Recent years have shown a continuous increase in the incidence of prostate cancer (PCa), especially in Europe, North America, and Oceania (1). An analysis of global trends in PCa indicates worsening health disparities between more developed [higher Social Development Index (SDI)] and less developed nations, with PCa burden showing a substantial increase in the Slope Index of Inequality (SII) from 329.90 in 1990 to 544.03 in 2021 (2). Although the Concentration Index (CI) shows a reduction in the concentration of PCa burden in SDI countries (from 0.44 in 1990 to 0.31 in 2021), the burden of PCa is more concentrated in these countries compared to low SDI countries. This can be attributed to healthcare access and screening facilities, and education about PCa. Furthermore, age-standardized rates (ASR) for PCa increased significantly worldwide, and the incidence rate is expected to increase notably in China between 2022 and 2046. With the population aged ≥65 years expected to reach 1.6 billion, age may become a primary determinant of PCa incidence in the future (3). These findings align with the rapidly aging population in Asia, which is expected to contribute to a continued rise in incidence and prevalence of PCa among Asian men (4). Historically, the incidence rate of PCa in Asian men has been observed to be lower compared to Western countries; a study by Siegel et al. (5) showed that Black men had a PCa incidence 1.3 times that of white men, and Asian men had a PCa incidence 0.7 times that of White men. Moreover, Down et al. (6) also came to a similar conclusion, and found that Black men had the highest PCa incidence at 24.7% (95% CI 23.3%, 26.2%); Asian men had the lowest at 13.4% (95% CI 12.2%, 14.7%); and the incidence for White men was 19.8% (95% CI 19.4%, 20.2%). However, the mortality-to-incidence ratio (MR/IR) of Asian men is higher, the 5-year survival rate is lower, and patients present with advanced-stage and metastatic disease (7). In 2011, a study showed that the MR/IR in Asia ranged from 0.3 to 0.6, whereas it was 0.12 in North America and 0.20 in Europe (8). The MR/IR (0.44) was significantly higher in Asian countries than in other places, except for Africa, suggesting that PCa poses a particularly significant health threat to the Asian population. In a study conducted by Zhang et al. (9), they discovered that PCa in Chinese and US populations exhibits notable differences in clinicopathologic features. Chinese patients tend to be older and harbor a higher proportion of poorly differentiated tumors with more advanced grade groups (Groups 4 and 5 were observed in 25% of Chinese patients compared to 17.11% of the USA cohort). In many Asian countries, PCa is frequently diagnosed at later stages, often after it has metastasized. This stands in stark contrast to countries like the United States, where a majority of PCa cases are diagnosed at an early, localized stage. Studies from China, for instance, reveal that over 60% of PCa patients are diagnosed at advanced stages, compared to the US, where 70% are diagnosed early (7). Additionally, the age-standardized 5-year overall survival rate for Chinese PCa patients (69.2%) is significantly lower than that observed in the United States (97.4%). These issues may be a result of late-stage diagnosis, limited access to prostate-specific antigen (PSA) screening, and less sensitive tests for Asian men (4, 10).

Furthermore, the PCa composition and characteristics in Asian men are different from other regions. Findings from a tumor marker analysis have identified distinct genetic variants and different frequencies of risk alleles for PCa in Asian men compared to Western populations, with a higher proportion of high-risk cases and different clinical and genomic characteristics (11). Studies suggest that specific gene mutations and variations linked to PCa are observed at different frequencies across racial groups (12). For example, studies have indicated that PTEN loss and TMPRSS2-ERG fusion are more prevalent in White and Black men than in Asian men. TMPRSS2-ERG fusion was discovered to have a prevalence of 50% in White men, but lower frequencies were reported in Asian populations (8-21%) (13). PTEN inactivation was reported in 70% of White men, and only 34% in Chinese patients. Again, current clinical tests cannot detect PCa patients with highly metastatic prostate cancer (mPCa), which accounts for about 30% of all newly diagnosed PCa in Central Asia (14). Consequently, advancements in diagnostic and therapeutic technologies and continued research into novel biomarkers are needed to offer promising avenues for improved detection and management of PCa.

PSA screening is a widely used PCa diagnosis biomarker currently recommended by international guidelines. Despite its wide application, PSA has limitations, particularly in the gray zone (4–10 ng/ml), with biopsy rates of 25% in China and 40% in America. Even with PSA levels over 20 ng/ml, the positive biopsy rate was reported as only 70% (10). Furthermore, in a landmark randomized controlled trial that recruited 61,000 men, approximately 76% of the biopsies performed for an elevated PSA level were false positives, illustrating PSA screening’s low specificity (15). This limitation can lead to increased prostate biopsies, which carry potential risks of infection ranging from 0.5% to 10.1% (16, 17). These findings show that PSA is an organ-specific marker but not disease-specific, and its elevation can be caused by factors other than PCa, such as non-cancerous inflammation and benign prostatic hyperplasia (4). This is an issue particularly in Asian men, as there is a higher rate of false positives in Asian populations compared to Western populations (6). Furthermore, some studies suggest that Asian men may have lower PSA levels overall, which could affect the accuracy of standard PSA cutoffs (4). Asian men in the UK were reported to have lower PSA levels at diagnosis compared to white men (18). Liu et al. (19) also found that serum PSA values in Chinese men older than 50 years were lower than those in other races, making the optimal PSA cutoff for PCa detection in the Chinese population unclear. Therefore, in PSA testing, it is necessary to fully consider racial differences and develop targeted screening and diagnostic strategies to improve outcomes and reduce overdiagnosis.

Prostate-specific membrane antigen (PSMA) is a type II transmembrane glycoprotein (20) ( Figure 1 ) commonly found to be highly expressed in prostate tumor cells, and its levels are about 100–1000 times higher than in normal prostate tissues and other tissues (21, 22). As the tumor cells proliferate, they utilize a greater quantity of folate to sustain their growth. This is facilitated by the folate hydrolase activity of PSMA (23). While PSMA can be found on non-cancerous prostate tissue and other tissues, its high expression and high specificity for PCa cells make it a valuable biomarker for diagnosis, therapy, and monitoring treatment response (24). PSMA can be targeted with radioactive tracers for positron emission tomography/computed tomography (PET/CT) imaging, as well as targeted therapy with radioactive isotopes. This approach is known as theranostics, a tool that utilizes radiopharmaceuticals to both image and treat cancer by targeting PSMA (25). PSMA PET/CT demonstrates superior detection rates for recurrences and small metastases even in patients with low levels of PSA, such as Asian men (26). Given the unique molecular genotypes of PCa in Asian men, PSMA theranostics could offer a new direction for precise diagnosis and treatment. However, there is currently a lack of clinical reporting on the Asian population, and related explorations are urgently needed.

PSMA exhibits higher expression levels in PCa cells, and these levels tend to increase with stage and grade of the tumor. This is particularly prominent in advanced PCa, metastatic disease, and when biochemical recurrence develops (BCR). This highly specific membrane surface expression feature makes it an extremely valuable diagnostic and therapeutic target (27). The structural distribution of the PSMA membrane provides surface accessibility for the molecules designed to interact with it, particularly the large extracellular domains and defined binding. This feature also allows for the development of diverse ligands, and high-affinity and specificity (28).

The core mechanism ( Figure 2 ) of diagnosis and treatment based on PSMA lies in the utilization of the specific binding ability of the designed molecules that target PSMA (29). At the diagnostic level, these designed molecules are conjugated with radioactive tracers (such as a Ga-68, positron emitter), which attach to the cancer cells, marking them for precise localization through PSMA PET imaging, thus achieving visual tracking of the primary lesion and metastatic lesions (30, 31). At the therapeutic level, the molecules are labeled with radioactive molecules, which could include Lu-177 (a β-particle emitter) or Ac-255 (a α-particle emitter). Once attached to PSMA, these radioactive molecules decay and deliver radiation directly to the cancer cells [(PSMA-targeted radioligand therapy (RLT)] (32). This action induces DNA double-strand breaks, which trigger cancer cell death while minimizing damage to surrounding healthy tissues (33).

The currently developed molecules that target PSMA include small molecules (PSMA-617 and PSMA-I&T), monoclonal antibodies (J591 antibody and antibody-drug conjugates), and RNA aptamers (34, 35). Through design optimization, these molecules can be specifically designed to bind to the intracellular or extracellular domains of PSMA (36). Table 1 provides a summary of the common clinical applications of PSMA-targeted ligands and radioactive molecules. With the advancements in clinical research, the development of PSMA-based theranostics has seen a shift from targeting the intracellular domain to targeting the extracellular domain, enabling internalization into viable cancer cells. This targets the limitations of earlier approaches that primarily targeted dying or necrotizing cells for the intracellular domain (56). PSMA-based theranostics has constructed a new diagnosis and treatment system integrating precise diagnosis and targeted therapy, providing a new solution for precise medical treatment of PCa, especially in the Asian population.

Elevated PSA levels can be caused by conditions other than PCa, such as benign prostatic hyperplasia (BPH) or prostatitis. This means a high PSA doesn’t always indicate cancer, thus causing a challenge to early and accurate diagnosis of PCa. Due to this low specificity, PSA testing can lead to unnecessary biopsies and treatments with potential side effects (57). Furthermore, PSA is not a structural or morphological feature, which means it cannot be directly used for PCa imaging (58). Therefore, the imaging typically relies on techniques such as CT, magnetic resonance imaging (MRI), and bone scans (BS), which can also have limitations when identifying subtle lesions. As a membrane-bound protein, PSMA can be targeted using radiolabeled molecules to visualize PCa cells. This means that PSMA imaging can often detect PCa that other imaging tests miss, particularly when PSA levels are low, thus providing more precise information (59). PSMA-based imaging tool, PSMA PET scan, utilizes a radioactive tracer that attaches to PSMA, allowing the scan to pinpoint the anatomic locations of the cells (60). It can also detect PCa metastasis to other parts of the body, as well as detect if the cancer treatment was effective. The effectiveness of the PSMA PET examination as a tool for the precise localization of tumor cells has been confirmed by studies showing a significant correlation between the level of PSMA uptake in the PSMA PET scan and the level of PSMA expression observed in the corresponding pathological sections.

Based on the above background, PSMA-targeted molecular imaging, particularly PSMA PET/CT, is reshaping the diagnostic pattern of PCa with superb advantages. PSMA PET/CT is more accurate and sensitive at identifying local, regional, and distant metastatic disease ( Figures 3 , 4 ), and this advantage is particularly significant in the diagnosis of BCR (61). Its enhanced sensitivity and specificity, particularly at PSA levels below 1 ng/ml, allow for early detection of recurrence and better guidance of treatment options (62). It is worth noting that PSMA PET/CT imaging uses two common types of PSMA tracers, namely Ga-68 and F-18. Between them, F-18 has a longer half-life than Ga-68, enabling it to offer slightly better spatial resolution (49). PSMA-based imaging can help in determining the extent of PCa, including lymph node involvement and distant metastases (63, 64). It is also highly sensitive in detecting BCR after treatment. These advantages can lead to more informed treatment decisions. Furthermore, and more importantly, it is less likely to produce inconclusive results compared to conventional imaging, and in some cases, may result in lower radiation exposure than the combination of CT and BS (65).

Following imaging, location, and staging of PCa facilitated by PSMA-based imaging, radioactive isotopes attached to a PSMA-targeted molecule are then delivered to the cancer cells, where they damage their DNA and lead to cell death. The PSMA-targeted molecules ensure that the radiation is delivered directly to the cancer cells, minimizing damage to the surrounding healthy tissues. The most commonly studied and used radionuclide to date is Lu-177. This radionuclide emits beta radiation, has a longer tissue range, and is used to treat smaller tumors and metastases, such as metastatic castration-resistant prostate cancer (mCRPC) (66). Ac-225 is also commonly used. It is an alpha-emitter; this radionuclide is more potent and has a higher therapeutic efficacy than Lu-177 due to its high linear energy transfer of the emitted alpha particles (67). This means that it induces double-stranded DNA breaks that are more difficult to repair. Both Lu-177 and Ac-225 hold significant promise for treating PCa in Asian men, particularly in advanced stages. In a prospective single-arm clinical trial, the application of ¹⁷⁷Lu-PSMA-I&T RLT showed favorable responses in East Asian patients with mCRPC (52). The patients tolerated the treatment well and experienced tumor remission with significant PSA decline. Furthermore, the development of PSMA-based theranostics that specifically target bone metastases is also vital, as Asian men can be diagnosed with late-stage PCa that may involve metastasis (4). Ra-223 is a relatively new drug that functions as a bone-seeking calcium mimetic. Its structure is similar to calcium, allowing it to be taken up and incorporated into the bone matrix, particularly in areas of high bone turnover, as present in bone metastases. Ra-223 is an alpha emitter, which means it delivers potent and localized alpha radiation that effectively kills cancer cells while minimizing damage to healthy surrounding tissues (68).

Of course, in clinical applications, attention should also be paid to the heterogeneity of PSMA imaging results. The performance and application effects of different PSMA PET markers vary among patients at different stages and classifications, and it is necessary to optimize the selection in combination with individual characteristics (69). However, PSMA imaging technology is evolving into an essential core instrument for the diagnosis and management of PCa, offering the dual benefits of accurate visualization and tailored diagnosis, particularly providing a groundbreaking approach to the diagnosis of advanced PCa in Asian men.

During the progression of PCa, most cases will ultimately advance to CRPC or mCRPC. As the final phase of PCa development, mCRPC is a significant contributor to mortality. Once the disease progresses to this phase, patients often have to rely on cytotoxic chemotherapy to prolong survival, but the prognosis is extremely poor. According to statistics, the 5-year overall survival rate of PCa patients in China (69.2%) is significantly lower than that in the United States (97.4%) (13). In addition to lifestyle, weak awareness of disease cognition, accessibility of screening programs and genomic differences, the proportion of advanced and new-onset metastases at diagnosis in Asian patients was significantly higher than that in the Western populations, making it difficult for traditional treatment strategies to meet the clinical needs of Asian PCa patients (7). Consequently, there is an urgent need for more effective new therapies to overcome these drawbacks.

Although the PSMA-targeted RLT has opened up new avenues for accurately targeting tumors by specifically recognizing the highly expressed PSMA on the surface of PCa cells, it does face certain limitations in clinical application. For example, the physiological overexpression of PSMA in salivary gland tissues leads to dose-limiting salivary gland injury during RLT (such as ¹⁷⁷Lu-PSMA-617 and ²²⁵Ac-PSMA-617), which severely limits the intensity of treatment (70, 71). RLT has dose-limiting toxicity (such as myelosuppression), and some patients are unable to complete the entire course of treatment due to hematological toxicity (72, 73). Moreover, the absorption efficiency of radioactive drugs by tumors varies greatly, potentially resulting in inconsistent therapeutic outcomes (74). In light of this, a systematic organization of innovative treatment strategies targeting PSMA, along with a prospective exploration of future developmental directions, can assist in generating new concepts for enhancing the current targeted treatment approaches for Asian PCa patients.

In the past decade, PSMA has emerged as a focal point in PCa research. As PSMA ligand technology continues to advance and mature, an increasing number of PSMA ligands are being utilized in clinical trials. Extensive research has demonstrated that PSMA imaging technology is capable of detecting lymph node metastases, bone metastases, and distant metastatic lesions that are challenging to identify using conventional imaging methods. This capability holds significant clinical implications for treatment planning and follow-up monitoring in patients with advanced PCa (110, 111). PSMA PET/CT is advancing at an unprecedented pace, marked by a substantial increase in the number of published studies and clinical trials. In accordance with the guidelines from the European Association of Urology (EAU), PSMA PET/CT is recommended for evaluating the likelihood of PCa recurrence and distant metastasis in patients with PSA levels exceeding 0.2 ng/ml who are candidates for salvage therapy. PSMA PET/CT is capable of accurately evaluating the size of the lesion and its relationship with surrounding tissues, thereby facilitating more precise tumor-nodes-metastasis (TNM) staging for PCa. This modality provides critical guidance for targeted biopsies, detection of BCR and metastasis, supports clinical decision-making processes, and enables effective evaluation of therapeutic efficacy (112, 113). However, it is important to highlight that the use of PET/CT in conjunction with PSMA imaging may not be appropriate for all patients with PCa. A comprehensive evaluation of the patient’s clinical stage, prior diagnostic and therapeutic history, as well as other pertinent factors, is essential. Future research should focus on thoroughly characterizing the patient population and clearly delineating the distinct features and requirements associated with different clinical stages. Moreover, domestic and international studies have yet to reach a consensus regarding the tangible benefits of relying solely on PSMA PET/CT for decision-making in PCa diagnosis and treatment (114, 115). Consequently, there is an urgent requirement for additional multicenter, randomized, controlled, and prospective studies to strengthen the scientific rigor and credibility of the findings.

PSMA-targeted therapy, particularly using RLT like ¹⁷⁷Lu-PSMA-617, has shown significant clinical benefits in reducing PSA levels and extending survival in patients with PCa. Nevertheless, clinicians must rigorously assess patient eligibility before initiating treatment to prevent unnecessary interventions. This assessment is vital because PSMA-targeted therapy, particularly PSMA-RLT, delivers radiation directly to PSMA-expressing cancer cells and therefore requires a high level of PSMA expression on the tumor to be effective. This necessitates the development of individualized treatment plans. Molecular profiling (such as gene mutations, aberrant signaling pathways), including genomics, transcriptomics, and proteomics, holds significant promise for refining patient selection and optimizing treatment efficacy in PSMA-targeted therapies for PCa (98). Additionally, dynamic treatment adjustments based on real-time PSMA molecular imaging (such as modifying dosages or combining with chemotherapy/immunotherapy based on changes in PSMA expression) will enable “real-time intervention”. Furthermore, additional in-depth investigations are required to assess the potential risk of damage to normal tissues resulting from high-dose PSMA drugs.

Key directions in mechanistic research related to PSMA’s role in the tumor microenvironment include investigating its involvement in angiogenesis and shaping immunosuppressive niches, which can inform combination therapies with anti-angiogenic or immunomodulatory agents (98). By understanding the diverse mechanisms of resistance including PSMA gene downregulation or compensatory activation of pathways (like androgen receptor reactivation) and developing targeted strategies, particularly by using combination therapies (integration of androgen receptor antagonists), it is hoped that long-term outcomes for patients with advanced PCa can be significantly improved.

PDT and PTT have demonstrated substantial efficacy in preclinical studies and have been successfully integrated with chemotherapy and other technologies. Nevertheless, the majority of these researches remain at the preclinical stage, and there is an urgent need to accelerate their clinical translation. In addition, the PSMA-RGS technology can be employed for PSMA ligand-guided precision surgery. However, the radiation effects on both the operator and the patient must be comprehensively evaluated. In this regard, PSMA-FGS serves as an effective and feasible alternative solution. In recent years, the rapid advancement of near-infrared fluorescence second window (NIR-II, wavelength range 900–1700 nm) technology has enabled significant progress in NIR-II fluorescence imaging for PCa marker targets and its guidance applications in surgical procedures. This approach demonstrates superior advantages in terms of signal-to-noise ratio, real-time imaging, multi-modality, and application scope compared to traditional optical imaging and near-infrared fluorescence first window (NIR-I) imaging. These enhancements provide a promising foundation for achieving complete tumor resection during surgery (109, 116–118). Therefore, PSMA-FGS offers a novel research avenue for the precision therapy of PCa and demonstrates significant potential for clinical translation.

In summary, the theranostic strategy targeting PSMA is anticipated to become one of the standard approaches for the routine screening and management of PCa in the future ( Figures 3 , 4 ).