Given its central role in cell cycle regulation and its elevated expression in various cancers, PLK1 has emerged as a promising target for cancer therapy. Inhibition of PLK1 has been shown to enhance the sensitivity of tumors to chemotherapy and radiotherapy (70). PLK1 inhibitors can be broadly categorized into ATP-competitive inhibitors that target the kinase domain (KD) and compounds that target the polo-box domain (PBD) (71).

BI 2536 is a potent ATP-competitive inhibitor that inhibits tumor growth in vivo and in vitro ( 72). Clinical trials have shown that BI 2536 can exert synergistic anti-tumor effects when combined with other chemotherapeutic agents, but the efficacy of single therapy is poor (73). Volasertib, an ATP-competitive inhibitor, exhibits sustained high-dose exposure in tumor tissues and has demonstrated antitumor activity and a favorable safety profile in multiple xenograft models (74). Overexpression of the ATP-binding cassette (ABC) drug transporter ABCB1 has been shown to cause ATP hydrolysis, which contributes to drug resistance in Volasertib. Therefore, combination therapy with ABCB1 modulators can be considered as a way to solve the problem of drug resistance (75). In addition, Volasertib exerts synergistic effects when combined with both MEK inhibitors and histone deacetylase (HDAC) inhibitors (76, 77). Onvansertib is a novel ATP-competitive PLK1 specific inhibitor, which can induce mitotic cycle arrest and apoptosis in tumor cells. Thus, the growth of xenograft tumors was inhibited (78). It is currently being tested in three clinical trials in combination with standard therapy (KRAS-mutated metastatic colorectal cancer, acute myeloid leukemia, and castration-resistant prostate cancer) and has shown promising drug resistance and safety profiles (79–81). However, this ATP-competitive PLK1 inhibitor has certain limitations. Firstly, the kinase domains of PLK family members (such as PLK1/2/3) are highly similar, resulting in reduced selectivity of existing drugs and easy to cause off-target effects. Secondly, PLK1 has complex and pleiotropic functions in the cell cycle regulatory network. When the inhibitor concentration is too high, PLK2/3 and other paraloproteins are unspecifically inhibited, resulting in dose-dependent cytotoxicity (such as bone marrow suppression and gastrointestinal reactions) (4). Finally, acquired mutations in the ATP-binding domain in tumor cells, such as Gatekeeper mutations in the kinase domain, may lead to decreased drug-binding affinity for PLK1 inhibitors and thus the phenomenon of acquired resistance (82).

Non-ATPcompetitive inhibitors, such as Rigosertib, which targets the PBD and inhibits both PLK1 and PI3K, have shown efficacy in killing tumor cells in vitro and in vivo. PBD inhibitors are more specific because of their high affinity for specific residues of PLK1 compared to ATP competitive inhibitors (71). Poloxin, a PBD inhibitor developed in 2008, causes mitotic arrest and apoptosis of cancer cells by inducing centrosome fragmentation and abnormal arrangement of spindles and chromosomes. In the xenograft mouse model, Poloxin was also shown to inhibit tumor growth. However, Poloxin is easily degraded in vitro and in vivo, resulting in a short half-life and difficult to maintain its efficacy. Moreover, due to its large molecular polarity and poor transmembrane permeability, it is difficult to reach an effective concentration in tumor cells (83, 84). However, Rigosertib has underperformed in clinical trials for high-risk myelodysplastic syndromes and metastatic pancreatic cancer, with patients showing no significant benefits over standard care. On the one hand, the phosphopeptide binding interface of PBD is relatively shallow. On the other hand, it may activate other mitotic kinases (such as Aurora A/B, WEE1) to compensate for PLK1 function (71, 85). However, some studies have shown that Rigosertib can also target the RAS pathway and overcome chemotherapy resistance. Therefore, combining this inhibitor with chemotherapy may improve efficacy in patients with KRAS mutations (86). Therefore, further research is needed to improve the specificity and reduce the resistance of PLK1 inhibitors, making them more effective in clinical applications. Recent studies have found that dual-target inhibitors targeting PLK1/BRD4 and PLK1/MEK can produce cumulative effects and exert long-term inhibitory effect on cancer cell growth (87–89) ( Table 2 ).

The tumor microenvironment (TME) is a critical determinant of cancer cell survival and metastasis, and the infiltration of immune cells into the tumor is a key factor influencing the efficacy of immunotherapy (95, 96). Accumulating evidence indicates that PLK1, beyond its well-established role in mitosis, exerts significant effects on the tumor microenvironment and is involved in tumor cell metastasis and immune cell infiltration (8, 97).

On one hand, PLK1 regulates the infiltration of a variety of immune cells. In lung cancer, PLK1 inhibits DC maturation and T-cell enrichment (98, 99).Moreover, PLK1 expression is positively correlated with myeloid-derived suppressor cells (MDSCs) and regulatory T cells. In addition, PLK1 was positively correlated with myeloid-derived suppressor cells (MDSCs) and regulatory T cells in breast cancer and node-predominant Hodgkin’s lymphoma (100–102). In summary, PLK1 modulates the function of immune cell infiltration, providing a foundation for the development of inhibitors targeting innate immune maintenance.

On the other hand, PLK1 has been shown to promote the polarization of tumor-associated macrophages (TAMs) from the M1 to the M2 phenotype (103). Tumor-associated macrophages can be polarized into two distinct phenotypes: M1 macrophages, which activate T-helper type 1 (Th1) T cells to induce a cytotoxic T-cell response against pathogens, thereby exerting tumor-killing activity and increasing hypoxia; and M2 macrophages, which promote tissue repair and wound healing, participate in angiogenesis, and secrete a variety of pro-inflammatory factors with pro-tumorigenic effects, thereby contributing to cancer progression (104, 105). In hepatocellular carcinoma, PLK1 interacts with PTEN and interferes with its nuclear translocation, leading to the inhibition of natural killer (NK) cell and T cell function by enhancing aerobic glycolysis and promoting M2 macrophage polarization (106). High expression of PLK1 inhibits the infiltration of M1 macrophages and their associated chemokines and marker genes into the glioblastoma immune microenvironment, whereas knockdown of PLK1 increases the infiltration and polarization of M1 macrophages (107).

In addition, PLK1 inhibitors can prevent and treat acute graft-versus-host disease (aGvHD) that may occur after leukemia transplantation by preventing activation and inducing apoptosis of already activated alloreactive T cells (Tallo cells) while inhibiting the molecular chaperone Hsp90 and inhibiting Tallo cell proliferation (108). There is also a link between PLK1 and Toll-like receptor (TLR) signaling, which plays a key role in innate immunity. TLRs are important sentinels of bacterial and viral infections, and PLK inhibitor-mediated blockade of TLR signaling can lead to adverse effects. Thus, in some patients receiving PLK1 inhibitors during cancer treatment, the risk of infection with invading microorganisms may be increased due to the impaired ability of the TLR recognition system to sense and initiate a cytokine response (109).

Inflammatory factors are a wide range of effector molecules involved in inflammatory response, including a variety of cytokines and chemokines. Many cancers arise from sites of infection, chronic irritation, and inflammation. Studies have shown that inflammatory factors can act directly on tumor cells. Inflammatory cells also modulate tumor growth by orchestrating the tumor microenvironment and influencing the adaptive immune response. Exploring the role of inflammatory factors in tumor immunity can provide a new way for cancer treatment in the future (110, 111).

An earlier study in 2013 found that PLK1 inhibitors could help treat colon cancer or early-stage lesions with high levels of inflammatory cell infiltration (112). Some studies have suggested that the high selectivity of PLK1 inhibitors for the BET bromodomain is the reason why PLK1 inhibitors can be used as drug targets for cancer and inflammation (113). Further studies have found that the activation of PLK1 inhibits the expression of TNF-induced cyclin D1, providing a potential mechanism for TNF-α’s involvement in inflammation-induced cancer (114). Recently, PLK1 has been identified as a novel negative regulator of the RIG-I and IFN-inducing pathways. RIG-I is capable of upregulating the expression of pro-inflammatory cytokines, inducing inflammation in the tumor environment, and activating neighboring immune cells, while IFN plays an important role in T cell proliferation, antigen sensitivity, cytokine production, and migration (115, 116). PLK1 also promotes the polarization of tumor-associated macrophages to upregulate the expression of IL-1A/1B, VEGFA, and IL-6, and the increased activity of these genes and factors is inversely associated with survival in patients with advanced lung adenocarcinoma (61).

Studies have highlighted the role of PLK1 in regulating inflammatory factors in sepsis and related diseases, offering potential insights for anti-inflammatory strategies in tumor treatment. Sepsis and cancer share several pathophysiological features, and the immune dysfunction associated with sepsis may influence the progression of malignant tumors (117, 118). For instance, in sepsis-induced acute lung injury (ALI), the activation of the ROS-mediated NLRP3 inflammasome is suppressed through modulation of the PLK1/AMPK/DRP1 signaling axis (119). Additionally, PLK1 has been identified as a key contributor to sepsis-induced myocardial dysfunction (SIMD). Its expression is upregulated in lipopolysaccharide (LPS)-treated mouse hearts and neonatal rat cardiomyocytes (NRCM). Inhibition of PLK1 attenuates the activation of the NF-κB signaling pathway, thereby mitigating LPS-induced myocardial injury, inflammation, and cardiac dysfunction (120). In contrast, PLK1 exhibits a protective role in sepsis-induced intestinal barrier dysfunction. Overexpression of PLK1 reduces IL-6 levels by suppressing NF-κB signaling, thereby alleviating intestinal epithelial damage (121, 122).

Programmed death-ligand 1 (PD-L1) is widely expressed in human tumors and plays a critical role in immune evasion. By binding to its receptor PD-1 on activated T cells, PD-L1 inhibits T cell activation signaling, thereby promoting tumor immune escape (123). Blockade of the PD-L1/PD-1 pathway has shown significant anti-tumor effects in patients with advanced cancer and is considered the gold standard for developing new immune checkpoint blockade (ICB) therapies and combination treatments. However, the response rate to anti-PD-L1 antibodies remains limited in several solid tumors (124). Consequently, improving the sensitivity of cancer patients to immune checkpoint inhibitors and expanding the population benefiting from immunotherapy are critical areas of future research.

Recent studies have revealed that PLK1 inhibitors can synergize with PD-L1 immune checkpoint inhibitors in tumor immunotherapy. Analysis of the TCGA dataset identified PLK1 as one of the proliferation-related kinases highly expressed in cancers with chromosome 9p copy number gains (CNGs) involving PD-L1. This finding is relevant to a variety of cancers, including lung cancer, melanoma, bladder cancer, head and neck cancer, cervical cancer, soft tissue sarcoma, prostate cancer, gastric cancer, ovarian cancer, and triple-negative breast cancer (125).

Research has shown that PLK1-induced phosphorylation of Vimentin promotes PD-L1 expression by activating TGF-β signaling and interacting with p-Smad2/3, contributing to metastatic progression in lung adenocarcinoma (LUAD) (126). Meanwhile, in vivo experiments confirmed that PLK1 inhibitor combined with PD-L1 inhibitor could significantly reduce tumor progression in mice compared with the two drugs alone. Because inhibition of PLK1 can induce the up-regulation of PD-L1 through the MAPK pathway and enhance the sensitivity of tumor cells to immune checkpoint inhibitors (127). Additionally, there are studies reported that PLK1 inhibition suppresses Rb phosphorylation in lung cancer. In various cancer cell lines, phosphorylated Rb inhibits the transcriptional activity of NF-κB and the expression of PD-L1 mRNA (128, 129). These findings suggest that PLK1 inhibitors may influence tumor immunotherapy efficacy in lung cancer by modulating the Rb/NF-κB/PD-L1 axis.

In pancreatic cancer, PLK1 inhibition similarly upregulates PD-L1 expression but also enhances sensitivity to PD-L1 blockade, ultimately leading to tumor suppression. This combination therapy can transform immunologically “cold” tumors into “hot” tumors, thereby improving anti-tumor immune responses. Mechanistically, PLK1 inhibition or depletion increases nuclear localization of NF-κB by reducing Rb phosphorylation, which upregulates PD-L1 expression (130). This mechanism supports the proposed role of the PLK1/Rb/NF-κB/PD-L1 axis in lung cancer and highlights its potential relevance across multiple cancer types.

The article published reported that PLK1 has the ability to alter the transcriptional profile of Her2+ breast tumors in the living environment, affecting the effector capacity of NK and T cells. This coordinated interaction in the tumor microenvironment ultimately upregulates PD-L1 and CD206 in the later stages of tumor progression and induces the NF-kb signaling pathway, promoting immune evasion (131).

Genetic instability in tumor cells often results in a high frequency of mutations, and the expression of non-synonymous mutations can generate tumor-specific antigens known as neoantigens. These neoantigens are highly immunogenic because they are not expressed in normal tissues. Neoantigen-targeting cancer vaccines primarily include nucleic acid vaccines, dendritic cell vaccines, tumor cell vaccines, and synthetic long-peptide vaccines (SLPs) (132).

In recent years, it has been found that PLK1 may be a universal tumor antigen recognized by cytotoxic T lymphocytes for cancer immunotherapy. PLK1-specific CD4(+) and CD8(+) T cells can be induced by mPLK1 RNA/DC vaccine and exert anti-tumor effects (94). Inoculation of bone marrow cells CD8 T against the cellular epitope synthesis of PLK1: PLK1122 (DSDFVFVVL) yields a large number of long-lasting antigen-specific CD8 T cells. The use of a peptide vaccine that simultaneously targets PLK1 and blocks PD-L1 can lead to complete tumor eradication and long-term survival in mice with clonal heterologous C1498 myeloid leukemia (133).

However, PLK1 as a target of direct immunotherapy still faces multiple challenges, mainly involving target specificity, immunogenicity and tumor heterogeneity. PLK1 still has basal expression in normal proliferating cells. Systemic targeting of PLK1 may cause “on-target, off-tumor” toxicity, leading to bone marrow suppression or gastrointestinal injury. Such risks may be further amplified by the long-term activating effects of immunotherapy (134). PLK1 did not show strong immunogenicity in human models, and experimental data showed that PlK1-derived peptides only weakly activated T cells in peripheral blood of patients (135). In addition, in a study utilizing a DNA vaccine model to compare the immunogenicity of G2/M-related antigens, it was observed that PLK1-immunized mice did not exhibit any anti-tumor effects. This may be related to the fact that PLK1 is not preferentially expressed in the cancer stem cell (CSC) or cancer initiation cell (CIC) population (136). In summary, PLK1 may be an attractive target antigen for cancer immunotherapy, but is more likely to act as an accessory target rather than an independent immunotherapy antigen.