89 Prostate cancer remains one of the leading causes of cancer-related deaths globally, with its advanced stages posing significant challenges to current treatments. Despite promising advancements in immunotherapy for various cancers, prostate cancer has largely evaded the benefits due to its immune-cold tumour microenvironment. This condition refers to its resistance to immune cell infiltration, which is critical for immunotherapy success. The findings were published in the journal Trends in Endocrinology & Metabolism. A recent review highlights the pivotal role of tumour-intrinsic genetic and epigenetic factors in creating this immune-cold environment. Genetic alterations in tumour suppressor genes such as PTEN and TP53 have been shown to drive an immunosuppressive microenvironment. These mutations lead to an increase in immunosuppressive cells and proteins, further blocking immune responses. Loss of PTEN, for example, is associated with poor immune cell infiltration and a heightened resistance to immune checkpoint inhibitors, key agents in immunotherapy. Similarly, dysregulation of transcription factors like the androgen receptor (AR) has been implicated in exacerbating this resistance. Androgen deprivation therapy, a standard treatment for advanced prostate cancer, inadvertently promotes the development of castration-resistant prostate cancer. This resistant form often displays heightened immunosuppressive features, including an increase in exhausted T cells and immune checkpoint proteins such as PD-L1. Addressing these genetic and epigenetic changes is crucial to shifting the tumour microenvironment from immune-cold to immune-hot, a state conducive to successful immunotherapy. The study also highlights the promise of targeting histone modifiers like EZH2, which influence tumour immune responses through gene expression regulation. Inhibiting EZH2 has been shown to increase immune cell infiltration and improve responses to immunotherapy in preclinical models. Combining these inhibitors with immune checkpoint therapies may pave the way for more effective treatments. Further complicating treatment, the immune-cold nature of prostate cancer is highly context-dependent. The tumour microenvironment evolves across different stages and types of the disease, such as neuroendocrine prostate cancer, which exhibits minimal immune infiltration. Personalised approaches that consider the patient’s unique tumour characteristics and genetic makeup are essential to developing effective therapeutic strategies. While these findings offer a pathway to improving outcomes, significant challenges remain. Identifying optimal combinations of therapies, understanding the timing of interventions, and addressing tumour heterogeneity are among the hurdles to integrating these approaches into clinical practice. However, the growing understanding of tumour-intrinsic regulators and advances in single-cell technologies provide hope for tailoring immunotherapies to the complexities of prostate cancer.