Prostate cancer (PCa) is one of the most common cancers in European males. Although therapeutic approaches have changed in recent years, and several new drugs have been approved by the Food and Drug Administration (FDA), androgen deprivation therapy (ADT) remains the standard of care. Currently, PCa represents a clinical and economic burden due to the development of resistance to ADT, paving the way to cancer progression, metastasis, and to long-term side effects induced by ADT and radio-chemotherapeutic regimens. In light of this, a growing number of studies are focusing on the tumor microenvironment (TME) because of its role in supporting tumor growth. Cancer-associated fibroblasts (CAFs) have a central function in the TME because they communicate with prostate cancer cells, altering their metabolism and sensitivity to drugs; hence, targeted therapy against the TME, and, in particular, CAFs, could represent an alternative therapeutic approach to defeat therapy resistance in PCa. In this review, we focus on different CAF origins, subsets, and functions to highlight their potential in future therapeutic strategies for prostate cancer.

Glial-origin brain tumors, particularly glioblastomas (GBMs), are known for their devastating prognosis and are characterized by rapid progression and fatal outcomes. Despite advances in surgical resection, complete removal of the tumor remains unattainable, with residual cells driving recurrence that is resistant to conventional therapies. The GBM tumor microenviroment (TME) significantly impacts tumor progression and treatment response. In this review, we explore the emerging role of purinergic signaling, especially the P2X7 receptor (P2X7R). Due to its unique characteristics, it plays a key role in tumor progression and offers a potential therapeutic strategy for GBM through TME modulation. We discuss also the emerging role of the P2X4 receptor (P2X4R) as a promising therapeutic target. Overall, targeting purinergic signaling offers a potential approach to overcoming current GBM treatment limitations.

Prostate cancer (PCa) is the second leading cause of cancer-related mortality in men, with bone representing the predominant metastatic site. Progress in treating bone metastatic disease is hindered by lack of preclinical models that faithfully recapitulate the bone microenvironment while reducing animal use. Biomaterial-based platforms offer a powerful alternative, enabling controlled reconstruction of bone composition, metabolic cues, and tumour-matrix interactions. A defining feature of PCa progression is citrate-centred metabolic reprogramming. While healthy prostate epithelial cells accumulate and secrete citrate, aggressive PCa cells import and oxidise it to sustain growth. Given the citrate-rich nature of prostate tissue and bone, we hypothesised that bone-derived citrate may be exploited by metastatic PCa cells to support bone colonisation. We developed a bone-mimetic platform by functionalising hydroxyapatite nanocrystals with citrate (HA-Nc-Cit) and incorporating them into collagen-based 3D matrices within a microfluidic chip. HA-Nc-Cit were characterised and citrate release quantified. Metastatic PCa cells were analysed for migration, viability, clonogenicity, metabolic reprogramming, and citrate transporter expression. HA-Nc-Cit released physiologically relevant citrate levels. Citrate exposure enhanced migration of androgen-independent PC3 cells and, within collagen type I-enriched matrices, increased clonogenicity, upregulated plasma membrane citrate transporter, suppressed glycolysis, and promoted lactate fermentation and mitochondrial biogenesis, without affecting respiratory chain or lipid metabolism. Citrate buffering supported PC3 clonal survival under acidic stress mimicking tumour acidification. In conclusion, citrate-functionalised HA-Nc promotes bone tropism of aggressive PCa by enhancing migratory potential, modulating tumour metabolism, and buffering extracellular acidification, underscoring the value of biomaterial-based models for studying bone-tumour interactions and guiding therapeutic development. STATEMENT OF SIGNIFICANCE: PCa often spreads to bone, but current models fail to capture the complexity of bone environment, limiting progress in treatment development. In this study, we created a 3D bone-mimicking system by binding citrate, a key bone metabolite, to hydroxyapatite nanocrystals mimicking bone mineral and embedding them in collagen-based matrices. This platform shows how citrate not only fuels PCa cells but also buffers the acidic conditions they create, making bone more prone to tumour growth. Unlike traditional models, such biomaterial-based approach combines mineral chemistry, metabolism, and pH regulation in a controlled setting. This work introduces a tool to study bone-tumour interactions and guide future therapies for metastatic PCa.

In the original publication [1], the reference 22 was retracted and it has been replaced the new reference as below:22