Germline and somatic mutation of PTEN is known to contribute to many cancers, highlighting the importance of this tumour suppressor in cancer initiation, progression, and metastasis. Germline mutations of PTEN are the cause of four autosomal dominant inherited syndromes: Cowden syndrome (CS) [21], Bannayan–Riley–Ruvalcaba syndrome (BRRS) [22,23], Proteus syndrome (PS), and PS-like syndrome [24], which share common features, including the development of multiple benign hamartomas, and are all classified under the umbrella term of the PTEN hamartoma tumour syndromes (PTHSs) [12,13]. PTHS patients have an increased lifetime risk of developing specific malignancies, mainly breast cancer (approximately 80%) [12,13], thyroid cancer (approximately 30%) [12,13], renal cell carcinoma (approximately 34%) [13], endometrial cancer (approximately 28%) [13], and colorectal cancers (approximately 9%) [13]. In individual PHTS patients exhibiting clinical phenotypes, PTEN germline mutations are reported in 25-85% of CS patients [21,25,26], 60% of BRRS [21,22,25,27], up to 20% of PS [28], and between 50 and 67% of PS-like syndrome patients [24]. Interestingly, germline PTEN mutations are also associated with a subset of patients with autistic behaviour and extreme macrocephaly [29].

Somatic mutations of PTEN are frequently associated with tumorigenesis with somatic alterations of PTEN being described in over 50% of cancers of various types [30]. PTEN somatic mutations are most prevalent in prostate cancer [31], endometrial cancer [32], melanoma [33,34], non-small-cell lung cancer [35,36], kidney [37], breast cancer [38], and glioblastoma [39]. PTEN somatic alterations include the complete loss or inactivation of one allele (functional haploinsufficiency) due to point mutations and/or deletions and/or epigenetic silencing through hypermethylation of the PTEN promoter, which is characteristic of some advanced and metastatic cancers [1,4]. Deletion of both alleles of PTEN occurs at a lower incidence but is seen mostly in metastatic breast cancer, melanomas, and glioblastomas [1,4,40]. In contrast, a recent study showed that patients with high PTEN expression levels in endometrial cancer had low tumour malignancy, decreased cancer cell proliferation and a better prognosis [41]. There are different mechanisms of PTEN loss or inactivation, with some being more prevalent in specific tumour types (Table 1) [30,42,43].

The effect of the loss or mutation of PTEN is not dichotomous, and subtle changes in PTEN cellular levels have been shown to lead to deleterious consequences relating to tumour incidence, penetrance, and aggressiveness in several epithelial cancers [11,78]. In the hypomorphic transgenic Pten mouse, it has been shown that in susceptible organs such as the prostate, PTEN protein expression levels need to reach dramatically low levels (reduced by 70% compared to normal levels) to initiate tumorigenesis, however, in the mammary glands, a more subtle reduction (reduced by 20% compared to normal levels) can initiate tumorigenesis [78]. Thus, PTEN does not follow the ‘two-hit’ paradigm or stepwise model of tumour suppressor gene function but rather presents a new continuum model of tumorigenesis whereby tumorigenesis occurs in an incremental dose-dependent manner [11,78]. This has been evidenced in gastric cancer, where PTEN expression was shown to gradually decrease with increasing gastric cancer progression [79].

There are several recent studies that have explored the relationship between PTEN loss and tumour immunity, showing PTEN loss contributes to alterations in the tumour microenvironment (TME) to produce an immunosuppressive niche. The evidence suggests that PI3K signalling may influence the composition and functionality of the TME, thereby modulating the immune response in cancer. Vidotto et al. (2023) analysed PTEN copy number in 9793 cases from 30 tumour types, derived from the Cancer Genome Atlas, and showed that reduced tumour PTEN expression occurs with hemizygous loss leading to tumour anti-cancer immune responses [80]. In another integrative analysis of TCGA samples, Lin et al. (2021) found that both PTEN loss and activation of the PI3K pathway were associated with reduced T-cell infiltration and an enhanced immunosuppressive status in multiple tumour types [81]. Overall, the effect of PTEN loss of function in the different cellular compartments swings the balance towards an immunosuppressive TME [82]. There was also a correlation between PTEN loss and poor response to immunotherapy [81]. Interestingly, PTEN loss has also been shown to promote resistance to therapy in breast cancer. Reducing PTEN levels in breast cancer cells conferred resistance to trastuzamab, and patients with PTEN-deficient breast cancers showed poorer therapeutic responses with this drug. Thus, PTEN deficiency has become a good predictor for trastuzumab resistance [83,84]. Reduced PTEN expression has been shown in vivo, in mouse models, to be due to specific miRNAs. An example being PTEN as a target of mi-R22 in breast and prostate cancers, which have been shown to have a strong influence in a cancer immune TME, playing a role in cancer initiation, progression, and metastasis [85]. Importantly, in vivo, knockdown of miR-22 appears to invoke tumour resistance in an immunocompetent environment [85]. These findings open new avenues for immuno-targeting, such as modulating miRNAs targeting PTEN, hence improving the efficacy of immunotherapy and overcoming therapy resistance.