As with many other cancers, development, progression, and therapeutic response in prostate cancer (PCa) are significantly influenced by the cross-talk between cancerous cells and the surrounding tumor microenvironment (TME).¹ The TME is a highly complex system in which the tumor dynamically interacts with several host cells. The host components include stromal cells, extracellular matrix, endothelial and vascular cells, immune cells, and various soluble factors such as interleukin 6 and receptor activator of nuclear factor κB ligand.² Tumor cells within the TME can transform the extracellular matrix, stimulating angiogenesis and releasing growth factors and fibroblasts. As this dramatic stromal reaction increases, tumor aggressiveness rises, as indicated by the growth of the Gleason score, which represents an indicator of adverse clinical outcomes and recurrence.³ Indeed, histological studies demonstrated the infiltration of TME host immune cells in almost 90% of PCa specimens.⁴ The impact of the host immune system on cancer outcomes is very complex, as the innate and adaptive immune responses can both provide antineoplastic activity and enhance the propagation of carcinogenesis.⁵ For instance, cytotoxic T lymphocytes, commonly found in TME, secrete transforming growth factor-β, which both supports tumor growth and induces immune suppression.⁴ Therefore, manipulation of TME through inhibition or activation of specific molecular and cellular targets has been extensively studied in cancer therapy.

In PCa, the most investigated model of TME modulation is androgen deprivation therapy (ADT).⁶ Androgens lead to continuous activation of the androgen receptor in PCa cells and promote an immunosuppressive TME. ADT, by blocking the steroidogenesis, causes TME changes that appear to improve the outcome of external beam radiotherapy in terms of overall survival, with wide application in clinical practice.⁷

We strongly believe that this beneficial effect of TME manipulation could be applied to other PCa treatments. Therefore, TME could also become a key target of PCa focal therapies, which are ablative techniques using various technologies such as high-intensity focused ultrasound (HIFU), cryotherapy, photodynamic therapy (PDT), and irreversible electroporation (IRE). Each of these techniques has proven and inherent TME response that may be potentially enhanced by systemic therapy (see Figure). For instance, HIFU could provide an initial boost to the immunotherapeutic treatment of PCa.¹ The main effect of HIFU is thermal ablation by heating the tumor tissue above about 60 °C, resulting in coagulative necrosis and cavity creation.⁸ Thermal energy destroys cancerous tissue at the delivery site leading to a dramatic reduction of the microcirculatory bed; the higher the degree of reduction, the lower the probability of relapse.⁹ Besides, mechanical damage leads to the release of danger signals, such as damage-associated molecular patterns and the activation of heat shock proteins, with relevant changes in TME and immune response.¹ Heat shock proteins, such as HSP60, operate as molecular chaperones for exogenous antigens released during mechanical lysis. Antigens chaperoned by HSP60 may activate dendritic cells, leading to cytotoxic T cell (CTL) infiltration and tumor killing.¹⁰ The immunotherapeutic efficacy of HIFU has been studied in many types of cancer. Hu et al confirmed that HIFU enhances the infiltration of dendritic cells (DCs) into the TME of mice with colon adenocarcinoma, suggesting combining this procedure with other therapies to achieve better clinical outcomes.¹¹ Similarly, Ran et al demonstrated that HIFU increases cluster of differentiation (CD)3+ and CD4+ levels into TME and thereby suppresses tumor growth and progression of PCa mice.¹²

Another focal therapy for PCa whose effect is mediated by changes in the TME is cryotherapy, which deploys extremely low temperatures to induce both necrosis and apoptosis of tumor cells.^8,13 Oppositely to high-temperature ablation techniques, cryotherapy enhances the immune response by preserving tumor antigens and cytokines.⁴ A growing body of evidence suggests that necrosis, occurring mainly in the inner zone of the tissue, leads tumor cells to release damage-associated molecular patterns, triggering the immune response through the maturation of DCs and, consequently, CTL activation.⁴ However, apoptosis, which occurs mainly in the peripheral margin of the ablated organ, leads to a lack of secretion of danger signals, thus contributing to immunosuppression.¹⁴ Cerqueira et al investigated the TME changes before and after cryoablation showing a significant increase in CTLs.¹³ Furthermore, Ross et al examined cryotherapy combined with ADT and pembrolizumab, showing greater local control of low to intermediate risk disease.¹⁵ This study represents a great example of symbiotic action with ablation and systemic therapy.

Similarly, tumor cell necrosis is the goal of PDT, another focal therapy technique that deploys a specific wave length laser to trigger the photosensitizer and therefore generate reactive oxygen species.⁴ The immunological effect achieved by PDT is exacerbated in the TME, with the attraction of neutrophils, DCs, and macrophages, which activate CTLs and natural killer cells against cancerous cells and lead to the secretion of interleukin (IL)-1, IL-6, IL-8, IL-10, and IL-12.¹⁶ A preclinical mouse model of PCa suggested that combining PDT with an anticholinergic stimulating factor can inhibit myeloid tumor infiltration into TME, thus improving overall survival and reducing tumor growth.⁴

Additionally, IRE is a PCa focal therapy that employs electrical impulses to disrupt cell membranes.⁸ Due to this controlled, nonthermal energy delivery mechanism, vascular tissue can be preserved during IRE treatment, potentially increasing tumor infiltration of CD8+ CTLs⁸ into TME. IRE decreases regulatory T cells and myeloid-derived suppressor cells in the TME.¹⁷ Similarly, Burbach et al explored the combination of IRE and checkpoint inhibitors in PCa mice, which were associated with increased tumor-specific CD8+ T cells in the blood and TME.¹⁸

In summary, focal therapy outcomes as known today could be improved with a combination of energies and a systemic treatment option like ADT.⁵ The results of ongoing prospective studies (CHRONOS trial and ENHANCE trial) are awaited to confirm these findings.^19,20 Furthermore, novel approaches like the one explored in the RTIRE trial (NCT 05345444) will shed light on the potential combination of energy (IRE) and a lower dose of radiotherapy (32.5 Gy in 5 fractions). We feel that improved assessment and intervention of TME are critical to the development of effective focal therapies for PCa to consolidate cancer control without affecting functional outcomes.