they are associated with potential cardiovascular adverse reactions, especially when antibody component targets antigens expressed in the heart, such as HER2-targeted ADCs, including trastuzumab-based conjugates, which inhibit myocardial growth factor signaling, impair mitochondrial function, and increase oxidative stress, collectively leading to cardiomyocyte apoptosis and contractile dysfunction (77). Clinically, it manifests as left ventricular ejection fraction (LVEF) decline and HF. Certain ADCs can induce off-target direct interference with myocardial cell survival signals (such as the neuregulin-1/HER2 pathway), further leading to protein stress, oxidative stress, and possible inhibition of protective pathways [such as hepatocyte growth factor receptor (HGFR) signaling] in myocardial cells, which may be related to the activation of heat shock protein pathways (78).

Metabolic enzyme inhibitors

Drug-metabolizing enzymes (DMEs), mainly encompassing phase I oxidases such as cytochrome P450 (CYP) superfamily and Phase II fusion enzymes including UDP-glucuronosyltransferases, sulfotransferases and carboxylesterases, play a core role in biotransformation and elimination of exogenous substances, and inhibition of DMEs is an important mechanism in pharmacology and toxicology (79). Although intentional inhibition can be therapeutically utilized to enhance drug exposure or overcome metabolic resistance, it more commonly manifests as an unintended mechanism of adverse drug reactions.

Therapeutic role and classification

DME inhibitors are classified by chemical structure, mechanism, and kinetics. Structurally, many molecules share conserved motifs that confer high-affinity binding via hydrogen bonds, hydrophobic interactions, π-π stacking, or covalent linkages. Drug design aims to optimize these interactions to enhance potency and selectivity and reduce off-target activity. Kinetic analysis using Michaelis-Menten or Lineweaver-Burk plots and K determinations is essential for classification and pharmacokinetic prediction. Integrating computational docking with experimental kinetics improves in vivo effect prediction. Genetic polymorphisms (e.g., in CYP2C19 or CYP2D6) can alter enzyme activity and susceptibility to inhibition, underscoring the role of pharmacogenomics in personalized therapy and risk reduction.

Mechanistic insights—cardiovascular toxicity

Cardiovascular toxicity caused by DME inhibition mainly originates from pharmacokinetic drug-drug interactions, where inhibitors reduce the clearance rate of co-administered drugs, thereby increasing plasma levels and half-life (80). If the substrate itself has cardiac toxicity, this may trigger toxicity, for example, ketoconazole reduces the generation of protective epoxyeicosatrienoic acid (EETs) by inhibiting CYP2J2 in the heart, thereby decreasing the heart’s self-protection and repair ability, and increasing the risk of myocardial ischemia, arrhythmia, HF, and other conditions (81). Enzyme induction generally increases metabolism and lowers drug exposure, but can also boost the formation of reactive or cardiotoxic metabolites. Both inhibition and induction thus critically modulate drug safety.

Monitoring and clinical management of targeted therapy-induced cardiotoxicity

Targeted anticancer drugs have increased survival rates, but cardiac toxicity limits long-term use, while actual incidence may be underestimated, as cardiac toxicity is the main cause of morbidity and mortality in survivors, thereby requiring early detection and proactive management. International guidelines recommend using risk stratification and multimodal strategies that integrate baseline risk assessment, serial biomarkers, and advanced imaging (82,83).

Monitoring strategies

Early detection of subclinical injury is very important, and baseline cardiac function assessment should be established before treatment. Including medical history (previous HF, ischemic/valvular disease, arrhythmias, previous anthracyclines medication history), physical examination, electrocardiogram (ECG), echocardiography and serum biomarkers: high-sensitivity cardiac troponin (hs-cTn) and BNP or N-terminal pro B-type natriuretic peptide (NT-proBNP), to identify occult injury or elevated filling pressure (84), with the integration of clinical, imaging and biomarker data supporting risk stratification.

High risk: confirmed HF, significant valvular disease, previous high-dose anthracycline treatment history, or significantly elevated biomarkers (troponin ≥99th percentile, BNP >100 pg/mL), while moderate risk: presence of conventional risk factors (hypertension, diabetes, dyslipidemia) but no structural disease; possible borderline biomarker elevation. Low risk: no cardiovascular disease history, normal imaging, biomarkers within reference range. During the treatment period, monitoring guided by serial imaging examinations, where speckle tracking echocardiography is most sensitive for early dysfunction, with global longitudinal strain decrease of 10–15% being able to predict impending cardiotoxicity, generally preceding LVEF decline (85). Tissue Doppler can detect early systolic changes. Cardiac MRI provides superior volumetric data and tissue characterization (fibrosis/edema) when echo is limited. If neither is feasible, multi-gated radionuclide angiography provides reproducible LVEF, though its use has declined due to radiation and lack of strain assessment (86).

Parallel biomarker monitoring adds early signals of myocardial injury or hemodynamic stress. Rises in cTnI/T indicate cardiomyocyte injury; BNP/NT-proBNP reflect wall stress. BNP levels above 100 pg/mL offer high specificity for cardiotoxicity, whereas a threshold as low as 30 pg/mL yields approximately 81% sensitivity for predicting early functional decline. Dynamic hs‑cTn increases help distinguish acute from chronic changes. Testing at baseline, mid-cycle, and post-therapy, aligned with imaging, improves detection and facilitates timely cardioprotection.

Clinical management approaches

Management should be individualized to baseline risk, imaging trends, biomarker dynamics, and severity. Pharmacologic therapy is the cornerstone: angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) for asymptomatic LVEF decline >10% from baseline and for symptomatic HF, given their benefits on remodeling, oxidative stress, and energy efficiency (87). Beta-blockers (often combined with ACEI/ARB) provide additive protection, partly by modulating cardioprotective signaling. Metformin may be a useful adjunct with VEGF pathway inhibitors by activating AMPK and restoring myocardial energetics (88). In selected patients, aldosterone antagonists and statins may increase anti-remodeling, anti-inflammatory, and lipid-lowering benefits. ICI cardiotoxicity requires early identification and cessation of ICI treatment, with timely initiation of corticosteroid therapy, rather than strict drug control, and by enhancing cardiovascular resilience through customized exercise and nutritional counseling. Considering the complexity of treatment-related cardiac effects, close cooperation between oncology and cardiology is very important. Early referral to cardio-oncology services can help adjust treatment plans in a timely manner, thereby implementing evidence-based prevention and integrating rehabilitation, which aim to maintain cancer control while also protecting long-term cardiovascular health.

Future perspectives

Future research on targeted cancer therapy should prioritize minimizing treatment-related cardiotoxicity by means of five synergistic approaches while maintaining anti-tumor efficacy: (I) implementing rational structural modifications of high-risk drugs (for example, anthracyclines, antibody-drug conjugates) to preserve efficacy while reducing disruption to cardiomyocyte metabolic pathways, such as free radical generation and mitochondrial function; (II) using multi-omics methods (genomics, proteomics, metabolomics) to comprehensively elucidate mechanisms of targeted and non-targeted cardiac injury, thereby identifying susceptibility biomarkers and achieving mechanism-based prevention; (III) application of precision medicine, including high-throughput sequencing and genome-wide association studies for genetic risk stratification, and customized treatment regimens based on patient-specific pharmacogenomics and metabolic characteristics; (IV) developing innovative delivery platforms (nanocarriers, liposomes, antibody-mediated systems) to achieve localized, controlled drug release, thus reducing systemic exposure and non-targeted cardiac effects; (V) creating novel cardioprotective agents specific to mechanisms of targeted therapy injury, integrating with wearable devices and imaging based on sensitive biomarkers for real-time monitoring, which enables detection of subclinical dysfunction and early intervention. Integration of drug innovation, mechanistic research, individualized medicine, advanced delivery systems, and active monitoring represents a feasible and effective pathway that can substantially reduce the risk of cardiotoxicity and enhance the safety and therapeutic efficacy of targeted cancer therapy.

Conclusions

This review summarizes the key mechanisms and mechanism-based effective management of cardiac toxicity associated with targeted cancer therapy. By integrating existing research, this work provides a structured framework for clinical practice. As a review article, it has selection bias and needs to be continuously updated. Future research should prioritize mechanism studies, predictive modeling, cardiac protection strategies, and early integration of cardiac safety assessments in drug development to optimize tumor efficacy and cardiovascular outcomes.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1494/prf

Funding: This study was supported by Jiangsu University Industry-University-Research Project “Research and Development of New Medical Bioremediation Materials” (No. HX20221019 and HX20250134).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1494/coif). X.S. is a staff member of BioRegen Biomedical (Changzhou, Jiangsu) Co., Ltd. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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