Circular RNAs in metabolic reprogramming and therapy resistance in prostate cancer: emerging links to the tumor immune microenvironment

Therapy resistance in prostate cancer can emerge at different disease stages; castration-resistant prostate cancer (CRPC) is one clinically important state, and resistance to individual therapies may overlap but is not synonymous with CRPC. Metabolic reprogramming—including changes in glycolysis, de novo lipogenesis, glutamine metabolism, and mitochondrial homeostasis—has been implicated in prostate cancer progression and treatment resistance, although the strength of evidence varies across pathways and treatment settings. CircRNAs have been reported to modulate selected metabolic nodes in prostate cancer, although direct links between circRNA-associated metabolic changes and acquired therapy resistance are established only in a subset of studies. This review evaluates circRNAs as candidate regulators of selected metabolic processes in therapy-resistant prostate cancer. Mechanistically, individual circRNAs have been associated with selected metabolic changes through proposed miRNA-mediated interactions and, in some reports, peptide translation or protein scaffolding. These metabolic changes could, in principle, intersect with immunometabolic programmes such as lactate-associated suppression, lipid-linked macrophage states, and adenosine signalling; however, direct evidence that individual circRNAs control these immune-cell processes in CRPC remains limited, as detailed in the evidence tiers later in this review. Therapy-specific resistance networks are organised for enzalutamide/androgen deprivation therapy, docetaxel, PARP inhibitors and radiotherapy, distinguishing metabolism-dependent axes from signalling, mitotic, DNA-repair and exosome-propagated routes. Beyond mechanistic insights, circRNAs hold promise as non-invasive liquid-biopsy biomarkers and as druggable targets amenable to antisense oligonucleotide silencing, mimic delivery, and engineered circRNA vaccines. Major barriers to clinical translation include incomplete multi-therapy metabolic maps, sparse stage-resolved evidence across the hormone-sensitive→CRPC→neuroendocrine continuum, and unresolved delivery, safety, and regulatory challenges. Overall, current evidence supports circRNA-associated metabolic vulnerabilities as a promising preclinical research framework; however, circRNA-targeted metabolic interventions for therapy-resistant prostate cancer have not yet been clinically validated.