The clinical diagnosis for CTIT is indispensable to include a definite history of using a certain anti-tumor drug that may cause thrombocytopenia and the symptoms of thrombocytopenia gradually decrease or disappear after stopping the drug. Besides, other causes of thrombocytopenia have been excluded, such as aplastic anemia, acute leukemia, radiation sickness, immune thrombocytopenic purpura, bone marrow invasion by tumors, and hyperactive spleen function (7).The diagnosis of thrombocytopenia is primarily established through laboratory testing, which includes a complete blood count (CBC) that reveals the platelet count. A platelet count below 150,000 platelets per microliter is generally considered thrombocytopenia. Non-chemotherapy-related thrombocytopenia is generally diagnosed when the platelet count falls below 100 × 10⁹/L, which differs from the criteria for grade 1 CTIT. The grading criteria for CTIT is shown in Table 1 . Further laboratory investigations may include peripheral blood smears to assess platelet morphology and the presence of any atypical cells, as well as specific tests to determine the underlying cause, such as bone marrow biopsy, immunological assays for autoimmune conditions, and viral serologic tests for infections like HIV or hepatitis (8, 9). Diagnostic criteria vary depending on the suspected etiology; for example, in ITP, the diagnosis may be supported by the exclusion of other causes of thrombocytopenia and the presence of specific clinical signs (10). Overall, a comprehensive approach combining clinical evaluation and targeted laboratory tests is essential for accurate diagnosis and management.

Early-detection biomarkers for CTIT can be grouped into four categories and is shown in Table 2 : peripheral complete blood count–derived parameters, bone marrow–megakaryocyte kinetic indices, soluble protein/nucleic acid biomarkers, and imaging/functional indicators (11, 12). All of these can provide an early warning before the absolute platelet count falls below the critical threshold.

CIT’s prevalence varies significantly depending on the types of cancer and the specific chemotherapy regimens employed. CIT was most commonly observed in non-small cell lung cancer (NSCLC) (25%), ovarian cancer (24%), and colorectal cancer (18%) (2). Studies have shown that CIT can affect up to 50% of patients undergoing certain chemotherapy protocols, particularly in hematological malignancies and solid tumors treated with myelosuppressive drugs (13). A clinical study in the United States enrolled adult patients with solid tumors and hematological malignancies receiving chemotherapy to investigate the risk of thrombocytopenia in chemotherapy regimens. The overall incidence of CIT was 13%, grade 3 thrombocytopenia (PLT: 25-50×10⁹/L) and grade 4 thrombocytopenia (PLT: < 25 × 10⁹/L) was 4% and 2%,respectively. The incidence of thrombocytopenia varies by tumor type and chemotherapy regimen, with grade 3 thrombocytopenia occurring in approximately 4% of patients with solid tumors and 16% of patients with hematologic malignancies (14). Thrombocytopenia prevention can ensure that chemotherapy goes smoothly as planned and is beneficial to the long-term survival of patients. In a systematic review and meta-analysis which included 125 clinical trials and 20,128 patients, the incidence of ICIIT was 1.16%,82 patients occurred ICIIT-related deaths (15). The incidence of thrombocytopenia caused by chemotherapy drugs, targeted therapy drugs and immune checkpoint inhibitors (ICIs) is listed in Table 3 .

Thrombocytopenia present with a variety of clinical symptoms that are often indicative of its severity and underlying causes, not only characterized by reduced platelet count. Patients may experience easy bruising, prolonged bleeding from cuts and spontaneous bleeding, such as petechiae or purpura on the skin. In more severe cases, patients might present with significant hemorrhage, including gastrointestinal bleeding or intracranial hemorrhage, which can be life-threatening. The clinical manifestations can vary depending on the etiology of the thrombocytopenia. For instance, in cases of immune thrombocytopenic purpura (ITP), patients may exhibit more pronounced skin manifestations, while those with thrombocytopenia due to bone marrow suppression may show signs of anemia or leukopenia as well (4, 33). Additionally, patients with underlying conditions such as liver disease may present with coagulopathy, further complicating the clinical characterization. In addition to causing bleeding in skins and internal organs, CIT may also lead to a delay in subsequent chemotherapy cycles, dose reduction, treatment interruption, and a decrease in relative dose intensity (delivered dose intensity/standard dose intensity), thereby affecting therapeutic efficacy (34). Understanding these manifestations is crucial for timely diagnosis and management, as they can significantly affect patient outcomes. The median time to the first drop in platelet count is 1–2 weeks after chemotherapy; with certain agents, CIT may appear beyond 2 weeks (14). ICIIT typically occurs within 12 weeks after drug initiation, with a median onset of approximately 41 days (35, 36); however, it can arise at any time, even after treatment has been discontinued.

CTIT is characterized by decreased platelet count due to the cytotoxic effects of anti-tumor drugs, understanding the multifactorial causes of CTIT is essential for effective management and prevention strategies. The risk factors for CTIT are listed in Table 4 and can be grouped into four dimensions—patient baseline, tumor, treatment, and comorbidities. All key points are derived from high-quality cohort studies published in 2024 and the most recent expert consensus (37).

A multivariable model regression analyses exhibited three predictive variables for CIT which includes high ferritin, estimated glomerular filtration rate(eGFR)<60ml/min/1.73m² and body mass index (BMI)<23kg/m²,and the model owned good predictive accuracy (38). Among a comprehensive analysis of various clinical and laboratory indicators, tumor site, treatment line, AST levels, oxaliplatin, and capecitabine were identified as important factors that influenced the occurrence of CIT (39). In a retrospective study, serum potassium ion, serum lactate dehydrogenase, platelet count, red blood cell count, and estimated glomerular filtration rate were predictors of serious CIT (40). One study also reported that chemotherapy, bone or brain metastasis were risk factors for thrombocytopenia during radiotherapy (41). Renal function is an important factor affecting chemotherapy-related thrombocytopenia (38), and patients with inadequate renal function have a greater degree of thrombocytopenia and poorer tumor treatment outcomes. The reason is that improved renal function leads to enhanced elimination of chemotherapy drugs, thereby reducing the adverse effects on megakaryocytes.

The occurrence of CIT is multifactorial, involving various mechanisms that disrupt normal hematopoiesis and platelet production (7). Chemotherapy drugs are known to not only target cancer cells but also exert a significant inhibitory effect on bone marrow hematopoiesis (42). The cytotoxic effects of chemotherapeutic agents can lead to reduction in the number of megakaryocytes, the precursor cells that give rise to platelets. Additionally, the bone marrow microenvironment may be altered by chemotherapy, leading to further impairment of hematopoietic function and exacerbating thrombocytopenia (43). Chemotherapy drugs can cause drug-induced immune thrombocytopenia, platelet antibodies can be detected in the blood of patients, resulting in increased destruction of platelets. Previous studies have reported that repeated use of oxaliplatin can induce and sustain immune responses, leading to immune thrombocytopenia (44–47). Oxaliplatin can cause injury to the hepatic sinusoidal endothelial cells, disrupting the sinusoidal barrier and subsequently leading to collagen deposition and veno-occlusive fibrosis. This damage increases intrahepatic vascular resistance and causes portal hypertension. Thrombocytopenia in this context is moderate but prolonged, typically appearing after about 18 weeks of treatment (46, 48). Due to splenomegaly, there is an increase in the sequestration and destruction of platelets within the spleen (49).

Thrombocytopenia was observed in 7%–25% of patients treated with a carboplatin-based regimens, which occurred more frequently than those receiving cisplatin-based regimens (50). When gemcitabine is used as a single-agent chemotherapy, the incidence of thrombocytopenia is approximately 3.4% to 12%. This incidence is significantly higher when used in combination chemotherapy regimens(such as gemcitabine/carboplatin) (51–54). Thrombotic thrombocytopenic purpura (TTP) is a rare but severe complication in the treatment of gemcitabine characterized by hemolysis, thrombocytopenia, renal insufficiency and neurological symptoms with an incidence of 0.015% to 1.4% (55). Anthracycline drugs exert their antitumor effects by intercalating into the DNA double helix, thereby inhibiting the synthesis of DNA and RNA. However, this mechanism also exerts toxicity on normal hematopoietic cells, particularly on megakaryocytes in the bone marrow, leading to a reduction in platelet production (56). During the metabolic process in the body, anthracycline drugs generate free radicals, which lead to oxidative stress and subsequently damage hematopoietic cells in the bone marrow and platelets (57). The incidence of grade 3 thrombocytopenia during bortezomib treatment for relapsed, refractory myeloma is relatively high, which is approximately 14.5% (58).

ICIs have become a breakthrough in cancer treatment. For patients with NSCLC, ICIs are generally safer and better tolerated compared to cytotoxic drugs. However, their immune-related adverse events (irAEs) are increasingly receiving concern in clinical practice, especially the hematological irAEs (haem-irAEs), which are infrequent but can be life-threatening (59). The incidence rate of immune-related thrombocytopenia (irTCP) is 1.16%, with 82 cases of death related to ICIIT (0.45%) (15, 60). When used alone, the incidence of thrombocytopenia with PD-1/PD-L1 inhibitors is only 0.2%, but when combined with other treatments, the incidence can significantly increase to 6% to 6.8% (61–63). Consequently, ITP has emerged as the most prevalent haem-irAE in immunotherapy. Intravenous immunoglobulin (IVIG) is a common method for treating primary immune thrombocytopenia (ITP). In the treatment of ITP, IVIG can temporarily block the destructive effects of antibodies on platelets, thereby increasing the number of platelets. The interval between treatments depends on the platelet count and the condition of the disease, usually once a week (63). In addition, IVIG is also used in other irTCP conditions, such as ICIIT, and can rapidly increase platelet count to a safe level, especially in emergency situations (64).

A retrospective study launched by Ohio State University Comprehensive Cancer Center reviewed patients treated with ICIs between January 2011 and June 2017. The results indicated that out of 1038 patients treated with ICIs, 89 (8.6%) developed grade 3 or 4 thrombocytopenia, and 18 (20%) were attributed to ICIs after manual review and exclusion of other causes (accounting for 1.73% of the entire cohort). Thrombocytopenia and leucopaenia occurred earlier than the other hem-irAEs among ICI-treated cases such as autoimmune hemolytic anemia, with a median time of 40 days, and the onset of haem-irAEs was earlier in patients treated with combination therapy than monotherapy (65). The incidence of irTCP seemed to be lowest among patients treated with PD-1/PD-L1 monotherapy (p = 0.059). Patients who developed grade 3 or higher irTCP had poorer overall survival (66). In previous case reports related to ICIIT, corticosteroids, immunoglobulins, and TPO-RAs were administered, with 5 cases showing improvement and 3 cases resulting in death (67). A retrospective study of 2,360 melanoma patients treated with ICIs showed that less than 1% of patients experienced thrombocytopenia, with the majority of these patients’ platelet count returning to normal on their own (68).

The number of reported ITP cases is the most common in nivolumab and pembrolizumab in a systematic review study, there were 125 cases of ITP reported with pembrolizumab and 160 cases reported with nivolumab,338 cases totaled for all drugs. Higher incidence of ITP cases associated with PD-1 inhibitors nivolumab and pembrolizumab in comparison with oxaliplatin was noticed, but similar reporting with the PD-L1 inhibitors atezolizumab, avelumab,and durvalumab. In the literature review, melanoma (35%) and non-small-cell lung cancer (39%) were identified as the predominant types of cancer reported ICIIT in the case studies (69).

Some mechanisms at the cellular level have been proposed in irTCP caused by anti-tumor immune therapy (65, 70) and is shown in Figure 1 . ICIs such as PD-1 and PD-L1 inhibitors can cause immune system activation and exhausted CD4⁺ helper T cells and CD8⁺ cytotoxic T cells are reactivated (36). These activated T cells can secrete cytokines (such as IFN-γ, TNF-α, etc.) that lead to changes in the bone marrow microenvironment, thereby damaging hematopoietic stem cells and megakaryocytes (71). Cytokine storm induced by immunotherapy is a systemic inflammatory response that can be triggered by various causes, including infection, autoimmune diseases and adverse reaction to cancer immunotherapy (72).In the process of immunotherapy, cytokine release syndrome (CRS) is especially conscious of when using ICIs and immune cell therapies and relevant to adverse reaction to cancer immunotherapy (73). Cytokines manifest over-activating of the immune system which increases the incidence of irAEs after initiating ICI and serves as prediction of platelet count decrease (74). ICIs may induce or increase the production of specific anti-platelet antibodies, which can bind to platelets, marking them for phagocytosis and destruction by macrophages (75, 76). When patients have platelet antibodies in their bodies, the transfused platelets may be rapidly destroyed, leading to ineffective transfusion. The detection of platelet glycoprotein-specific auto-antibodies is a test with high specificity for antibody-mediated immune thrombocytopenia, which can differentiate between immune and non-immune thrombocytopenia.

Moreover, activated T cells secrete a large number of serum cytokines, such as IL-23 and IL-17,which can lead to reduced platelet production and increased platelet destruction. In immune thrombocytopenia (ITP), the levels of IL-23 and IL-17 are elevated (77). IL-17 plays a particularly important role in the production of inflammatory cytokines and the infiltration of white blood cells and can promote inflammatory responses of the immune system (78). IL-17 can inhibit the differentiation and maturation of megakaryocytes mediated by TPO, and affect platelet production and function, thereby further exacerbating the pathological process of ITP (79, 80). IL-23 can lead to reduced platelet production in ITP patients through the differentiation and proliferation of Th17 cells (81). Conversely, interleukin-6 (IL-6) is a multifunctional cytokine that plays an important role in immune responses, inflammatory reactions, hematopoiesis, and metabolic regulation (82). IL-6 can act synergistically with other cytokines to promote the growth of early bone marrow stem cells and enhance the differentiation of blood cells, including the production of platelets. IL-6 is a strong inducer of acute-phase proteins, which can induce hepatocytes to synthesize acute-phase proteins at the transcriptional level, including thrombopoietin (TPO), thereby indirectly affecting platelet production (83). The signaling pathways activated by IL-6 can affect the activation state and function of platelets, including platelet aggregation and adhesion.

Platelets expressing PD-L1 on their surface are direct target cells for ICIs. A study revealed that PD-L1 was transferred to platelets from tumor cells after co-incubated with various NSCLC cell lines, platelet PD-L1 (pPD-L1) was correlated with tumor stage, metastasis and overall survival (84). Platelets with high PD-L1 stimulated by atezolizumab mark improved immune surveillance and prevent T cell-mediated immune suppression (85).

Targeted therapy has emerged as a revolutionary approach in oncology, focusing on specific molecular targets associated with cancer. Unlike traditional chemotherapy, which indiscriminately affects rapidly dividing cells, targeted therapies aim to interfere with particular pathways critical for cancer cell survival and proliferation. Targeted therapies are designed to attack specific cancer cells, can inadvertently affect normal hematopoiesis, leading to adverse effects such as thrombocytopenia. For instance, the introduction of drugs targeting specific oncogenic pathways has been associated with varying degrees of hematological toxicity, including platelet depletion. Recent studies have highlighted the intricate relationship between novel targeted therapies and thrombocytopenia. Furthermore, the mechanisms underlying this relationship often involve the disruption of megakaryocyte function or direct toxicity to bone marrow, which is crucial for platelet production. In particular, therapies for metastatic breast cancer and non-small cell lung cancer have shown a correlation with significant drops in platelet levels, necessitating careful monitoring of blood counts during treatment (86).

Thrombocytopenia is a common adverse effect associated with various targeted therapies, including PARP inhibitors, EGFR inhibitors, and CDK4/6 inhibitors. A meta-analysis of randomized controlled trials involving PARP inhibitors indicated a significant increase in the risk of thrombocytopenia, with an incidence rate of 2.54 (RR, 2.54; 95% CI, 1.87-3.45; p < 0.00001) compared to control groups. Notably, the risk of high-grade thrombocytopenia (grade ≥3) was also elevated (RR, 2.76; 95% CI, 1.83-4.16; p < 0.00001) (87). In the context of EGFR inhibitors, studies have shown that agents like cetuximab and erlotinib can lead to thrombocytopenia, particularly in patients with pre-existing conditions or those receiving concomitant therapies (88). Meanwhile, CDK4/6 inhibitors, such as palbociclib, ribociclib, and abemaciclib, have been associated with varying degrees of hematologic toxicity, including thrombocytopenia, with palbociclib showing a higher incidence compared to the others (89, 90). A systematic review indicated that 51.1% of patients receiving CDK4/6 inhibitors experienced hematological toxicity, with thrombocytopenia being reported in 2.1% of cases (91). These findings highlight the prevalence of thrombocytopenia as a significant concern in patients undergoing targeted therapy, necessitating vigilant monitoring and management strategies.

Poly ADP-ribose polymerase (PARP) inhibitors are a class of anti-cancer drugs that target PARP and play an important role in the treatment of hereditary cancers with the same “rogue gene,” such as breast cancer, ovarian cancer, prostate cancer, and pancreatic cancer (92–95). PARP1 is expressed in the megakaryocytic lineage and is involved in regulating the differentiation of bone marrow cells. PARP inhibitors affect the proliferation and maturation of megakaryocytes by inhibiting PARP1, thereby reducing the production of platelets (96). Inhibitors (e.g.,niraparib, olaparib) trap PARP1 at DNA damage sites, block repair pathways and trigger the accumulation of DNA breaks, thereby suppress the differentiation and maturation of CD34⁺ bone-marrow progenitors into megakaryocytes, reducing the formation of polyploid megakaryocytes and markedly decrease proplatelet formation and platelet release (97). Thrombocytopenia usually occurs in the first month of treatment and gradually shows a trend of recovery in the second or third month, with most cases being mild to moderate, that is, grades 1 to 2 (95). The combination of targeted therapies with chemotherapy has further implications for the risk of thrombocytopenia. Studies have demonstrated that the concurrent use of PARP inhibitors with chemotherapy regimens can exacerbate the incidence of hematological toxicities, including thrombocytopenia. Despite potential responsiveness, patients receiving PARP inhibitors alongside chemotherapy experienced a significant higher rate of grade 3 thrombocytopenia compared to those receiving chemotherapy or PARP inhibitors alone (98). This synergistic effect may be attributed to the myelosuppressive nature of both treatment modalities, which can lead to compounded risks of cytopenia. Moreover, the use of CDK4/6 inhibitors in combination with endocrine therapy has been shown to improve progression-free survival but also results in a higher incidence of adverse events, including thrombocytopenia (99, 100). Therefore, understanding the incidence of thrombocytopenia associated with these targeted therapies, especially in combination with chemotherapy, is crucial for optimizing treatment regimens and improving patient outcomes.

The incidence of thrombocytopenia associated with ADCs, particularly trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd), has been a focus of recent clinical studies. For instance, a systematic review revealed that T-DM1 was linked to a higher incidence of thrombocytopenia, with reported rates of grade 3 or higher thrombocytopenia reaching approximately 28.1% in TKIs treatment failed breast cancer patients (101). Furthermore, a retrospective cohort study highlighted that patients of Asian ancestry experienced a significantly higher incidence of dose adjustments due to thrombocytopenia when treated with T-DM1 or T-DXd, suggesting potential genetic predispositions that warrant further investigation (102). In clinical practice, the management of thrombocytopenia in patients receiving ADCs often necessitates dose modifications or supportive therapies, such as TPO-RAs, to mitigate treatment interruptions and enhance patient safety (88).

The mechanism by which PARP inhibitors induce thrombocytopenia primarily involves their impact on megakaryocyte differentiation and function. Research indicates that the inhibition of PARP activity can disrupt the signaling pathways essential for megakaryocyte maturation, leading to impaired platelet production. This effect is particularly pronounced in patients with pre-existing low platelet count or those undergoing combination therapies that exacerbate myelosuppression (103). Additionally, ADCs, which deliver cytotoxic agents directly to tumor cells, can inadvertently affect normal hematopoietic cells, including megakaryocytes, resulting in diminished platelet output (104). By delivering cytotoxic agents directly to cancer cells, ADCs can inadvertently affect normal hematopoietic cells, including megakaryocytes. The cytotoxic payload can lead to cell death in these progenitor cells, resulting in reduced platelet production. Additionally, the immune response elicited by ADCs can further contribute to thrombocytopenia through mechanisms such as increased phagocytosis of platelets by activated macrophages (105). The interplay between these therapies and the immune system also plays a crucial role. For example, in ITP, the presence of auto-antibodies against platelets can lead to their premature destruction, a complication that may be exacerbated by certain cancer therapies. Furthermore, the activation of immune pathways by these drugs can lead to an increase in macrophage-mediated clearance of platelets, thereby contributing to thrombocytopenia (106, 107). Moreover, the role of the tumor microenvironment in modulating these effects cannot be overlooked. Tumors can secrete various cytokines that influence hematopoiesis and megakaryocyte function, potentially exacerbating the thrombocytopenic effects of both PARP inhibitors and ADCs (108).

Platelet transfusion remains a critical intervention for managing thrombocytopenia, particularly in patients undergoing chemotherapy, those with hematological malignancies, or individuals with severe bleeding disorders. The primary indications for platelet transfusion include active bleeding, planned surgical procedures, and prophylaxis against bleeding in patients with severely low platelet count (109). Platelet transfusion can effectively reduce the risk of bleeding and mortality, which is the fastest and most effective way to treat severe thrombocytopenia, but it also has risks and complications. For instance, patients may have an allergic or febrile reaction to platelet products. Platelet transfusions may exacerbate thrombosis and should be approached with caution. Platelet transfusions can lead to alloimmunization, where the recipient develops antibodies against donor platelets, resulting in transfusion rejection. This condition complicates further injection and may necessitate the use of HLA-matched platelets, which are not always available (110, 111). Additionally, the risk of transfusion-related acute lung injury (TRALI) and other adverse reactions further complicates the use of platelet transfusions. Transfusions of components containing platelet antibodies may trigger acute and severe thrombocytopenia with transfusion reactions and bleeding (112). Recent studies indicate that the effectiveness of platelet transfusions can be influenced by various factors, including the storage conditions of platelets and the presence of underlying conditions in the recipient, such as sepsis or disseminated intravascular coagulation (DIC).The activity of platelets is greatly affected by temperature, and the optimum storage temperature is 22°C ± 2°C.The shelf life of platelets at room temperature is only 3–7 days. Maintaining an adequate supply of platelets requires a lot of resources, and platelets stored at room temperature are prone to bacterial contamination, which may lead to infection and even sepsis (113).

Interleukin-11 (IL-11) has emerged as a therapeutic cytokine in the treatment landscape for various hematological disease conditions. Its application primarily revolves around its ability to stimulate megakaryocyte and platelet production, making it a potential effective agent for thrombocytopenia. This cytokine has been shown to enhance platelet recovery in patients suffering from CIT, thereby reducing the incidence of severe thrombocytopenia and its associated complications. Research has demonstrated that rhIL-11 can effectively shorten the duration of thrombocytopenia and increase platelet count, making it a valuable option in the therapeutic arsenal against CIT (114).

TPO plays a vital role in the regulation of platelet production and is primarily produced by liver and works on the thrombopoietin receptor (TPO-R), which is expressed on megakaryocytes and hematopoietic stem cells. Cellular mechanisms of activation of TPO-RAs are shown in Figure 2 . TPO activates JAK/STAT and Ras/MAPK signaling pathways by binding to the surface receptor and induces tyrosine phosphorylation of a variety of proteins, including JAK2 and STAT5 proteins, thereby activating megakaryocytes and promoting their proliferation and differentiation into platelets (132). This process is essential for maintaining normal platelet count, which is crucial for hemostasis and the prevention of bleeding disorders. In the context of cancer treatment, the disruption of this process can ultimately lead to CTIT (133). Thrombopoietin (TPO) receptor agonists have emerged as a novel therapeutic approach to mitigate this adverse effect, playing vital pharmacological roles in enhancing platelet count. These agents mimic the action of endogenous TPO by stimulating the TPO-R, thereby being increasingly recognized as a crucial component of supportive care in cancer treatment.

A network meta-analysis indirectly evaluated the effects of five TPO-RAs in treating ITP. The analysis included 20 RCTs with data from 2,207 patients. All TPO-RAs significantly improved platelet response and reduced the incidence of bleeding events. compared to placebo. Avatrombopag and lusutrombopag showed the best platelet increase response, while avatrombopag having a non-significant advantage over lusutrombopag. Lusutrombopag had the lowest risk of bleeding compared to placebo, followed by eltrombopag, romiplostim, and avatrombopag. Romiplostim had the lowest rate of severe adverse events, followed by avatrombopag, eltrombopag, and lusutrombopag (134).

Caffeic acid tablets, an emerging therapeutic agent, primarily composed of caffeic acid which was originally found in coffee extracts and structurally belongs to hydroxycinnamic acid compounds (164). Caffeic acid have been shown to promote megakaryocyte maturation and enhance platelet production. As an antioxidant, caffeic acid effectively neutralizes free radicals, thereby protecting cells from oxidative damage, which is a contributing factor in various chronic diseases, including cancer and cardiovascular disorders (165–167). In vitro studies demonstrated that the combination of caffeic acid and hydroxydaunorubicin (DOX) exhibits a significant inhibitory effect on lung cancer cells. Caffeic acid modulates the proliferation of lung cancer cells via the MAPK signaling pathway (165).

A total of 35 publications with 2533 patients were included in a meta-analysis study to evaluate the efficacy and safety of caffeic acid tablets (CFA). The study showed that CFA significantly increased platelet counts compared to the control group. CFA demonstrated better clinical efficacy in treating thrombocytopenia, with complete remission defined as PLT≥100× 10^⁹/L and partial remission as 50×10^⁹/L < PLT < 100×10^⁹/L.CFA also significantly increased white blood cell counts, neutrophil counts and reduced the incidence of grade III and IV myelosuppression (167). In hepatocellular carcinoma cells, caffeic acid inhibited the expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinase 9 (MM-9) which induces tumor invasiveness and metastases (168). Caffeic acid predominantly suppresses the growth of estrogen receptor (ER) positive breast cancer cells (169).

The application of traditional Chinese medicine (TCM) in the treatment of cancer is gradually gaining attention, especially in terms of modulating immune responses, improving patients’ quality of life, and reducing side effects (170). The therapeutic mechanisms of TCM are primarily reflected in its multi-component and multi-target characteristics, which sharply contrast with the single-target drug design in modern medicine. TCM can be used as an adjuvant therapy to enhance the efficacy of conventional cancer treatments (170). Chemotherapy often causes severe side effects, including nausea, vomiting, myelosuppression, and organ dysfunction. TCM can help alleviate these adverse reactions (171, 172). For instance, a systematic review and meta-analysis involving 22 randomized controlled trials (RCTs) with 1834 postoperative breast cancer patients revealed that TCM combined with chemotherapy significantly improved therapeutic efficacy, immune function, and reduced adverse reactions such as leukopenia and thrombocytopenia (173). While some RCTs suggest benefits, evidence remains preliminary due to methodological heterogeneity and lack of large-scale trials. A study found that combining Traditional Chinese Medicine (TCM) with capecitabine-based chemotherapy in colorectal cancer (CRC) is more effective than capecitabine alone. The combination therapy enhances tumor response rates and reduced the risks of thrombocytopenia (174). Moreover, a network meta-analysis highlighted the efficacy of various TCM injections, such as Aidi and Compound Kushen injections, in improving treatment responses and reducing adverse effects when used in conjunction with chemotherapy in colorectal cancer patients (175).