Cancer is one of the leading causes of death globally. It is a widespread disease that affects millions of people around the world [1]. Research is essential to understand the causes, risk factors, and patterns of cancer occurrence to develop effective prevention, early detection and treatment modalities [1]. Cancer cells have developed various strategies to evade the normal regulatory mechanisms that limit cell proliferation [2]. These phenotypic changes allow cancer cells to continue growing and dividing uncontrollably, contributing to tumor development and progression [2]. Cancer cells exhibit a characteristic alteration known as polyploidy. Polyploidy is associated with various solid tumors and hematopoietic cancers [3]. Polyploidy, an important cancer hallmark, contributes to cancer metastasis and therapy resistance (Fig. 1) [4].

Normally, cells in the human body contain a specific number of chromosomes organized into pairs, with two sets of chromosomes in each cell (diploid). Polyploidy occurs when a cell gains extra sets of chromosomes, resulting in three or more sets instead of the usual two [5]. In cancer cells, polyploidy is often associated with chromosomal instability and aneuploidy, which is the presence of an abnormal number or structure of chromosomes [6,7]. Polyploidy in cancer cells can arise through different mechanisms. During cell division, errors can occur, leading to an unequal distribution of chromosomes among daughter cells [8]. In some cases, the cell may fail to complete the final step of cell division called cytokinesis, resulting in a cell with double the usual number of chromosomes [8]. Alternatively, some cancer cells may undergo endoreplication, where DNA replication occurs without subsequent cell division, leading to polyploid cells [6,9].

Interestingly, polyploidy can confer both advantages and disadvantages to cancer cells [4,8]. Polyploid cells may be more resistant to apoptosis, or programmed cell death, and may be able to adapt more easily to environmental stresses [10]. In addition, polyploid cells may be more likely to exhibit enhanced genetic diversity and increased heterogeneity, providing a reservoir of cells with different genetic traits. This diversity may offer a survival advantage in challenging environments, allowing some polyploid cells to adapt and thrive even under adverse conditions [6]. However, polyploidy can cause cell death pathways to be activated through apoptosis caused by mitotic catastrophe, high maintenance costs, stress linked to polyploidy, and increased genomic and chromosomal instability [[11], [12], [13]]. The positive and negative effects of polyploidy on cancer cells might be due to the different levels of polyploidy resulting in different outcomes.

In animals, the significance of different levels of polyploidy has not been well established. Studies on polyploidy are not very well established in animals as it is more complex and they are more tolerant to genetic changes [14]. Polyploidy consists of more than two sets of chromosomes. An increased number of chromosomes lead to a genome duplication event that may contribute to epigenetic changes as well as genetic variations due to the loss and gain of DNA sequences [15]. The level of polyploidy varies with cell size, and higher polyploid cells exhibit reduced biomass [16].

Polyploidy has also been associated with cancer, aging and diabetes [17]. Mammalian organs, particularly the liver, brain, heart and eye, exhibit an increase in polyploidization with age [5]. We discuss recent insights about polyploidy in this review, including its generation, hallmarks, effects on cancer cells and new directions for polyploidy research. In the end, we proposed some of the experimental strategies that might answer some of the unanswered questions in the field of polyploidy regarding cancer.