Skin cancer remains a significant global health challenge, with rising incidence and associated mortality in late-stage and drug-resistant cases. This underscores a continuing need for more effective novel therapeutic options that can be utilized for efficient management of skin cancers. A promising approach involves exploiting novel targets, which are dysregulated in skin cancer, either alone or in combination with existing therapeutics. Among these, polo-like kinases (PLKs), a family of serine/threonine kinases, has emerged as promising candidates due to their essential role in cell cycle and maintaining genomic stability, key hallmarks of cancer. Within this family, polo-like kinase 4 (PLK4) stands out as a structurally distinct member and the master regulator of centriole duplication, ensuring this process occurs only once per cell division. Dysregulation of PLK4 can disrupt genomic integrity, contributing to tumorigenesis, thus making it a promising target for cancer management. Notably, PLK4 is frequently overexpressed in several cancers, including skin cancer, and its precise role in skin cancer is an area of current investigation. Further, several small-molecule PLK4 inhibitors such as centrinone, YLZ-F5, CFI-400945, and RP-1664 have demonstrated efficacy in targeting PLK4. Among these, CFI-400945 has advanced to clinical trials, where it has shown modest anti-cancer activity. In this review, we provide a comprehensive overview of the known functions of PLK4 in skin cancer. Additionally, we discuss potential mechanistic insights into PLK4′s involvement in skin cancer progression by extrapolating evidence from studies in other cancer types including colorectal cancer, thyroid cancer, lymphomas, leukemia, etc., while identifying gaps for future research.

Prolonged and chronic exposure to UV radiation is a risk factor for multiple skin cancers. As the incidence of UV‐associated skin cancers continues to rise, there is a pressing need for a deeper understanding of the underlying mechanisms driving these pathologies. Polo‐like kinases (PLKs), a family of enzymes consisting of five members (PLK1‐PLK5), have been implicated in various aspects of skin carcinogenesis. The inhibition of PLKs is currently being explored as a potential strategy for cancer management. While much of the research has predominantly concentrated on PLK1, recent studies are increasingly shedding light on the role of other PLK family members, given their growing importance in cancer progression. Understanding the relationship between UV‐associated skin cancers and PLKs could open new avenues for more effective management of skin cancers. In this review, we discuss the critical mechanisms associated with UV and PLKs in causing skin cancers, followed by the potential role of UV in modulating PLKs in different skin cancers. We also examine the prospect of targeting PLK signaling to enhance therapies for UV‐induced skin cancer and improve patient responses. So far, there is not enough literature focused on the simultaneous effects of PLKs and UV using skin cancer models, emphasizing the need for further research to completely understand the role of PLKs in UV‐induced skin carcinogenesis.

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 (PLK), 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. Although 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, transforming growth factor beta (TGFβ) signaling, and FAS/FASL signaling. Although 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 and enhance clinical responses.

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 (PLK), 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. Although 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, transforming growth factor beta (TGFβ) signaling, and FAS/FASL signaling. Although 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 and enhance clinical responses.

Supplementary Table S1. List of PLK inhibitors in clinical trials for the treatment of various malignancies, along with the status of the clinical trial.