Acute myeloid leukemia (AML) is a diverse group of hematologic malignancies that are characterized by the abnormal growth and differentiation of precursor cells, and to clinical manifestations such as infection, anemia and bleeding (1). The clonal expansion results in the accumulation of immature myeloid precursors in the bone marrow, peripheral blood and/or other organs and tissues (2,3). AML usually occurs in older individuals and incidence increases with age, with the median age at diagnosis being 68 years (4). The development of genome sequencing technology has made it possible to deeply sequence AML samples to describe the mutation spectrum and understand the biological heterogeneity (5). Although increased understanding of the pathophysiology, next-generation sequencing and the recent approval of numerous treatment options, including BCL2, FMS-like tyrosine kinase 3 (FLT3) inhibitor, isocitrate Dehydrogenase 1/2 (IDH1/2) inhibitors and allogeneic hematopoietic stem cell transplantation have transformed the way AML is approached, the estimated 5-year survival rate is 62% for patients under the age of 50 years, 37% for patients aged 50–64 years old and only 9.4% for patients ≥65 years at diagnosis, leaving much room for improvement (6,7). The biological and clinical heterogeneity of the disease makes AML difficult to treat, and selective targeted inhibitors combined with chemotherapy may contribute towards improving efficacy.

Signal transducer and activator of transcription 3 (STAT3), a member of the STAT family, has an important function in controlling the proliferation of healthy and cancerous cells (8–10). STAT3 has four recognized subtypes, including STAT3α (92 kDa), STAT3β (83 kDa) and STAT3γ (72 kDa) and STAT3δ (64 kDa), of which STAT3α and STAT3β are produced by alternative splicing (11). The constitutive activation of STAT3α plays a key role in the activation of carcinogenic pathways and involves in the regulation of apoptosis, proliferation, differentiation and evolution of numerous neoplasms, while STAT3β is generally considered to be a dominant negative regulator of cancer (12). STAT3γ and STAT3δ are derived from proteolytic processing and have no transcriptional effect (13).

In hematopoietic cells, STAT3 facilitates aberrant signal transduction by enlisting receptor complexes that have undergone tyrosine phosphorylation. Upon being phosphorylated, the STAT3 protein forms dimers and migrates to the nucleus, where it initiates transcription proteins, ultimately resulting in tumorigenesis (14). Since STAT3 is an important transcription factor in pathogenesis and chemotherapy resistance, a number of studies have been conducted targeting STAT3. Constitutive STAT3 activation is observed in ~ 50% of newly diagnosed AML. In addition, patients with leukemia cells demonstrating constitutive STAT3 activation have a shorter disease-free survival rate (15,16). The antitumor effects of blocking STAT3 activity have been demonstrated in both solid tumors (17–20) and AML (21,22). Therefore, STAT3 has been recognized as a promising protein target for the development of broad-spectrum therapeutic drugs (23).

STAT3 is a signaling molecule that relays information from cell surface receptors to the nucleus. It is activated by a variety of soluble mediators, such as interleukins (IL-2, IL-3, IL-5, IL-6, IL-7, IL-9, IL-11), cytokines [granulocyte colony-stimulating factor (G-CSF), epidermal growth factor, platelet-derived growth factor] and hormones (growth hormone, prolactin, leptin) (24,25). Fig. 1 illustrates the various functional domains of the STAT3, including an N-terminal domain, a DNA-binding domain, a linker domain, an Src homology 2 (SH2) domain and a C-terminal transactivation domain (26).

The activation of STAT3 involves the interaction between specific cytokines and its receptors on the cell membrane, which triggers the activation of tyrosine kinase. The receptor-kinase complex undergoes phosphorylation and subsequently serves as a docking site for STAT3. The recruited STAT molecules are phosphorylated at Tyr705 and Ser727 of mitochondrial STAT3. Following activation, STAT3 is transferred to the nucleus where it acts as a transcription activator, stimulating the transcription of genes responsible for regulating cell proliferation, differentiation and apoptosis (Fig. 2) (27–31).

The constitutive STAT3 activity is often associated with adverse outcomes in human cancer, as it promotes tumor cell proliferation, survival and metastasis, while impairing antitumor immune responses (32,33). The phosphorylation of STAT3 can be activated in various cancerous cells, including multiple AML cell lines and primary cells obtained from AML patients (14,16).

STAT3 is crucial for maintaining the balance of myeloid cells, as it can block myeloid differentiation and plays an important role in leukemogenesis (21,26,34). STAT3 regulates cell survival and proliferation through its target genes (MYC, cyclin D1, baculoviral IAP repeat-containing 5 and BCL2). The inhibition of STAT3 can induce cell apoptosis, and constitutive STAT3 activity is associated with adverse prognosis in patients with AML (16,35).

Genetic mutations or external factors can frequently disrupt the normal STAT3 signaling pathway (36–38). In 28–44% of patients with AML, constitutive STAT3 activation has been observed at the initial stage of diagnosis, whereas when patients experience a recurrence, constitutive activity is absent or decreased (15,16,38). The factors contributing to the increased activation of constitutive STAT3 in AML cells seem to differ among individuals. A potential factor is the continual activation of the IL-6 signaling pathway, and another factor contributing to this is the occurrence of activating mutations in the SH2 domain of STAT3, specifically between residues 585 and 688 (15,37).

Based on these findings, STAT3 has become a desirable focus for AML treatment. However, Lee et al (39) revealed that feedback activation of STAT3 in PC-9 NSCLC cells promotes drug resistance through the activation of multiple kinases, including EGFR, MET and KRAS. Therefore, the combination of STAT3 inhibitors with other chemotherapies (cytarabine + mitoxantrone/idarubicin/etoposide) may be effective against refractory or relapse AML.

In previous years, multiple inhibitors targeting STAT3 for patients with AML have been studied (Table I). The present review will briefly review some of the most impressive developments regarding these inhibitors in the following paragraphs.

AML is a challenging type of hematological neoplasm characterized by a diverse range of genetic and cytogenetic markers, as highlighted in the most recent classification systems issued by the World Health Organization and International Consensus Classification (66,67). The use of personalized treatments based on the specific molecular data of patients is markedly increasing in the field of oncology, allowing for targeted therapies aligned with the underlying pathobiology of the disease (68).

STAT3 is an important regulator in normal hematopoiesis, and constitutive activation of STAT3 is associated with the occurrence and prognosis of AML. Currently, targeted STAT3 inhibitors are being tried in the treatment of several cancers, including AML. Due to STAT3 and its associated upstream JAKs that play a crucial role in AML, inhibitors targeting this pathway are an important direction for improving AML efficacy. Selective targeting of the JAK/STAT pathway has shown promising results both in vitro and in vivo models (26). Targeted IL-6/JAK/STAT3 inhibitors have also been revealed to be beneficial for treating ovarian, prostate and myeloproliferative neoplasms, with potential to inhibit tumor growth (14). Furthermore, the proliferation of cancer cells can be driven by a diverse range of activated kinases, including EGFR, HER2, ALK and MET. Specifically, inhibition of enzymes can lead to autocrine activation of STAT3, which suppresses tumor cells through the FGF/JAK/STAT3 feedback loop (39). Therefore, these comprehensive summaries may provide new strategies and insights for targeted STAT3 therapy in AML. Some notable STAT3-targeting inhibitors in hematological malignancies, such as BBI608 (trial no. NCT02352558) and AZD9150 (NCT05986240), have been identified and have undergone clinical trials and achieved good therapeutic effects. However, despite extensive research and ongoing clinical trials, the efficacy of STAT3 inhibitors in clinical studies remains inconclusive (Fig. 3). The present review mainly focused on various inhibitors targeting STAT3 and systematically elucidated the mechanism of various STAT3 inhibitors in AML, current research status and existing challenges, which is expected to contribute to future research.

In order to enhance our understanding of STAT3 in AML, it is crucial to gain deeper insights into the biological traits and roles of STAT3 within primary AML cells. The investigation of STAT3 regulatory effects on the proliferation, apoptosis and cell cycle of AML primary cells, especially in AML cells with high STAT3 phosphorylation, may be of great use. Incorporating STAT3 inhibitors into chemotherapy has the potential to revolutionize clinical practice and improve treatment outcomes for patients with AML due to numerous ongoing studies in this field.