The Trifecta of Polo-like Kinases, Cancer, and the Immune System: Emerging Intersections and Therapeutic Insights

Abstract

Cancer remains one of the most pressing global health challenges, with immunotherapy being a promising treatment option. However, numerous clinical challenges such as recurrence and resistance persist, underscoring the urgent need for a deeper understanding of the mechanisms that influence immune responses in cancer. Polo-like kinases (PLKs), a family of enzymes with five members, PLK1 through PLK5, have been implicated in cancer progression, and their inhibition is being actively explored for cancer management. While past studies of the PLK family are largely confined to their role in the cell cycle and corresponding chromatin dynamics, recent research has unveiled important connections between PLKs and cancer immunity, particularly in relation to critical signaling pathways such as interferon (IFN) signaling, immunogenic cell death (ICD), TGF-β signaling, and FAS/FASL signaling. While much of the research has focused on PLK1, additional members of the PLK family are beginning to attract attention due to their potential implications in cancer immunity. Understanding the intricate role of PLKs in cancer immunity is an emerging field with tremendous potential. This review offers a comprehensive overview of current knowledge connecting the members of the PLK family with cancer immunology and provides considerations for further research to uncover how PLK signaling can be strategically targeted to optimize cancer immunotherapy to enhance clinical responses.

1. Introduction

This review discusses the emerging role of Polo-like kinases (PLKs) in cancer, with a particular focus on their immunomodulatory functions. While both PLK-targeted therapies and immunotherapies have shown promise in cancer management, each faces significant limitations when used alone. DNA replication and cell division are tightly regulated processes essential for maintaining genomic instability and cellular survival (1). Errors in these processes can lead to genomic instability, which is a hallmark of cancer and often results in uncontrolled cell proliferation. One predominant form of genomic instability is chromosomal instability (CIN), which arises from abnormalities in centrosome number, the spindle assembly checkpoint, sister chromatid cohesion, and kinetochore-microtubule attachments(1,2). These errors can lead to DNA damage, tumor heterogeneity, aggressive cancer phenotypes, and therapeutic resistance by accelerating mutation acquisition and altering gene expression patterns (3,4).

The PLK family of serine/threonine kinases (PLK1-PLK5) plays key role in regulating genomic stability and cell cycle progression. These kinases are generally characterized by a conserved N-terminal catalytic domain (PLK1-PLK4) and the presence of either one (PLK4) or two (PLK1–3) highly conserved polo-box domains (PBDs), which are involved in subcellular localization, target binding, and cis-acting regulation of activity. PLK5 has a truncated N-terminal catalytic domain, rendering it inactive, and it remains unclear whether human PLK5 has 1 or 2 PBD (5) (Figure 1). The PLKs play crucial and sometimes overlapping roles in cell cycle regulation, mitosis, and cellular stress response (6–11). Their dysregulation is a common feature in various cancers, making them important players in tumor development and/or progression (12).

Figure 1. Structural organization of different PLKs.

Structurally, PLKs are composed of a conserved N-terminal catalytic serine/threonine (ST) kinase domain (KD) (PLK1-PLK4) along with two PBDs (PLK1-PLK3) or a single PBD along with a two cryptic PBDs (CPB). PLK5 has a truncated N-terminal catalytic domain, rendering it inactive, and a clear PBD with homology to the second PBD on PLK1. It remains unclear whether human PLK5 has 1 or 2 PBDs. The PLK1 destruction box (D-box) and PLK4 downstream regulatory element (DRE) are known for regulatory sites controlling proteolytic turnover of PLKs 1 and 4. In three-dimensional space, the polo-cap (PC) is formed from the end sequence of the KD to PBD region linker folding over the PBDs. Created in BioRender. Jaiswal, T. (2026) https://BioRender.com/is0f8wa.

Due to the established role of PLKs in cell cycle regulation, they are being tested as targets for cancer management. For example, the PLK1 inhibitor Onvansertib and the PLK4 inhibitor CFI-400945, were granted fast-track designation by the FDA for clinical trial for the treatment of certain cancers. While these inhibitors are generally well-tolerated and exhibit favorable pharmacokinetics, their clinical success, especially in advanced-stage cancers, has been limited due to potential side effects including by hematological toxicities such as neutropenia and thrombocytopenia as well as lack of predictive biomarkers for patient response (13–15). Although no PLK inhibitors have yet received FDA approval, several are currently being evaluated in clinical trials for the treatment of various cancers, as summarized in Supplementary Table S1.

In parallel, cancer immunotherapy has transformed oncology by harnessing the immune system to eliminate malignant cells (16,17). Some of the major breakthroughs in cancer immunotherapy include drugs like Pembrolizumab (18), Nivolumab (19) and Ipilimumab (20) that target immune checkpoints such as PD-1 and CTLA-4. By inhibiting these checkpoints, these drugs can reinvigorate robust T cell expansion and T cell mediated killing of cancer cells (21–23). Adoptive cell therapy has also achieved significant success in treating metastatic melanoma, leading to the accelerated FDA approval of Lifileucel for this indication (24). CAR-T therapies such as Tisagenlecleucel (25) and Axicabtagene Ciloleucel (26) have also demonstrated remarkable success in treating certain blood cancers, underscoring the transformative potential of this approach. Sipuleucel-T (Provenge), an FDA-approved cancer vaccine, is used to treat metastatic prostate cancer by stimulating the immune system against prostate-cancer-associated prostatic acid phosphatase (PAP) (27). However, many tumors remain refractory to immunotherapy due to immune exclusion, acquired resistance, toxicity, lack of predictive biomarker for response and interpatient variability in treatment response (28–31). Thus, there is an urgent need to identify connections between different immune pathways and other cancer-associated pathways for developing approaches, including those that combine immunotherapy with targeted therapies. Interestingly, recent studies have revealed a link between the PLK family and various immunomodulatory pathways that are crucial for host anti-tumor immunity and immunotherapy responses (32). including type I IFN Signaling (33), TGF-β-mediated immunoregulation (34), FAS/FASL mediated apoptosis (35), ICD (36), and immune cell function (37,38). These findings suggest that PLKs not only regulate cell division and genomic stability but also influence anti-tumor immune responses.

Understanding how PLK family members intersect with immune pathways may provide a unique opportunity to develop combinatorial therapeutic strategies that integrate PLK-targeted inhibitors with immunotherapy. Such approaches may enhance tumor immunogenicity, overcome resistance, and improve clinical outcomes, particularly in tumors unresponsive to monotherapies. Our review highlights the multifaceted roles of PLK1–5 in cancer biology and their emerging functions in immune modulation, emphasizing the therapeutic potential of combining PLK inhibition with immunotherapy to advance cancer treatment.

2. Polo-like Kinases in Cancer

PLKs have been linked to multiple aspects of cancer development and/or progression and thus have emerged as lucrative targets for cancer management. While PLK1 is primarily associated with oncogenic functions, PLK2, PLK3, and PLK5 often act as tumor suppressors (reviewed elsewhere (39)). PLK4 is known to have a tumor promoter function and its roles in centrosome duplication and genomic stability make it a potential target in cancer treatment (40,41). The PLKs’ roles in cellular processes that are critical for cancer cell proliferation, make them key targets for therapeutic intervention against cancer (41). A very brief account of the roles of different PLK family members in cancer is provided below.

• PLK1, the most well-studied member of this family, is pivotal in cell cycle regulation. It is involved in various stages of mitosis, including centrosome maturation, spindle assembly, chromosome segregation, and cytokinesis (11). PLK1 is frequently overexpressed in several cancers, including breast, colorectal, lung, and prostate cancers (42). Its overexpression supports increased cell proliferation, tumor growth, epithelial-mesenchymal-transition, and poor prognosis (43–45). Given its role in cell division, PLK1 is the target for the development of small-molecule inhibitors such as volasertib and onvansertib (46). These inhibitors aim have been shown to disrupt mitosis, induce cell cycle arrest and ultimately block cancer cell division, leading to cancer cell elimination (46).

• PLK2 plays a role in centrosome duplication and the DNA damage response. It also contributes to the maintenance of genomic stability (47). Unlike PLK1, PLK2 is primarily known to act as a tumor suppressor. It is often downregulated in certain cancers such as B-cell lymphomas and gliomas (48,49). However, in certain other cancers high PLK2 expression is associated with resistance to chemotherapy and poor clinical outcomes (50). Thus, PLK2 exhibits divergent roles across cancers, with its function strongly dependent on tumor type and biological context.

• PLK3 is involved in cellular responses to stress, including DNA damage and hypoxia. It can induce cell cycle arrest and apoptosis in response to stress signals (51,52). Similar to PLK2, PLK3 acts as a tumor suppressor (52). It is frequently downregulated in cancers such as lung and colorectal cancers (53,54). PLK3 deficiency can lead to increased tumor growth and resistance to apoptosis (55).

• PLK4 is a structurally unique member of the PLK family as it contains a PBD along with two cryptic PBDs, non-canonical PBDs that give PLK4 a unique winged architecture, crucial for the activation of the kinase, self-regulation, and degradation (56). PLK4 is crucial for centrosome duplication, and its proper regulation ensures normal centrosome numbers, preventing aneuploidy and genomic instability (57). Aberrant PLK4 expression can lead to centrosome amplification, a hallmark of many cancers (58). Overexpression of PLK4 is associated with tumorigenesis in breast, prostate, and colorectal cancers (59–61). Due to its role in centrosome amplification, PLK4 is considered a potential target for cancer therapy. Inhibitors targeting PLK4 such as CFI-400945 (14) could be useful in treating cancers characterized by centrosome abnormalities (62,63).

• PLK5 is less studied compared to the other PLKs. It is primarily expressed in the brain and lung tissues and has been shown to be involved in neurodevelopment (64). Interestingly, in a study from our lab, PLK5 has been suggested to act as a tumor suppressor (65). PLK5 expression is often reduced in gliomas and neuroblastomas (64). Its downregulation may contribute to uncontrolled cell proliferation in these cancers (66).

In conclusion, PLKs play a pivotal role in cancer development and targeting them could serve as an efficient cancer management strategy. The following section will explore their connections to the immune system.

3. Polo-like Kinases and Cancer Immunity

The role of most of the PLK family members is reasonably well established in cell cycle dynamics, especially proliferation and cell death, as a result of intense research during the past few decades. However, only recently their roles in influencing tumor immunity have been appreciated. Emerging data has suggested that PLKs may be involved in regulating the activity of various immune-related pathways known to be critical in anti-tumor immunity, such as IFNs and transforming growth factor beta (TGF-β) signaling, the response to immune-derived cell death signals, and immune checkpoint signals. Further, PLKs are expressed in various immune cells, including T cells and dendritic cells (DCs), where their potential roles in anti-cancer immunity are emerging. Below, we describe the roles of PLKs in key immune pathways and how they influence interactions between cancer and immune cells to shape tumor-immune responses.

3.1. Roles of PLKs in Type I IFN Signaling

Type I IFN are pleotropic cytokines that can influence numerous cancer cell functions, such as proliferation, differentiation, migration, and cell death (67). However, the most appreciated roles of the type I IFN family are immune-related, as type I IFN signaling can stimulate pro-inflammatory responses needed for immunotherapy success (68,69). Mechanistically, type I IFN signaling operates through both cancer-cell-extrinsic and cancer-cell-intrinsic pathways. Type I IFN remodels TME to enhance T cell trafficking, support effector functions, and stimulate antigen-presenting cells in a non-cell-autonomous manner (70). Cancer cell-intrinsic type I IFN signaling can enhance antigen presentation, increase immunogenicity, and promote susceptibility to immune-mediated cell death (71). Recent research has identified multiple important roles of certain PLKs in directing type I IFN signaling, implicating them as important regulators of anti-tumor immunity and potential targets to control immunotherapy responses. Below, we discuss how different PLK family members can regulate type I IFN signaling, and how such regulation may impact the cancer-immune interface (Figure 2).

Figure 2. PLKs in type I IFN signaling.

Type I IFN signaling can play a crucial role in promoting pro-inflammatory responses essential for the success of immunotherapy and the development of strong anti-tumor immunity. Members of the PLK family including PLK1, PLK2, and PLK4 have been implicated in modulating Type I IFN signaling through distinct mechanisms. PLK1 dampens IFN signaling downstream of MAVS and contributes to inhibition of type-I-IFN-induced caspase-3 cleavage. PLK2 is a non-canonical ISG, which promotes IFN-mediated cell death by enhancing GSDME cleavage PLK4 inhibition initiates type I IFN signaling by activating the cGAS-STING pathway through a combination of cGAS upregulation and cytosolic DNA release, together shaping a more immunostimulatory TME. Created in BioRender. Jaiswal, T. (2026) https://BioRender.com/hle9x7x.

PLK1 was the first member of the PLK family to be linked with type I IFN signaling. Type I IFN signaling activation in rhabdoid tumors has been shown to downregulate PLK1 to drive growth arrest and apoptosis (72). Type I IFN signaling has been shown to elicit cell death, specifically via interferon beta (IFN-β) induced caspase 3 cleavage (73). Interestingly, PLK1 knockdown in rhabdoid cells augmented caspase 3/7 activity, (72) suggesting that PLK1 inhibition may contribute to type I IFN-induced cell death. Thus, its overexpression as seen in various cancers may prevent cancer cell apoptosis under immune pressure. An important inducer of type I IFN signaling during tumor progression is the mitochondria-bound mitochondrial antiviral-signaling (MAVS) protein, which responds to cytosolic RNAs detected by the helicase sensors- retinoic acid-induced gene-I (RIG-I) or melanoma differentiation-associated gene-5 (MDA-5) (33,74). MAVS subsequently can complex with multiple partners to activate the transcription factors responsible for type I IFN production (33). A yeast two-hybrid screen revealed PLK1 as a MAVS binding partner (33). PLK1 binds to MAVS using its PBD, which can occur at a basal level regardless of cell cycle phase but binds the most when PLK1 levels are highest around G2/M phase. Interestingly, while PLK1 alone did not affect type I IFN induction, in the presence of MAVS, PLK1 was shown to inhibit expression of type I IFN targets. Accordingly, PLK1 overexpression in MAVS containing cells could also block type I IFN production, including IFN-β, while PLK1 knockdown increased MAVS activity. Mechanistically, the PLK1-PBD was found to prevent the binding of MAVS with TNF receptor-associated factor 3 (TRAF3), a signaling partner that can help activate downstream transcription factors to support IFN signaling (33). Thus, PLK1 opposes the MAVS-mediated induction of type I IFN signaling. However, it remains unclear whether PLK activity regulates cytosolic RNA to influence MAVS. Further studies examining the TME across cancer types and context(s) are needed to clarify to what extent PLK1 expression during tumor progression enables escape from type I IFN signaling, and whether PLK1 targeting can faithfully enhance the type I IFN responses permissive of successful immunotherapy outcomes and cancer cell death.

Induction of type I IFN signaling results in the translation of IFN-stimulated genes (ISGs), an essential step in the IFN mediated responses which are needed to support anti-tumor immunity (75). Interestingly, ubiquitin-specific protease 18 (USP18) acts as a negative regulator of type I IFN signaling. Deletion of USP18 has been shown to trigger the expression of both canonical and non-canonical ISGs, including the PLK family member PLK2 (75). USP18 deletion sensitizes acute myeloid leukemia (AML) cells to type I IFN-mediated cell death by inducing Gasdermin (GSDM) E cleavage. PLK2 has been reported to be necessary for GSDME cleavage and maximal type I IFN-mediated cell death (75). Importantly, PLK2 was sufficient to prolong survival in syngeneic PLK2-inducable leukemia models in vivo, regardless of USP18 expression (75). These findings suggest PLK2 promotes type I IFN-induced responses and ICD.

Several PLKs have demonstrated roles in regulating chromosomal stability and participating in double-stranded DNA (dsDNA) repair (76–80). As chromosomal stability is dysregulated and CIN ensues during cancer progression, the accumulation of cytosolic dsDNA can lead to the activation of the stimulator of interferon genes (STING) signaling (70,81). Given that STING is a driver of type I IFN signaling (82,83), modulating PLKs may prime cancer cells for enhanced STING activation and more robust type I IFN responses. Indeed, in AML, PLK4 inhibition induced expression of IFN response and senescence-associated secretory phenotype (SASP) gene signatures, while the genes associated with immune regulation (for example, FBXO44, CLCF1, BFSP1 etc.) were downregulated (84). Additionally, higher ploidy cells with more potential for cytosolic DNA release induced greater cytokine expression upon PLK4 inhibition (84). Notably, PLK4 inhibition increased expression of proinflammatory cytokines often associated with type I IFN responses in tumor immunity in a STING-dependent manner, including interferon gamma (IFNγ) and tumor necrosis factor alpha (TNFα), the combination of which is an important source of robust anti-tumor activity through cytokine-mediated cell death (84). Further, inhibition of PLK4 stimulated macrophage phagocytosis and T cell mediated cytotoxicity in AML co-cultures; and these phenotypes could be suppressed by STING inhibition. Furthermore, PLK4 inhibition synergized with macrophage phagocytosis-stimulating anti-CD47 therapy to robustly suppress tumor burden and prolong mouse survival in an immunocompetent AML mouse model. It is thought that the proinflammatory cytokines released downstream of PLK4 inhibition and subsequent STING activation are responsible for macrophage and T cell stimulation, but this hypothesis remains to be definitively explored (84).

Similarly, PLK4 inhibition in hepatocellular carcinoma (HCC) cells induced expression of pro-inflammatory cytokines associated with anti-tumor immunity, in a STING-dependent manner (85). STING activation was dependent on cytosolic DNA accumulation, which occurred as part of PLK4 inhibition-mediated genomic instability. Further, in vivo PLK4 inhibition via CFI-400945, was shown to cause increased tumor infiltration of CD4⁺ and CD8⁺ T cells, natural killer (NK) cells, and macrophages (85). PLK4 inhibition outperformed PD-1 blockade monotherapy and further improved overall survival when PLK4 inhibitor was used in combination with anti-PD-1 blockade (85). In another study, PLK4 knockdown in glioma cell lines resulted in stimulation of anti-tumor cytokine secretion including CXCL5, CCL2, CXCL6, CCL8, CXCL7, CCL23 and increased anti-tumor macrophage infiltration (86). In an orthotopic glioma model, PLK4 inhibitor-treated mice displayed reduced glioma growth and increased infiltration of inflammatory inducible nitric oxide synthase (iNOS)-expressing macrophages in the tumor. PLK4 knockdown in glioma induced production of CXCL5 and CCL2, which were described to be STING-dependent in AML and HCC, suggesting a similar IFN-related mechanism may be at play (86).

PLK4 inhibition can also increase cGAS expression (84), a DNA sensor necessary for STING clustering and activation, contributing to STING signaling and type I IFN-mediated anti-tumor immunity upon PLK4 inhibition (82). Thus, PLK4 overexpression that occurs during cancer progression may provide a therapeutic opportunity for inducing a robust type I IFN response capable of enhancing anti-tumor immunity, as high PLK4 levels may prime cells for STING activation via the accumulation of chromosomal abnormalities, and PLK4 inhibition may augment STING signaling via cGAS induction as a large amount of cytosolic DNA is simultaneously released.

Interestingly, recent evidence has demonstrated that chronic cGAS—STING signaling may promote cancer progression and immune evasion. Specifically, downstream of STING, non-canonical nuclear factor kappa-B (NF-κB) activation drives interleukin (IL) IL-6/ signal transducer and activator of transcription 3 (STAT3) signaling loops in cancer cells to promote their metastatic progression and create an immunosuppressive TME (70,87–89). It has been shown that PLK4-driven centrosome-amplified breast cancer cells are highly sensitive to STAT3 inhibitors (90). Therefore, PLK4 inhibition alone may suffice to drive acute STING signaling and anti-tumor IFN responses in cases where cGAS was poorly expressed but restored upon PLK4 inhibition. In addition, in cases with chronic STING signaling supported by PLK4-mediated CIN acting as an integral part of tumor progression, PLK4 inhibitors could be paired with STAT3/IL-6 inhibitors to prevent the pro-tumor role of chronic STING signaling from dominating.

The role of other PLKs in STING signaling remains to be investigated, but similar parallels may exist given their commonality in centrosome regulation. Taken together, PLK4 appears to play a similar role to PLK1 by blocking type I IFN induction, albeit through alternative means. Additionally, PLK1 may have a secondary IFN-related role in preventing type I IFN-induced cell death, while PLK2 may promote this sensitivity. Further research can address whether PLK4 targeting, or concomitant PLK1/4 inhibition, is a viable means to improve immunotherapy outcomes and exactly how the PLK family members regulate multiple facets of type I IFN signaling during tumor progression.

3.2. Role of PLKs in TGF-β-mediated Immunoregulation

As anti-tumor immune responses are mounted, cancer cells can maladapt TGF-β signaling to enable immune evasion and facilitate their survival (91). Despite its initially tumor-suppressive role, TGF-β secreted by cancer cells can inhibit the effector functions of NK cells and T cells or can cause infiltration and expansion of cancer-promoting myeloid cells (myeloid derived suppressor cells, MDSCs) (91–93). Signaling through TGF-β receptors (TGFβRs) I and II can also activate a variety of cell-intrinsic immune evasion programs (93,94). Therefore, it is unsurprising that TGF-β is associated with immunotherapy resistance. Strategies targeting TGF-β are under investigation to improve anti-tumor immune responses (93–95). Recent reports have demonstrated role for PLKs, especially PLK1, in TGF-β production and related signaling events serving to direct tumor immune escape (Figure 3).

Figure 3. PLKs in TGF-β-mediated immunoregulation.

Cancer cells can hijack and maladapt TGF-β signaling to evade immune surveillance and promote their survival. Members of the PLK family, particularly PLK1 and PLK2, exhibit distinct interactions with the TGF-β pathway. PLK1 activation contributes to a positive feedback loop that enhances TGF-β production and drives the secretion of immunosuppressive cytokines, partly through the phosphorylation of FOXM1. Additionally, TGF-β upregulates the PLK1–vimentin axis, which in turn activates downstream STAT3 and SMAD2/3 signaling pathways, reinforcing tumor-promoting effects. In contrast, TGF-β signaling suppresses PLK2 expression, suggesting a potentially tumor-suppressive role for PLK2 in this context. Created in BioRender. Jaiswal, T. (2026) https://BioRender.com/i5z87oi.

The relationship between PLK1 and TGF-β was recently identified in non-small cell lung cancer (NSCLC) cells (34). TGF-β signaling was shown to induce PLK1 phosphorylation, in turn, active PLK1 promoted cancer progression and dedifferentiation. Importantly, PLK1 activation resulted in transcription of multiple TGF-β-related signaling pathway genes, serving to reciprocally enhance TGF-β signaling. This mechanism demonstrates a positive feedback loop between PLK1 activation and TGF-β signaling (34). A follow up study found that upon TGF-β-mediated activation, PLK1 binds to FOXM1 and directly phosphorylates it at serine (S) positions S715, S25, and S361. TGF-β-induced and PLK1-mediated FOXM1-phosphorylation, specifically at site S25, enhanced NSCLC proliferation and migratory capacities in vitro, and metastasis in vivo (96). S25 phosphomimetic FOXM1 mutant cells were found to be enriched for a variety of cytokines linked with immune-suppression, including IL-6 and CXCL1. Co-culturing NSCLC cells with THP-1 cells (monocytes) or human monocyte-like cells resulted in the increased expression of hallmark macrophage markers that are associated with anti-inflammatory function. Importantly, S25E phosphomimetic FOXM1 mutant NSCLC cells significantly increased expression of TGF-β1 and VEGF-A in the THP-1 cells and prevented the THP-1-mediated reduction in viability of NSCLC cells during co-cultures, as compared to wild-type FOXM1 expressing NSCLC cells (96). Overall, this study identified PLK1 as a key node in TGF-β signaling, which cumulates in the induction of anti-inflammatory macrophage polarization through cell surface protein and secretome changes. The anti-inflammatory macrophages then produce their own TGF-β and other cancer-promoting cytokines (96). Thus, TGF-β-PLK1 signaling potentially creates a positive feedback loop serving to convolute the TME with overexpression of TGF-β, increased expression of immune-suppressive cytokines, and the polarization of macrophages to a tumor-suppressive anti-inflammatory phenotype.

Moreover, TGF-β-mediated activation of PLK1 resulted in an increased expression of vimentin. PLK1 was shown to bind vimentin and phosphorylate it at multiple sites (97). In turn, the PLK1/vimentin axis can induce STAT3 and SMAD2/3 signaling, leading to PD-L1 transcription. A phosphomimetic vimentin mutant mimicking PLK1 phosphorylation prevented T-cell mediated killing of NSCLC cells in co-culture (37,97). Together, PLK1 has been implicated in contributing to TGF-β feedback loops capable of polarizing myeloid cells and neutralizing adaptive immune effector responses. While these functional studies are currently limited to NSCLC, PLK1 has also been shown to promote immune evasion in a breast cancer mouse model, where it has been linked to TGF-β signaling signatures(37). Additional studies could further clarify the importance of PLK1 in TGF-β-mediated immunosuppression, and whether PLK1 targeting can provide similar benefits to those achieved by TGF-β inhibitors.

The roles of PLK2 and the other PLK family members in TGF-β-mediated cancer immunoregulation remain to be established. Only one study has demonstrated that treatment of lung fibroblasts with TGF-β led to decreased PLK2 expression (98). Further research is needed to reveal the involvement of other PLK family members in TGF-β-mediated immunosuppression.

4.3. Role of PLKs in FAS/FASL mediated Cell Death

The immune system employs a variety of mechanisms to detect and eliminate malignant cells. One such mechanism relies on the FAS ligand (FASL/CD95L), a transmembrane protein predominantly expressed on activated T lymphocytes and NK cells. FASL couples with the FAS receptor (FAS/CD95), which can be expressed on the surface of cancer cells, and when engaged results in caspase and FADD recruitment, leading to subsequent apoptotic or necroptotic cancer cell death (99). Despite being recognized as a major system of T cell mediated cytotoxicity, most cancer cells can resist FASL-mediated cell death. In fact, once this resistant state is achieved, FAS signaling can be co-opted by cancer cells to contribute to tumor progression instead of their death (99,100). PLKs have been shown to participate in FAS signaling (Figure 4).

Figure 4. PLKs in FAS/FASL mediated and immunogenic cell death.

Fas ligand (FASL, or CD95L) binds to its receptor FAS (also known as CD95), which can be expressed on the surface of cancer cells. This interaction recruits caspases to FADD, triggering apoptotic or necroptotic cell death. After CDK1 phosphorylation of pro-caspase (CASP) 8, PLK1 can phosphorylate it, preventing T- or NK-cell-induced death. PLK1 also supports “immune cold” cell death, by inhibiting DAMP release, which can activate DCs and an adaptive immune response. In contrast, PLK3 phosphorylation of pro-CASP8 promotes CASP8 activation, supporting cell death, and PLK3 promotes the release of DAMPs and DC activation as part of ICD. Created in BioRender. Jaiswal, T. (2026) https://BioRender.com/0mhxtup.

Based on a series of in vitro experiments, Helmke et al. described the role of PLK3 in FAS/FASL stimulation (101). At a basal level, the PLK3 C terminal region, including the PBD, binds to the cytosolic portion of FAS, stimulation with FASL can further enhance this association (101). Importantly, upon FASL stimulation, recruitment of signaling components to FAS forms the death-inducing signaling complex (DISC) (101,102). Caspase 8 (CASP8) is a DISC component needed for cell death, and PLK3 is shown to bind to CASP8 where it phosphorylates threonine (T) T273 (101). FAS stimulation was found to result in PLK3-mediated phosphorylation of CASP8. Further, PLK3 inhibition prevented CASP8 activation and PLK3 overexpression sensitized cells to CD95-mediated apoptosis, together supporting a pro-apoptotic role for PLK3 in the DISC complex upon FAS signaling (101). In human anal cancer samples, PLK3 expression was shown to be correlated with T273-phosphorylated CASP8, which was speculated to be indicative of CD8⁺ T cell accumulation and FAS signaling (101).

PLK1 can also interact with CASP8, in apparent opposition to PLK3 (103). During mitosis, the cyclin-dependent kinase 1 (CDK1)/Cyclin B1 complex can phosphorylate pro-CASP8 at S387, which subsequently allows PLK1 binding and PLK1 phosphorylation of pro-CASP8 at S305. This phosphorylation prevents pro-CASP8 processing upon FAS stimulation, therefore preventing CASP8 induction of cell death (103). Accordingly, PLK1 inhibition could sensitize colon cancer cells to FASL-mediated cell death. Kinase-dead PLK1 mutant cells were extremely sensitive to FASL, and these cells could process CASP8, while phosphomimic PLK1 mutant cells resisted CASP8 activation and FASL-mediated cell death (103). Importantly, while PLK3 can bind to CD95 and promote FASL-mediated cell death at any time, regardless of the cell cycle, (101) the restriction of Cyclin B1 expression to mitotic periods limits the potential for PLK1 to interact with pro-CASP8 and prevent its processing (103). However, as PLK1 can stage mitotic commitment (104), one may speculate that the PLK1 overexpression in cancer can allow for enhanced PLK1 binding to pro-CASP8 to prevent immune-mediated cell death.

Another mechanism of immune-mediated cell death relies on the exocytosis of cytotoxic granzymes from immune cells into targeted cells. Studies have shown that some granzymes cleave CASP8 (105,106); however, whether the PLK1 phosphorylation of pro-CASP8 prevents granzyme-mediated caspase processing remains unknown. These studies show PLK3 can positively participate in the DISC processing of CASP8, while PLK1 can alter pro-CASP8 to prevent processing in the DISC and provide opposing roles for PLK1 and PLK3 in regulating FASL-induced cytotoxicity. Further research is needed to determine to what extent PLKs affect the outcomes of FAS/FASL signaling to control immune evasion, and how important PLK modulation is for sensitizing tumor cells to immune-mediated cell death. The generalizability of PLK-CASP8 interactions, and potential roles of additional PLK family members in this process remain to be explored.

Future research should elucidate how various members of the PLK family may complement or counteract each other in regulating cells in response to type I IFN signaling, FAS/FASL interactions, granzyme processing, and mitotic catastrophe. Additionally, it will be important to investigate that to what extent corresponding cell death mechanisms induce an immune response or remain immunologically silent.

3.4. Role of PLKs in Immunogenic Cell Death

ICD is a form of cell death where antigenic and immunostimulatory cellular components are released into the TME (107,108). In tumors, these released cellular contents can be taken up by antigen-presenting cells, which are then activated by accompanying damage-associated molecular patterns (DAMPs). This process triggers the strong induction and activation of adaptive anti-tumor immune responses (107,108). PLK1 inhibition or genetic depletion in prostate cancer cells was shown to lead to mitotic catastrophe and necroptosis (109). A recent study specifically addressed the immune-related effects of PLK1-inhibition-induced cell death (36). PLK1 inhibition induced ICD in the Lewis lung carcinoma (LLC) mouse model, with a dose-dependent increase in levels of the DAMPs calreticulin and ATP. Moreover, PLK1 inhibition improved CD8⁺ T cell infiltration, as well as CD4⁺ and CD8⁺ T cell activation (36). PLK1 inhibition in LLC cells was found to improve cancer cell uptake by DCs in co-culture, and increased surface expression of CD80/86 on DCs, indicating their activation. Given the increase in expression of PLK1-inhibition-mediated DC activation markers, Zhou et al. developed a PLK1-inhibitor killed LLC cell vaccine, which outperformed no vaccine or LLC freeze-thaw vaccination in vivo. The PLK1-inhibitor killed LLC cell vaccine prevented tumor growth in 5/8 mice during subsequent live challenge and demonstrated the immunogenic nature of PLK1-inhibition-mediated cell death (36). This vaccination strategy also increased IFNy expression in tumor infiltrating CD4⁺ and CD8⁺ T cells (36). Contrary to PLK1, PLK2 has been observed to support DAMP release during cell death (75), but little is known regarding how this may influence immunotherapy outcomes or the TME.

Further research validating the roles of PLK1 and PLK2 in ICD, alongside establishing the contributions of PLK3, PLK4, and PLK5 to ICD, could pave the way for novel combinatorial therapies in cancer treatment (Figure 4).

3.5. Role of PLKs in Immune Checkpoint Regulation/Blockade

PLK1 has been described as a negative regulator of PD-L1 (110). In murine pancreatic cancer cell lines, PLK1 was found to phosphorylate retinoblastoma protein (RB), leading to diminished NF-κB signaling-mediated expression of PD-L1 (110). PLK1 inhibitors, BI6727 and GSK461364A both induced PD-L1 upregulation, independent of IFNγ, in an NF-κB signaling-dependent manner (110). In the immunotherapy-resistant KPC (Kras^G12D/+; Trp53^R172H/+; P48-Cre) pancreatic ductal adenocarcinoma (PDAC) mouse model, anti-PD-L1 therapy alone did not lead to any improvement in overall survival, but PLK1 inhibition with BI6727 synergized with anti-PD-L1 treatment to extend overall survival and strongly diminished tumor growth. The combination therapy was associated with heightened CD8⁺ T cell tumor infiltration, which anti-PD-L1 treatment alone could not achieve. Moreover, the combination therapy also increased CD4⁺ T cell and DC infiltration, while decreasing the presence of anti-inflammatory macrophage populations in tumors. Another study employing NSCLC models found PLK1 knockdown, or inhibition with the small molecule inhibitor volasertib, led to increased PD-L1 expression (111). Using the LLC lung cancer model in vivo, anti-PD-L1 monotherapy failed to control tumor growth, but the combination of volasertib and anti-PD-L1 antibody led to robust inhibition of tumor growth and extended overall survival (111). These results were replicated using a nanoparticle delivery system for volasertib and anti-PD-L1 antibody, which also led to an increased CD8⁺ T cell to regulatory T cell ratio in tumors (111).

Contradictory evidence exists supporting PLK1 as an enhancer of PD-L1 expression. In a mouse model of long-term PLK1 overexpression in breast cancer, constitutive PLK1 induction led to increased CIN, characterized by high somatic copy number alteration and aneuploidy (37). Murine breast tumors with the PLK1-mediated CIN phenotype were characterized by high infiltration of immunosuppressive arginase-1 (ARG1)-expressing macrophages and regulatory T cells, and a diminished NK cell counts. These tumors cells were enriched in PD-L1 expression, and their infiltrating CD8⁺ T cells also had increased expression of the T cell immunoreceptor with Ig and ITIM domains (TIGIT) and t-cell immunoglobulin and mucin domain 3 (TIM-3) immune checkpoints (37). Extending analysis to The Cancer Genome Atlas (TCGA) in breast cancer, high PLK1 was associated with robust expression of immune checkpoints including TIGIT, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), lymphocyte-activation gene 3 (LAG3) and TIM-3, and molecules characteristic of anti-inflammatory macrophages such as IL-10 and IDO1 (37). PLK1 has also been linked to PD-L1 expression in NSCLC downstream of TGF-β signaling (97). These data demonstrate PLK1 can control immune checkpoint expression through multiple means, inhibiting PD-L1 expression, preventing anti-PD-L1 therapy responses, or by creating a TME characterized by high immune checkpoint expression across multiple cell types.

In one study, the suppression of T-cell immunity by PLK3 has been linked to its positive correlation with immune checkpoint proteins PD-1, PD-L1, CTLA-4, LAG-3, TIM-3, and more, as inferred from the bulk RNA-seq data (112).

Bulk-RNA seq analysis of clear cell renal cell carcinoma samples revealed that PLK4 expression was correlated with the expression of a variety of immunosuppresive cytokines and immune cell checkpoints. Notably, this included IL-10, LAG3, TIGIT, and CTLA-4 (113), suggesting a potential role of PLK4 in Treg polarization or TIL dysfunction. (114) Accordingly, genes positively associated with PLK4 across all cancer types were enriched for regulation of Treg differentiation and the PD-L1/PD-1 checkpoint pathway (86).

While current knowledge primarily links PLK1, PLK3 and PLK4 to immune checkpoint regulation, further research may uncover additional and intriguing connections between PLKs and the regulation of immune checkpoints (Figure 5).

Figure 5. PLKs in immune checkpoint regulation/blockade.

Left: PLK1 has been shown to phosphorylate the RB protein, which suppresses NF-κB signaling and consequently reduces NF-κB–mediated expression of PD-L1. In other contexts, PLK1 has been shown to augment TGF-β signaling by phosphorylating vimentin, which promotes PD-L1 expression. PLK1 inhibition plus ICB has demonstrated preclinical success characterized by T and NK cell activation, reduced MDSCs and increased DCs in tumors. Right: Bulk RNA-sequencing has correlated PLK1, PLK3, and PLK4 with different immune checkpoints in multiple cancer types, such as TIGIT, CTLA-4, LAG3, TIM-3, PD-L1, and PD-1. Created in BioRender. Jaiswal, T. (2026) https://BioRender.com/gg74bf0.

3.6. Role of PLKs in Immune Cell Function

A few studies have identified potential immune-cell-intrinsic roles of PLK signaling, adding an important direction to our understanding of PLKs in tumor immunity. In a pooled genome-wide CRISPR-knockout screen in primary human T cells that aimed to identify genes relevant for T cell activity under immunosuppressive conditions, PLK3 knockout increased baseline proliferation, while PLK4 knockout increased the proliferation of T cells treated with cyclosporine, as reported in the extended data by Carnevale et. al. (115). Therefore, while some studies have provided indirect evidence for PLK4 in promoting Treg development or negatively regulating T cell activity, further functional studies are required to directly address this hypothesis.

PLK1 can also modulate the function of various immune cells. A potential caveat of PLK1 inhibition is the necessary level of PLK1 needed for proper T cell function. Specifically, PLK1 has been shown to have an important role in the proper assembly and function of the immune synapse (IS). It has been shown that TCR signaling phosphorylates PLK1, which polarizes to the IS and supports IS formation. Silencing PLK1 results in defective IS formation and impaired lytic-granule-mediated target cell killing, due to defects in microtubule dynamics (38). PLK2, on the other hand, was shown to be upregulated in activated T cells in dogs (116).

Beyond the classical implications in tumorigenesis, recent research has also identified roles for amplified centrosomes in the natural development and functional programs of numerous specialized cell types (117). This phenomenon includes DCs. In response to stimulation, DCs can undergo G1 cell-cycle arrest to acquire two or more centrosomes (117). A recent study found that PLK2 expression in DCs was induced by lipopolysaccharide (LPS) stimulation. While PLK2 knockout did not interfere with DC proliferation or maturation, it almost completely attenuated production of DCs with two or more centrosomes. Diploid DCs with extra chromosomes were more adept at responding to chemotactic cues, attracting and activating T cells, and secreting cytokines involved in T cell activation (117). These findings concur with other recent reports, demonstrating that PLK2 is upregulated in response to toll-like receptor (TLR) signaling and retinoic acid-inducible gene I (RIG-I)-like receptors (RLR) signaling (118–120). PLK2 and PLK4 double knockout also impaired DC cytokine production upon LPS stimulation (118). In mouse macrophages, poly(I:C) stimulation induced PLK2 expression, which enhanced interferon regulatory factor 3 (IRF3) nuclear translocation and was necessary for downstream production of pro-inflammatory cytokines involved in type I IFN response, such as IFN-β and CXCL10 (120). In mouse microglia, LPS-mediated PLK2 induction was shown to be important for NF-κB signaling (121). In mouse bone-marrow-derived macrophages and DCs, PLK2 was shown to bind and phosphorylate A disintegrin and metalloproteinase 17 (ADAM17), resulting in the release of TNFα from pro- TNFα on the cell membrane (122). Thus, PLK2 may broadly support the activation of DCs, and potentially other myeloid cell types, but the importance of this in anti-tumor immunity remains an open question.

An interesting study demonstrated that PLK1 was overexpressed in nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). Regulatory T cells (CD4⁺FoxP3⁺), PD-1⁺/TIM-3^– cytotoxic T cells and FoxP3⁺/TIM-3^– CD8⁺ T cells (which are also thought to be regulatory) were also more frequently detected near PLK1-high lymphocyte predominant (LP) cells even though exhausted cytotoxic T cells were nearly absent (36). A cytotoxic host response is a dominant feature in NLPHL cases that transform into more aggressive forms of the disease. Despite NLPHL-mediated immune evasion, the cytotoxic host response remained persistent. The increased frequency of Tregs surrounding PLK1-high LP cells suggests a disease model in which Treg-mediated immunosurveillance remains intact and actively engaged within the local microenvironment. These observations support the potential use of immune checkpoint inhibitors along with PLK1 inhibitors as a therapeutic approach for NLPHL, aiming to enhance immune response and overcome tumor-induced immune evasion (123).

Thus, emerging evidence highlights potential involvement of PLKs, specifically PLK1, PLK2 and PLK4, in immune cell function. (Figure 6) They are implicated in the regulation of immune responses including promoting T cell activity and DC activation. Further research might also shed light on the role of other members of the PLK family in immune cell function.

Figure 6. PLKs in immune cell function and TME modulation.

PLK1 phosphorylation downstream of TCR triggering supports cytotoxic T cell function by supporting cytoskeletal remodeling necessary for IS formation, TCR trafficking to the IS, and lytic granule release at the IS. PLK2 expression can be induced by TLRs and RLRs. PLK2 can then support DC activation and locomotion through centrosome duplication and broadly supports inflammatory gene/type I IFN responses via IRF3 and NF-κB signaling in multiple myeloid cell types. PLK2 also phosphorylates ADAM17, leading to release of mature TNF-α from pro-TNF-α on the cell surface. PLK3 knockout has been shown to support baseline proliferation of T cells, while PLK4 knockout has been shown to support proliferation of T cells in immune-inhibitory conditions (cyclosporin treated). Created in BioRender. Jaiswal, T. (2026) https://BioRender.com/b3rdi19.

3.7. Role of PLKs in TME Modulation

Recent advancements in immunotherapy face the challenge of immunosuppressive TME, leading to poor clinical outcomes. The TME is composed of both immunostimulatory and immunosuppressive populations and the balance between their proportions is a key to better clinical outcomes. Thus, drug delivery strategies focused on the modulation of TME can be of great significance for directing and improving cancer immunotherapy (124). The role of different members of the PLK family in modulating the TME has recently garnered attention (Figure 6). For example, using genetically engineered mouse models and single-cell RNA-seq analysis, Kong et al. demonstrated that PLK1 plays a crucial role in promoting an immunosuppressive tumor TME in lung adenocarinoma (LUAD). Constitutive PLK1 overexpression in the KRAS P53 (KP) LUAD mouse model decreased tumor infiltration of DCs, NK cells, T cells, and B cells, while increasing pro-tumor macrophage infiltration and polarization. PLK1 impaired class II major histocompatibility complex (MHC-II) expression on DCs and tumor cells and promoted macrophage/MDSC polarization in a CXCL2-dependent manner. These findings highlight PLK1 as a novel modulator of the TME in LUAD and further suggested its potential as a therapeutic target for improving tumor immunity (125). Further, PLK1 has been correlated with diminished antigen presentation and reduced lymphocyte infiltration scores in multiple cancer types as shown by bulk RNA-seq datasets (126). Moreover, PLK1 broadly reduced expression of multiple NF-κB-target inflammatory cytokines, including IL-2, IL-4, IL-7, IL-9, and IL-21, which are needed for T cell proliferation/ survival, and reduced expression of several chemokines including CXCL9, CCL5, CCL19, CCL21, CCL22, CXCR5 and CCR7 that promote chemotaxis into tumors (110). PLK1 has also been shown to decrease the expression of IL-12 and IL-27, which are required for IFNγ production, thus inhibiting an inflammatory response. Bioinformatic analysis has also shown a negative correlation between PLK1 and infiltration abundance of B cells, CD4⁺ T cells, and macrophages in LUAD (127). Additionally, another study has shown a higher abundance of tumor-promoting immune cells, such as Type 2 T helper cells, MDSCs and regulatory T cells, in the PLK1-high groups of invasive breast carcinoma (BRCA), which may be responsible for the worse prognosis (128,129). In uterine serous cancer patients, PLK3 gene amplification was associated with unfavorable immune status, while those with neutral PLK3 status had a more favorable immune environment (130). Although PLK3 has not been extensively studied in this context, Zhu et al. have shown that PLK3 overexpression in a glioma mouse tumor model promoted neutrophil recruitment and negatively regulated CD4⁺ and CD8⁺ T-cell infiltration, which contributed to T-cell anergy and glioma aggressiveness (112). Although the role of other members of the PLK family in TME modulation is not known yet, further research might shed light on their specific roles opening avenues for therapies combining PLK inhibitors and immunotherapy to overcome the challenges of monotherapy.

3.8. Role of PLKs in Tumor Immunometabolism

Metabolic rewiring is also considered as one of the hallmarks of cancer (1). The cancer cell switch to glycolysis-focused catabolism is common across solid tumors and provides metabolic pacification signals to immune cells in the TME while activating cancer-cell-intrinsic immune evasion pathways, together acting as a two-fold barrier against anti-tumor immunity (131,132). Specifically, the accumulation of a hypoxic and lactic acid-rich TME are established factors that cause T cell dysfunction and impair T cell immunometabolism (133,134), which leads to accumulation of cancer-promoting myeloid populations (135). Recent reports have established the roles of PLKs in influencing tumor metabolism and resulting impacts on anti-tumor immunity (Figure 7).

Figure 7. PLKs in immunometabolism.

ECT2 overexpression induces PLK1 expression. PLK1 can drive glucose metabolism 1) indirectly, by phosphorylating PDHA1, leading to mitophagy and less OXPHOS, and 2) directly, by binding to and phosphorylating PTEN, which leads to PI3K/AKT glucose metabolism. PLK1-mediated glycolysis supports lactate release into the TME via LDHA, which cumulates in reduced T/NK cell infiltration, and increased pro-tumor macrophage abundance in tumors. PLK1-mediated chromosomal instability can also cause metabolic changes as part of the SASP, leading to increased tumor Treg abundance. In contrast to PLK1, PLK3 inhibits glucose metabolism 1) by phosphorylation of PTEN in a manner preventing PI3K/AKT glucose metabolism, inhibition of HK2 expression, and by inhibiting hypoxia-inducible factor 1-alpha (α). L-Glutamine can induce PLK4 expression through an unknown mechanism. PLK4 can directly bind to AKT and phosphorylate it, supporting glucose metabolism, which may lead to pro-tumor macrophage polarization in the TME. Created in BioRender. Jaiswal, T. (2026) https://BioRender.com/bqvk3gb.

In hepatocellular carcinoma, overexpression of epithelial cell transforming 2 (ECT2) protein increased expression of PLK1, which lead to PLK1 association with phosphatase and tensin homolog (PTEN) and prevented its nuclear translocation (136). In turn, diminished PTEN translocation resulted in a shift to aerobic glycolysis that enriched the TME with tumor promoting macrophages, which were capable of suppressing CD8⁺ T cell proliferation and NK cell cytotoxicity in co-culture experiments. Macrophage polarization was lactate-dependent and could be rescued by lactate dehydrogenase A (LDHA) knockout (136). These findings revealed the PLK1-PTEN interaction as an important signaling node that promoted cancer cell glycolysis and accompanied lactic acid production, to ultimately dampen anti-tumor immunity in the TME. When bound to PTEN, PLK1 can also phosphorylate it in an inhibitory manner, leading to activation of phosphoinositide 3-kinases (PI3K) and a subsequent aerobic glycolysis metabolism shift (137). Similarly, PLK4 has been shown to promote glycolysis-favoring metabolism in glioblastoma by directly phosphorylating AKT serine/threonine kinase 1 (AKT1), which is downstream of PI3K (138). In contrast to PLK1 and PLK4, PLK3 has been shown to stabilize PTEN to prevent PI3K signaling (139). Moreover, through another mechanism, PLK3 was found to inhibit tumor glucose metabolism by downregulating hexokinase 2 (HK2) (54). Together, PLK1 and 4 support glycolytic favoring, while PLK3 opposes it. How PLK-PTEN-PI3K-related regulation of glycolysis is fine-tuned by different PLK members, and what are the resulting ramifications on anti-tumor immunity and metabolic changes to the TME, are emerging areas of research. Further, a study has shown that hexavalent chromium–transformed lung epithelial cells exhibit upregulated PLK1, which drives mitochondrial dysfunction, enhanced mitophagy, and increases proliferation by phosphorylating pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1) at T57, leading to pyruvate dehydrogenase complex (PDH) complex destabilization and impaired oxidative phosphorylation (OXPHOS). This phosphorylation in turn promotes metabolic reprogramming from OXPHOS to glycolysis, with cells relying more on the aspartate–malate shuttle to sustain the TCA cycle, a mechanism validated both in vitro and in vivo using PDHA1-T57D models. Importantly, combined inhibition of PLK1 (Onvansertib) and PDH inactivation (Dichloroacetate/DCA) synergistically suppressed lung tumor growth, supporting a potential combinatorial therapeutic strategy for lung cancer (140,141). Additional studies are needed to determine the exact nature of such immunometabolic changes across cancer types. Although the roles of PLK1 and PLK4 in this context are currently being investigated, additional studies are required to better understand the functions of PLK2, PLK3, and PLK5 in immunometabolism.

3.9. Miscellaneous role of PLKs in Immunity

Innate immunity is the body’s natural defense system, present from birth, that serves as the first line of defense against infections and harmful substances. While much remains unknown about how PLKs influence innate immunity, a study by Yun et al. revealed that nucleotide-binding oligomerization domain 2 (NOD2), an essential immune sensor for triggering innate immune responses, functions as a tumor suppressor in melanoma (142). NOD2 inhibits the expression of thymidylate synthase (TYMS), which in turn reduces melanoma cells’ resistance to chemotherapy. TYMS was found to form a complex with PLK1, thereby activating the PLK1 signaling pathway (142). Further, the combination of the PLK1 inhibitor with chemotherapy agents exhibited a synergistic effect, effectively suppressing melanoma cell proliferation, migration, and autophagy. Thus, targeting NOD2 and TYMS/PLK1 axis could serve as an effective means of melanoma treatment (142). This study opens the door for further studies to explore the potential connections between PLKs and innate immunity, offering new avenues for therapeutic strategies. Furthermore, Shin et al. demonstrated synergistic effects of targeting both PLK1 and PD-L1 in a myeloid leukemia model. However, rather than employing a small molecule inhibitor to target PLK1, they utilized a peptide-loaded DC vaccine. This vaccine incorporated a PLK1 epitope (DSDFVFVVL), which was identified for its ability to generate a substantial number of long-lasting, antigen-specific CD8⁺ T cells with therapeutic potential when combined with PD-1--PD-L1 blockade (143).

4. Conclusion and Future Perspective

In recent years, immunotherapy has emerged as an excellent approach for cancer treatment, sparking growing interest in its potential (16). Amidst advances in immunotherapy, the PLKs are now garnering attention for their roles in modulating immune responses. While most of the research on PLK signaling has focused on the role of PLKs in cancer cell proliferation, recent studies highlight their significant involvement in cancer immunity. The PLK family has been linked to several immunoregulatory pathways such as type I IFN signaling, TGF-β signaling, etc., together demonstrating a key influence in tumor immunity and immunotherapy responses. PLK1 inhibitors are currently being evaluated in clinical trials for the treatment of various malignancies (13–15, 144–148). The synergy between PLK inhibitors and immunotherapies could unlock new, more effective treatment strategies, particularly for tumors resistant to traditional therapies.

PLK1 plays a critical role in modulating immune evasion mechanisms and influencing immune cell function. Its involvement in immune escape pathways positions PLK1 as a promising target to improve the efficacy of immunotherapies. PLK1 inhibition has been shown to induce ICD (36) and could sensitize cancer cells to FASL-mediated cell death (103). Moreover, PLK1 inhibition has been shown to increase cell-surface HLA expression in multiple human cancer types. PLK1 expression is negatively correlated with B cells, NK cells and tumor-infiltrating lymphocytes numbers in certain cancers, potentially influencing the sensitivity of tumors to immunotherapy (126). Additionally, in preclinical models, inhibiting PLK1 has already been shown to sensitize tumors to ICB, potentially leading to more durable anti-tumor T cell responses (97,110). In studies investigating PDAC (110) and NSCLC (111) models, PLK1 has been shown to have a negative correlation with PD-L1 expression. However, in other studies involving NSCLC (36,97) and breast cancer (37) models, PLK1 has been found to positively correlate with PD-L1 expression. Beyond the possibility that different signaling pathways may provide the context to determine how PLK1 regulates PD-L1 the composition of the TME may play a crucial role in shaping the preferred signaling pathways, potentially steering the regulation of PD-L1 in one direction or another depending on the cellular context. PLK1 was also found to be associated with the expression of numerous other immune checkpoints in multiple cancer types, suggesting a link between PLK1 and T cell exhaustion or regulatory T cell infiltration. Based on these findings, combining PLK1 inhibitors with CAR-T cell therapy in PLK1-high tumors may enhance the cytotoxic activity of CAR-T cells by weakening cancer cell resistance to FASL-mediated cell death, reducing inhibitory checkpoint expression in the TME, and preventing the secretion of T-cell-pacifying cytokines, together making it easier for engineered T cells to exert their therapeutic effects. It remains to be explored whether PLK1 inhibition can prevent the immunosuppressive TME niche associated with CAR-T therapy resistance.

Other members of the PLK family, including PLK2, PLK3, and PLK4, offer additional opportunities for modulating the tumor-immune landscape. As discussed earlier, PLK2 has been shown to support type I IFN responses (75), and ICD by supporting DAMP release during cell death (75). PLK2 also supports the inflammatory activation of DCs (117) and potentially other myeloid cell types. Thus, restoring PLK2 function may help reestablish an immunostimulatory TME, improving immune recognition of tumors and enhancing immunotherapeutic responses.

PLK3, plays a role in cellular responses to stress such as hypoxia and DNA damage (51). Furthermore, we have also discussed earlier how PLK3 plays a pro—apoptotic role in the DISC complex upon FAS signaling (101), and was correlated with immune checkpoint proteins PD-1, PD-L1, and CD80 (112). This role of PLK3 suggests that PLK3 has some contradictory roles in modulating the immune landscape and further studies are needed to fully delineate the potential of combining PLK3 targeted therapies with immunotherapy.

PLKs, especially PLK4, are responsible for centrosome duplication and maintaining genomic stability, which may influence tumor immunogenicity by inducing genomic instability. This genomic instability could also lead to the formation of neoantigens, thereby making the tumor more susceptible to immune surveillance. PLK4 inhibition has been shown to stimulate cGAS-STING (84) and trigger type I IFN production that in turn could increase the presentation of these neoantigens. Thus, PLK4 inhibition could enhance the effectiveness of immunotherapies, particularly in tumors with low baseline immunogenicity. PLK4 inhibition could also increase extracellular expression of proinflammatory cytokines, including IFNγ, TNFα and IL-1β, stimulating macrophage phagocytosis and increasing T cell mediated cytotoxicity by negatively regulating Treg development (84). These are critical for successful immunotherapy responses and anti-tumor immunity.

Although PLK5 is primarily expressed in the lung and brain tissues and contributes to neurodevelopment (64), its role in immune modulation remains unclear. Our lab identified PLK5 as a tumor suppressor across 18 cancer types (65). Its downregulation in gliomas (64), may promote immune evasion, while re-expression suppresses tumor growth, but that remains to be explored. Since its re-expression has been shown to have tumor suppressing function in brain cancer (64), exploring PLK5’s functions could uncover novel strategies for modulating the immune response in brain tumors.

Overall, the potential to combine PLK-targeting strategies with cancer immunotherapy could lead to more robust and durable therapeutic responses. Further studies are needed to validate these concepts in preclinical and clinical settings, but the synergy between PLK inhibition and immunotherapy holds significant promise for developing more effective, personalized treatments for cancer patients.