Immunotherapy research for prostate cancer from 2000 to 2024: a bibliometric and visualization analysis

Introduction

Prostate cancer is the second most common malignant tumor among men worldwide, and its incidence and mortality rates are on the rise, particularly as the population ages. Data indicate that American men have the highest incidence of prostate cancer (1). In contrast, in China, approximately 70% of patients are diagnosed at a locally advanced or metastatic stage, leading to a significantly lower survival rate compared to those in Europe and the United States (2). Traditional treatments, such as surgery, radiotherapy, and hormone therapy, all aim to cure the disease; however, their effectiveness against metastatic castration-resistant prostate cancer (mCRPC) is limited. Historically, the 5-year survival rate has only increased from 30% to nearly 40% (3,4). In recent years, immunotherapy has emerged as a key focus for overcoming treatment limitations, due to its precise targeting and manageable side effects. Since 2000, immune checkpoint inhibitors (ICIs) [including programmed death receptor 1 (PD-1)/cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) antibodies], personalized neoantigen vaccines, and chimeric antigen receptor T (CAR-T) cell therapy have sequentially entered clinical research phases. Nevertheless, prostate cancer’s “cold tumor” characteristics—less immune cell infiltration and a low tumor mutation load—have resulted in a long-standing single-drug response rate of less than 10% (5,6).

Immunotherapy has emerged as an innovative treatment approach for prostate cancer, particularly for advanced and drug-resistant forms such as mCRPC. The primary strategies encompass activated lymphocyte therapy, NK cell therapy, and CAR-T/TCR-T cell therapy, among others (7,8). Within these strategies, gene-modified T cell therapy, including CAR-T targeting PSMA, has garnered significant research interest due to its potential to surmount the “cold tumor” characteristics of prostate cancer, which are marked by low antigen presentation and limited T cell infiltration (3,9). Initial clinical trials have demonstrated notable progress.

Bibliometrics utilizes a collection of mathematical and statistical techniques to evaluate and quantify the volume and quality of books, articles, and various other forms of publications (10). Tools such as CiteSpace and VOSviewer, acknowledged as the most powerful and widely used visualization tools, facilitate the tracking and analysis of research trends and emerging hotspots within specific fields (11,12). In this study, bibliometrics was applied to systematically organize and analyze the relevant literature on prostate cancer immunotherapy from the past two decades. The developmental trajectory of prostate cancer immunotherapy was clarified through visual means, with the goal of predicting future research trends and providing theoretical insights for research in this area. We present this article in accordance with the BIBLIO reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-414/rc).

Methods

Data source and search strategy

We retrieved the data from the Web of Science Core Collection (WoSCC) at Qinghai University Library on February 20, 2025.The search formula is TS = (“Prostat* Cancer” or “Prostat* Neoplasma*”) and (“Immunotherap*”), The date range spans from January 1, 2000, to December 31, 2024, and the literature type is specified as “English” and “articles” (Figure 1). The exhaustive search strategy employed by WoSCC is detailed in the supplementary document (Appendix 1).

Figure 1 Publications screening flow chart. WoSCC, Web of Science Core Collection.

Data analysis

VOSviewer (version 1.6.18) is a bibliometric analysis software capable of extracting key information from a vast array of publications (13). It is frequently utilized to construct networks of collaboration, co-citation, and co-occurrence (14,15). In this study, the software was primarily used to perform the following analyses: country and institution analysis, journal and co-cited journal analysis, author and co-cited author analysis, and keyword co-occurrence analysis. Within the maps generated by VOSviewer, each node represents a single entity, such as a country, institution, journal, or author. The size and color of the nodes indicate the quantity and classification of these entities, respectively. The thickness of the lines connecting nodes signifies the extent of collaboration or co-citation (16,17).

CiteSpace (version 6.1.R1), a bibliometric analysis and visualization tool developed by Professor Chen C (18,19), is utilized in this study to create a double-map overlay of periodicals and to conduct an in-depth analysis of the citation frequency of literature. Furthermore, the topic evolution analysis is performed using the R language package “Bibliometrix” (version 4.1.2) (https://www.bibliometrix.org), and the global distribution network of prostate cancer immune quality publications is constructed (20). This study also employs Microsoft Office Excel 2019 for quantitative analysis.

Results

Trends and annual publications

As depicted in Figure 1, an initial search yielded a total of 5,200 relevant literatures, out of which 2,774, dating from 2000 to 2024, were ultimately selected following the application of screening criteria. This subset includes 2,774 articles. Figure 2 illustrates the upward trend in the annual number of publications related to prostate cancer immunotherapy: increasing from 20 in 2000 to 188 in 2024. According to the WoSCC database statistics, the total number of citations for these 2,774 papers reached 130,344, with each paper averaging 46.99 citations.

Figure 2 Annual number of publications on endocrine therapy for prostate cancer, published between 2000 and 2024.

Contributions of states and institutions

The publications encompass research outcomes from 76 countries and 3,267 institutions. The leading ten nations are primarily situated in Asia, Europe, and North America (Table 1). The United States tops the list with 1,368 publications, constituting 44.42% of the total, followed by China with 651 publications (21.14%), Germany with 200 (6.49%), and England with 173 (5.62%). The combined output from China and the United States represents 65.56% of the top ten countries’ total, signifying their significant influence. The tabular analysis of institutions reveals that the total link strength of all institutions exceeds 0. Upon examining the total link strength of all publishing institutions, it is observed that the minimum value is 1. This suggests that a multi-center collaborative research ecosystem has been established in the field of prostate cancer immunotherapy. Figure 3 presents the visualization and analysis results of the national cooperation network, which comprises 77 nodes and 541 connections, visually demonstrating international collaboration patterns. In this framework, the sizes of the nodes reflect publication volumes, while the thickness of the lines indicates partnership intensity. Analysis of national centrality reveals that the United States demonstrates the highest mediating centrality (0.30), establishing its prominence in this domain.

Figure 3 National/regional networks of partnerships.

Refer to Table 1 for a list of the top 10 research institutions in this field from 2000 to 2024. Notably, the National Cancer Institute [130], Memorial Sloan Kettering Cancer Center [91], and the University of California, San Francisco [80] rank among the top three, signifying their significant influence in the field. In the density map of research institutions, the National Cancer Institute, Memorial Sloan Kettering Cancer Center, and other institutions located in the yellow area are identified as prominent institutions in this field, as depicted in Figure 4.

Figure 4 Research institute density map for the years 2000–2024.

Journals and co-cited journals

Publications on the immunotherapy of prostate cancer have been published in 628 journals. Cancer Immunology Immunotherapy has published the most papers (n=116), followed by The Prostate (n=113) and Clinical Cancer Research (n=110). Among the top 10 journals, Clinical Cancer Research has the highest impact factor (IF =10.86), followed by Cancer Research (IF =9.465). Subsequently, we screened out 36 periodicals and constructed a periodical network based on the criterion that the number of related articles was at least 15 (Figure 5A). Figure 5A shows that Cancer Immunology Immunotherapy has an active citation relationship with Clinical Cancer Research and The Prostate.

Figure 5 Visualization of journals (A) related to endocrine treatment research of prostate cancer and co-cited journals (B).

As indicated in Table 2, among the top 10 journals ranked by citation count, three have received over 5,000 citations. Cancer Research leads with 5,846 co-citations, followed by Clinical Cancer Research with 5,233, and the Journal of Clinical Oncology with 5,052. Furthermore, the journal with the highest impact factor is the New England Journal of Medicine, with an IF of 158.5, succeeded by The Journal of Experimental Medicine with an IF of 15.3. By applying a filter for journals with a minimum co-citation of 400, a co-citation network was constructed (refer to Figure 5B). As depicted, Cancer Research exhibits positive co-citation relationships with Clinical Cancer Research, the Journal of Clinical Oncology, and the New England Journal of Medicine, among others.

The double mapping superposition of periodicals depicts the citation relationships between periodicals and their co-cited counterparts, with the cited periodical cluster on the left and the co-cited periodical cluster on the right (20). As shown in Figure 6, the green path represents the primary citation pathway. Literature published in the fields of Molecular/Biology/Genetics/Health/Nursing/Medicine is primarily cited by literature in Molecular/Biology/Immunology, while literature in Molecular/Biology/Genetics is also cited by publications in Medicine/Medical/Clinical and other journals.

Figure 6 Dual image overlay of endocrine therapy research journals for prostate cancer.

The author’s contribution

Table 3 lists the 10 most prolific authors in the field of endocrine therapy for prostate cancer. Gulley JL from the National Cancer Institute ranked first (n=50). Followed by the University of Wisconsin Mcneel DG (n=44) and DRAKE CG (n=42) from Columbia University. In addition, Kantoff PW, Small EJ and Rosenberg SA are the top three authors with the most citations (704, 571 and 360 respectively).

We have established a collaborative network that includes authors with ten or more published papers (Figure 7A). Authors such as Gulley JL, Drake CG, Mcneel DG, Fong L, and Schlom J have the largest nodes due to the high relevance of their publications. Additionally, we have observed close cooperation among numerous authors. For example, Gulley JL collaborates closely with Schlom J, Madan RA, and Arlen PM; Schlom J has also actively cooperated with Hodge JW, among others. A visual diagram illustrating citation superposition has been created using VOSviewer software (Figure 7B), with the minimum citation threshold for authors set at 100. Ultimately, 55 authors who met this threshold were identified. It is evident that Kantoff PW, Small EJ, Rosenberg SA, and Gulley JL have significantly contributed to the field of immunotherapy research for prostate cancer.

Figure 7 Key authors in prostate cancer endocrine therapy research. (A) Collaboration network shows authors who are actively publishing papers. (B) Influence network highlights authors frequently cited together, indicating their impact on the field. Circle size: author’s total publications; line thickness: collaboration strength.

Co-cited references

Over the past twenty-five years, a total of 80,708 articles have reported on immune research related to prostate cancer. Table 4 presents the top 10 studies on immunotherapy for prostate cancer, which have been cited 1,976 times. The evolution of a research field, including its rise, development, and decline, can be observed through the clustering of co-cited documents. The greater the number of documents in a cluster, the more significant the field represented by that cluster. Figure 8 traces the evolution of key research themes through highly co-cited publications, with node size representing citation impact and colors indicating thematic clusters over time [2000–2024].

Figure 8 Prostate cancer endocrine therapy: topic clustering of highly cited publications.

Visual mapping of keyword frequency

Keyword frequency indicates a research hotspot within a field, and keywords with high centrality signify a milestone in that field. Table 5 presents the top 10 high-frequency and high-centrality keywords.

The focus of this research field is on high-frequency keywords. High centrality keywords indicate the status and influence of related content within the research domain, whereas co-occurrence keywords, derived from selected literature, highlight the research hotspots and development trends in a specific field. Figure 9A depicts the symbiotic keywords extracted from the 2,774 manuscripts included in this study.

Figure 9 Evolution of research hotspots in prostate cancer therapy. (A) Current high-impact keywords: Node size = keyword frequency (2000–2024). (B) Emerging trends change over time, with keyword clusters labeled by core themes (e.g., Cluster #1: biochemical recurrence).

Figure 9B illustrates a timeline diagram of keyword clustering, where seven cluster names denoted by # symbolize the foundational knowledge of the prostate cancer endocrine therapy research field and its chronological evolution. The connecting lines in the diagram indicate that two keywords co-occur within the same article. The average silhouette score(s) is typically utilized to assess the quality of clustering. Generally, a silhouette score greater than 0.5 suggests that the clustering is reasonable, and a score of 0.7 signifies that the clustering is highly reasonable. We have derived seven clusters with silhouette scores exceeding 0.7, indicating that the results are highly reasonable. Through such clustering analyses, current prominent research hotspots can be identified. In recent years, these hotspots have centered predominantly on immunotherapy, with core keywords encompassing “immune checkpoint inhibitors”, “PD-1/PD-L1”, “CTLA-4”, and “tumor-infiltrating lymphocytes”. Furthermore, this research field exhibits close associations with DNA damage repair-targeted therapies, featuring relevant keywords such as “PARP inhibitors”, “Orelaparib”, and “Lukaparib”.

Visual mapping of keyword appearance

Explosive keywords reflect the research frontiers in different periods. Figure 10 shows the 25 keywords with the highest explosion rate between 2000 and 2024. The red line indicates the time period of keyword explosion, and the blue line represents the time interval (21).

Figure 10 Top 25 keywords ranked by citation burst strength, reflecting surges in scientific attention.

Discussion

General information

The analysis of papers related to prostate cancer immunotherapy from 2000 to 2024 reveals a dynamic balance, with an average of 110.96 papers published annually. The citation count for these papers has been on the rise, suggesting that they are frequently referenced. These two observations indicate a sustained interest in prostate cancer immunotherapy, with a substantial number of articles holding research potential.

Upon analyzing the performance of countries and institutions in the fields of immunotherapy and related research on prostate cancer, it was found that the top ten countries contributed a total of 3,080 articles. The United States led with 1,368 articles, followed by China with 651, Germany with 200, and England with 173 articles. These figures highlight the leading roles of these countries in this research area. Further analysis of national cooperation networks indicates that countries have engaged in active cooperation and exchanges, particularly the United States, which has forged solid cooperative ties with China and European nations. From the perspective of institutions and departments, the top ten institutions and departments published 707 articles, which accounted for 11.4% of the total. Among these, the top five institutions are the National Cancer Institute [130], Memorial Sloan Kettering Cancer Center [91], University of California, San Francisco [80], University of Washington [67], and Johns Hopkins University [64]. Examining the cooperative networks of American countries and institutions confirms the prominent position of the United States in the field of prostate cancer immunotherapy. There is frequent collaboration among most countries, and those that frequently publish in prostate cancer immunotherapy research often assume core roles in this field, emphasizing the significant potential of cooperative research in these countries for the future. Overall, this research topic remains a hot area, with the number of related publications maintaining a dynamic balance.

In the citation network among academic journals, the journals being cited typically embody the most recent advancements within their respective research domains, while the citing journals form the foundational knowledge base of the discipline. Our comprehensive analysis of journal citations has revealed three primary citation flows: the fields of “molecular biology and genetics” and “health, nursing, and medicine” are increasingly converging with “molecular biology and immunology” as well as “medicine and clinical practice”. The focus on immunotherapy for prostate cancer is undergoing continuous evolution, reflecting significant shifts in scientific perspectives. While research in molecular biology remains active, contemporary studies highlight the critical importance of immunology and its clinical implications, which are now more pronounced than in previous investigations.

The analysis by the authors reveals that Gulley JL has the highest number of published articles, totaling 50, followed by Mcneel DG with 44, Drake CG with 42, Fong L with 39, and Schlom J with 35. Kantoff PW, Small EJ, and Rosenberg SA are the top three authors in terms of total citations, with 704, 571, and 360 citations respectively. High-productivity authors frequently maintain stable cooperative relationships with other authors.

The analysis of co-cited documents indicates that the research conducted by Kantoff et al. is the most frequently referenced work. This study provides an in-depth examination of immunotherapy strategies for castration-resistant prostate cancer. A double-blind, placebo-controlled, multi-center phase III clinical trial demonstrated that sipuleucel-T significantly extends overall survival in patients with mCRPC (22). Subsequently, the research by Kwon et al., the second most cited document, highlights that docetaxel, utilized as a first-line chemotherapy agent for mCRPC, can markedly enhance patient survival when administered in conjunction with endocrine therapy, especially in individuals presenting with high tumor burden or bone metastases. Nevertheless, it is crucial to acknowledge the manageable adverse effects associated with this treatment, such as neutropenia (23). Tannock et al. published a comparative study on the efficacy of docetaxel plus prednisone and mitoxantrone plus prednisone in the treatment of advanced prostate cancer, ranking third. Through analysis, it was found that docetaxel combined with prednisone administered once every three weeks could achieve a higher survival rate and improve pain, serum prostate-specific antigen (PSA) level, and quality of life compared to mitoxantrone plus prednisone (24).

Keywords effectively summarize the central research theme of an article, facilitating a swift understanding of its fundamental content. Through comprehensive keyword analysis, researchers can identify critical issues within their research field and anticipate future research directions. In the keyword co-occurrence graph, the size of each node reflects the frequency of keyword usage. According to the statistical analysis performed using CiteSpace software (Figure 9A), “prostate cancer” emerges as the most prominent node in the keyword network, underscoring its status as the primary focus of this study. Other notable nodes include “immunotherapy”, “expression” and “dendritic cells” which are pivotal in the exploration of immunotherapy for prostate cancer. In the keyword network diagram, the purple region of a node indicates goal-mediated centrality. Nodes exhibiting high centrality typically represent research hotspots or key focal points (25). Within the entire keyword network, “antitumor immunity” demonstrates the highest centrality, followed by “dendritic cells”, “cancer”, “in vitro”, and “immunotherapy”.

Evolution of the research trend in immunotherapy for prostate cancer

Over the past 25 years, research into immunotherapy for prostate cancer has evolved from initial exploration to significant advancements in combination therapy. Early research [2000–2010] primarily focused on the preliminary validation of immunomodulatory cytokines, such as interleukin (IL)-2 and interferon (IFN)-α, and vaccines, including Sipuleucel-T. However, the phase II trial of IL-2 monotherapy for metastatic prostate cancer revealed a partial remission rate of only 6% and considerable toxicity (26). Additionally, the phase I trial of IFN-α combined with chemotherapy demonstrated a PSA decrease rate of just 15%, falling short of the anticipated treatment endpoint (27). With the advancement of basic tumor immunology theories, such as the mechanism of dendritic cells in antigen presentation, Sipuleucel-T, an immunotherapy based on autologous dendritic cells, has entered the historical stage. Currently, clinical trials for this therapy predominantly focus on phase I/II, representing 82% of the total trials. Notably, Sipuleucel-T’s phase III IMPACT trial confirmed for the first time the significant benefits of immunotherapy on survival, extending the median overall survival time (mOS) by 4.1 months, a statistically significant improvement (P=0.03) (22). In 2010, Sipuleucel-T was successfully approved by the US Food and Drug Administration (FDA) (28). Despite this, the response rate of Sipuleucel-T is relatively low, and its high cost restricts its widespread application. In the 2010s, with the deepened understanding of the tumor immune microenvironment and immune escape mechanisms, the field of prostate cancer immunotherapy experienced a new breakthrough. Novel ICIs, such as CTLA-4 and PD-1/programmed death ligand 1 (PD-1/PD-L1) (including pembrolizumab and atezolizumab), have been utilized in the study of ICIs (29-32). Concurrently, the rapid progress in cell therapies like CAR-T cells and TCR-T cells has offered new hope for prostate cancer patients (33,34). Nevertheless, the objective response rate (ORR) of these single agents in prostate cancer is less than 5%, highlighting the challenge of “cold tumors” to immunotherapy (24,35). These innovative immunotherapies have demonstrated remarkable efficacy and low toxicity in clinical trials, propelling the shift in prostate cancer immunotherapy from monotherapy to combination therapy.

Over the past five years [2020–2024], with a deeper understanding of the regulatory mechanisms of the tumor microenvironment (TME) and advancements in multidisciplinary clinical trial design—such as the spatio-temporal collaboration of immunotherapy and radiotherapy—the research focus has gradually shifted towards combination therapy (36). For instance, the combination of immunotherapy with radiotherapy, chemotherapy, poly ADP-ribose polymerase (PARP) inhibitors, or new endocrine drugs has been shown to significantly improve the ORR and overall survival time (OS) (37). Taking the combination of CAN-2409 (an oncolytic virus) and radiotherapy as an example, the pathological remission rate reached 80.4%, and the mOS for the combination of pembrolizumab and docetaxel was 20.2 months (38). This trend indicates a shift from single-mechanism therapy to a multi-target collaborative therapy strategy. Furthermore, the personalized strategy of immunotherapy has garnered increasing attention. By utilizing biomarkers such as tumor gene mutation load (TMB), microsatellite instability (MSI), and PD-L1 expression levels, researchers can identify patients who are more responsive to immunotherapy, thereby achieving more precise treatments. This personalized treatment strategy not only enhances the therapeutic effect but also reduces the unnecessary use of drugs, lessening the economic burden and physical harm to patients.

Research hotspot of immunotherapy for prostate cancer

The purpose of keyword clustering is to summarize a specific topic, while keyword clustering analysis is used to identify popular themes within a research field. Through clustering analysis, it is possible to pinpoint the most discussed hot areas currently. The following elaborates on these trending research topics.

Immune combination therapy strategy

ICI combined with radiotherapy

PD-1 is primarily expressed on the surface of activated T cells, B cells, and myeloid cells, where it regulates immune responses by transmitting inhibitory signals to prevent autoimmune damage from overactivation (39). Its ligand, PD-L1, is widely expressed in normal tissues (such as the placenta and lung) and tumor cells. When PD-L1 binds to PD-1, it can inhibit the activation, proliferation, and cytotoxicity of T cells, thereby maintaining peripheral immune tolerance (40). In the tumor microenvironment, the high expression of PD-L1 (with a positive rate of about 10–30%) is one of the core mechanisms by which tumors evade immune surveillance, making it a key target for ICI (41). ICI, such as pembrolizumab and atezolizumab, can block the interaction between PD-1 and PD-L1 competitively, thereby relieving the inhibition of T cell function (42). Studies have shown that the level of IFN-γ secreted by T cells can increase by 5-fold after ICI treatment (in vitro experiment, P<0.001), and the density of tumor-infiltrating lymphocytes (TILs) can increase by 3–4 times (43). However, prostate cancer is a typical “cold tumor”, characterized by low T cell infiltration, a low tumor mutation load, and low PD-L1 expression, which leads to limited efficacy of ICI monotherapy (ORR of 5%, with no significant improvement in mOS) (44-46). This predicament has given rise to a combined therapeutic strategy, where radiotherapy reshapes the immune microenvironment to form a spatiotemporal synergy with ICI, becoming the key pathway to break through the efficacy bottleneck. Radiotherapy induces tumor cells to release damage-associated molecular patterns (DAMPs) such as ATP, HMGB1, CRT, activates dendritic cells (DCs), and enhances antigen presentation capacity by twofold, promoting a tenfold increase in the amplification of antigen-specific T cells in tumor-draining lymph nodes (47). At the same time, radiotherapy increases tumor mutation burden through DNA damage, enhancing T cell recognition (48). Studies have shown that radiotherapy activates the IFN-γ signal, causing tumor cell PD-L1 expression to increase by 2–3 times (immunohistochemical score H-score from 28 to 52, P=0.007), and the PD-L1 positive rate to increase from 12% to 35%, providing a target for ICI (49). ICI reduces T cell exhaustion markers (expression of TIM-3, LAG-3 decreases by 40%) and reverses radiotherapy-induced T cell dysfunction (in vitro killing efficiency increases by 40%), prolonging the immune response (50). A clinical trial combining stereotactic body radiation therapy (SBRT) (single dose of 8 Gy) with durvalumab (a PD-L1 inhibitor) showed an ORR of 35% (compared to an ORR of 12% with Durvalumab alone), and a median progression-free survival (PFS) extended to 8.1 months (hazard ratio HR =0.62) (51). In mCRPC, SBRT is primarily indicated for oligometastatic lesions (≤5 sites), with preferential targeting of bone metastases (e.g., in the spinal and pelvic regions) and lymph node metastases. A single-fraction dose of at least 18 Gy is required to achieve a local control rate exceeding 95% (52,53). The primary prostate lesion is considered an optional target only when it remains uncontrolled or exhibits local recurrence, with a typical dose of 35–36 Gy administered over 5–6 fractions. High-dose radiation (>10 Gy per fraction) induces tumor ablation by causing DNA double-strand breaks and microvessel destruction in cancer cells. Furthermore, SBRT promotes the release of tumor antigens and upregulates MHC-I/PD-L1 expression, thereby activating T-cell-mediated immune responses. When combined with pembrolizumab, it can reverse PD-1-mediated T-cell suppression and potentiate systemic immune responses, including the abscopal effect (54,55). In another study, SBRT (single dose of 20 Gy) combined with pembrolizumab, the ORR was 36%, and the observed rate of abscopal effect was 22% (56). These data indicate that the combined treatment strategy is effective, but it also brings a third-degree pneumonia incidence rate of 12% (vs. single drug ICI 5%), and a colitis incidence rate of 8% (57). This suggests that while pursuing efficacy, we must weigh its safety. At the same time, more related combined treatment trials are being conducted in the clinic. We have reason to believe that in the future, a reasonable and effective combined therapy will further enhance the killing effect of immunotherapy on tumors, opening new hope for the treatment of prostate cancer.

Combination therapy of PARP inhibitor and ICI

PARP inhibitors are a type of small molecule drugs that target the DNA damage repair (DDR) pathway. They interfere with the DNA repair process in cancer cells by selectively inhibiting the activity of the PARP enzyme, primarily including Niraparib and Rucaparib (58). Its core mechanism is mainly to block the base excision repair (BER) of single strand breaks (SSB) by PARP enzyme, which leads to the collapse of replication fork and the formation of fatal double strand breaks (DSB). At the same time, the DNA damage induced by PARP inhibitors can increase the load of new tumor antigens, activate STING pathway to promote the expression of PD-L1, and provide targets for ICI (59). The preclinical model showed that olapali combined with anti-PD-1 antibody increased the infiltration density of T cells by 4 times (CD8⁺ T cells/mm) (60). A Phase II trial demonstrated that the combination of olaparib (300 mg BID) and pembrolizumab (200 mg Q3W) in mCRPC patients with homologous recombination repair (HRR) gene mutations (such as BRCA1/2, ATM, etc.) resulted in a mOS of 28.5 months, compared to 16.4 months in the chemotherapy group [hazard ratio (HR) =0.62]. Additionally, the ORR was 55%, markedly higher than that observed in the chemotherapy group (25%) (61). Furthermore, the combination therapy of NiRapali and nivolumab has demonstrated a remarkable curative effect in patients with advanced pancreatic cancer (62). Research indicates that this combination therapy can significantly extend PFS and exhibits good safety. PARP inhibitors enhance the sensitivity of cancer cells to ICI treatment by disrupting the DNA repair mechanism. The synergy between the two creates a powerful combined effect, offering new hope for cancer patients (63,64). Current clinical practice guidelines—specifically the 2024 European Association of Urology (EAU) Guidelines and National Comprehensive Cancer Network (NCCN) Guidelines—explicitly recommend that patients with BRCA1/2 mutation-positive mCRPC prioritize PARP inhibitor monotherapy (e.g., olaparib or rucaparib) or PARP inhibitor combinations with novel endocrine therapies (e.g., olaparib plus abiraterone) as standard treatment regimens (65,66). Notably, combinations of PARP inhibitors with ICIs remain in the exploratory phase of clinical investigation (67). Consequently, for patients harboring homologous recombination repair (HRR) gene mutations, PARP inhibitor monotherapy or combined endocrine therapy constitutes the recommended first-line strategy. ICI-based combinations are restricted to clinical trial settings or individualized use following multidisciplinary team consultation. In the future, with in-depth studies into the mechanism of PARP inhibitors combined with ICIs and the development of additional clinical trials, it is expected that the applicable population for this therapy will expand, the therapeutic effect will improve, and new breakthroughs will be achieved in the field of cancer treatment.

Double-track breakthrough in bispecific antibody and oncolytic virus research

A bispecific antibody (BsAb) is a specially designed antibody capable of binding to both tumor antigens (such as PSMA) and immune cell surface molecules (such as CD3) simultaneously, circumventing the MHC restriction of traditional T cell activation and directly guiding T cells to target and destroy tumors. Its core advantage is its precision and reduced off-target toxicity (68,69). In the phase I trial of the PSMA×CD3 bispecific antibody (AMG 160), activated T cells selectively eliminated PSMA-positive tumor cells, resulting in a PSA reduction rate as high as 50% (70); the ORR for Xaluritamig in patients with mCRPC is 38.9%, and the incidence of cytokine release syndrome (CRS) is 75.5%, but only 1% of these cases are of grade 3 or above (71). Oncolytic viruses are a type of virus that, after genetic modification, selectively infect and lyse tumor cells. They also release tumor antigens and express immune-stimulating factors (such as cytokines and costimulatory molecules) to activate a systemic anti-tumor immune response (72). Following the combination of CAN-2409 (adenovirus + HSV-TK) with radiotherapy, the 3-year OS significantly improved to 89.2%, compared to 75.6% in the control group. The difference was statistically significant (HR =0.70, P=0.0155), indicating that the combined therapy significantly extended patient survival. Additionally, after two years of treatment, the pathological complete remission rate (PCR) of the combined group reached 80.4%, compared to 63.6% in the control group, which was also significantly different (P=0.0015) (73). Within this protocol, the primary target of radiotherapy—the irradiated area—is the primary tumor itself, including measurable lesions. The mechanism of CAN-2409 involves intratumoral injection. Radiotherapy directly kills tumor cells within the irradiated area, disrupts the tumor microenvironment, and releases tumor antigens along with danger-associated molecular patterns (DAMPs). This synergistic effect occurs in the same lesion as oncolytic virus therapy: radiotherapy’s DNA damage may enhance viral replication efficiency, while virus-mediated cell lysis could make tumor cells more sensitive to radiation. Both radiotherapy-induced immune cell death (ICD) and viral-mediated cell lysis collectively release massive amounts of tumor antigens and pro-inflammatory signals, thereby strongly activating the anti-tumor immune response (74,75); the combination of LOAd703 (an oncolytic adenovirus carrying CD40L/4-1BBL) with albumin-bound paclitaxel (nab-P) and gemcitabine (G) demonstrated a remarkable curative effect in treating solid tumors. Specifically, the infiltration density of CD8⁺ T cells increased by fourfold, and the ORR reached 28% (76). BsAbs and oncolytic viruses activate anti-tumor immunity through distinct mechanisms: BsAbs directly bridge T cells and tumors, whereas oncolytic viruses indirectly stimulate immune responses via virus lysis and antigen release. The clinical application of BsAbs and oncolytic viruses highlights their unique advantages in tumor immunotherapy (77,78). Regarding bispecific antibodies, in addition to PSMA×CD3 and Xaluritamig, researchers are continually exploring new combinations of targets to achieve a broader and more precise tumor-killing effect. In the field of oncolytic viruses, scientists have modified viral genes to enable selective infection and lysis of tumor cells (79,80). These viruses can also release tumor antigens and express immune-stimulating factors, thereby activating a systemic anti-tumor immune response. Clinical trial data for oncolytic viruses such as CAN-2409 and LOAd703 indicate that they have significant curative effects in treating certain types of tumors. Looking ahead, as research deepens and technology advances, the application prospects of bispecific antibodies and oncolytic viruses in tumor immunotherapy are expected to expand even further.

The dual engines of immunotherapy for solid tumors: the synergistic breakthrough of CAR-T and personalized neoantigen vaccines

The breakthrough of CAR-T therapy in solid tumors

CAR-T therapy is an innovative immunotherapy method that transforms patients’ T cells through genetic engineering technology. Its core mechanism involves introducing artificially designed chimeric antigen receptors (CARs) into T cells, endowing them with the ability to specifically recognize and attack tumor cell surface antigens. This overcomes the limitations of traditional T cells, which rely on MHC molecular recognition (81). By introducing secreted cytokines, such as IL-12 and IL-15, or employing gene editing technologies like CRISPR, the immunosuppression within the TME can be optimized (82). In the treatment of solid tumors, prostate-specific membrane antigen (PSMA) has emerged as an ideal therapeutic target due to its high expression in over 90% of prostate cancer cells—levels 100 to 1,000 times greater than in normal tissues (83,84). An article published in Nature Reviews Urology indicates that the heterogeneity of PSMA expression is influenced by the signal activity of the androgen receptor (AR), epigenetic regulation (such as promoter methylation), and the tumor microenvironment (including metabolic inhibition of liver metastases). Additionally, the PSMA-low subgroup is resistant to radioactive ligand therapy due to the overexpression of immune escape molecules such as CD47 and PD-L1. Consequently, it is necessary to combine targeted immune checkpoints or metabolic pathways to improve the therapeutic effect (84). In CAR-T therapy for 98 patients with advanced digestive tract tumors, the ORR was 38.8%, and the disease control rate (DCR) was as high as 91.8%. Notably, the ORR for patients with gastric cancer was 54.9%, the DCR reached 96.1%, and the median progression-free survival (PFS) was 5.8 months (85). In a phase I clinical trial of CAR-T cell therapy, 14 patients with prostate stem cell antigen (PSCA) positive mCRPC participated in the study. The results showed that the PSA level of 4 patients decreased by ≥30%, and the PSA level of 1 patient decreased by 90%. In addition, the soft tissue metastasis has been significantly reduced, and the disease control rate has reached 60–67%, which indicates that this therapy has preliminary clinical activity (86).

The data not only demonstrate the potential of CAR-T therapy in treating solid tumors but also highlight the challenges it encounters in clinical practice. Specifically, the occurrence of CRS and neurotoxicity suggests that safety and tolerance remain crucial areas for future research. To further refine CAR-T therapy, researchers are investigating novel structural designs for CARs to improve their targeting precision and minimize off-target effects. Concurrently, they are also exploring methods to enhance the tumor microenvironment, thereby improving the infiltration and viability of CAR-T cells and, consequently, the therapy’s efficacy.

Precision immunization innovation of personalized neoantigen vaccines

Individualized neoantigen vaccines are therapeutic vaccines tailored to patients based on tumor-specific mutations. Their goal is to activate the patients’ immune systems to precisely identify and eliminate tumor cells that carry specific new antigens (87). Unlike traditional cancer vaccines that adopt a “one-size-fits-all” approach, individualized neoantigen vaccines are crafted to align with each patient’s unique tumor mutation profile, embodying “the ultimate form of tumor precision immunotherapy”. During the antigen screening stage, tumor tissues and normal tissues are analyzed using whole exon sequencing (WES) and RNA-seq to identify somatic mutations. Tools such as NetMHCpan are used to predict the binding affinity of mutant peptides with MHC molecules (a score greater than 0.5 indicates high affinity), and to verify their ability to induce T cell responses (for example, IFN-γ secretion is detected by ELISpot). Subsequently, synthetic peptides or mRNA vaccines were used in combination with PD-1 inhibitors to enhance the amplification and killing function of T cells (88,89). The new antigens in the vaccines were absorbed by dendritic cells (DCs) and presented to MHC class I/II molecules, activating CD8⁺ cytotoxic T cells and CD4⁺ helper T cells. The specific T cells for the new antigen were cloned and amplified, infiltrating the tumor and recognizing cancer cells expressing the same new antigen, thus achieving precise killing (90,91). In an experiment involving patients with advanced melanoma, flow cytometry showed that the proportion of CD8+ new antigen-specific T cells increased from 0.1% at baseline to 1.2% (an amplification of 10 times), indicating that the vaccine significantly activated anti-tumor immunity; single-cell TCR sequencing confirmed that the vaccine-induced T cell clones could survive for a long time (>12 months), and the 2-year OS rate reached 85%, which was 30% higher than that of the historical control group (only using PD-1 inhibitors). Among patients with complete remission (CR), 80% have remained relapse-free for more than 3 years, indicating that the vaccine has successfully induced lasting immune memory (92,93).

While the algorithm predicts that only about 20% of new antigens can elicit an effective T cell response in vivo (for example, in the NeoVax test, 15 new antigens were screened for each patient, but only 3 could provoke an immune response) (94), there’s a risk that some antigens with high immunogenicity might be overlooked if they are not selected by the algorithm. This happens because the algorithm overly relies on MHC binding affinity, potentially leading to “false negative” outcomes (95). In the clinical trial NCT03639714, out of 20 predicted new antigens designed for colorectal cancer, only four could stimulate a T cell response, and one of these was an antigen not recommended by the algorithm, thus missed (96). Therefore, it is crucial to develop a deep learning model that integrates MHC binding, TCR recognition, and tumor clone expression. For instance, the PanPep algorithm developed by Tongji University has reduced the false positive rate by 50% (97). Additionally, the combined use of ICIs, such as PD-1 inhibitors, can reverse vaccine-induced T cell depletion (for example, in the Keynote-603 clinical trial, the ORR of the combination treatment group increased to 65%) (98). Simultaneously, combined CAR-T therapy: endogenous T cells activated by the vaccine can eliminate heterogeneous tumor cells that CAR-T therapy cannot target (as reported in Nature 2023, the long-term survival rate of the glioma model doubled after combined therapy) (99).

Despite this, the development of individualized new antigen vaccines faces numerous challenges. For example, the process of selecting and verifying new antigens is complex and time-consuming, requiring high-precision experimental techniques and extensive bioinformatics analysis (100). Additionally, the preparation and storage conditions for vaccines are extremely rigorous, and the stability and safety of vaccines must be ensured (101). To overcome these issues, scientists are persistently exploring new technologies and methodologies to enhance the research and development efficiency and therapeutic efficacy of individualized new antigen vaccines. For instance, by refining the algorithm model, the accuracy of new antigen prediction is increased; improving the vaccine preparation process through advanced bioengineering technology; and developing new adjuvants to boost the immunogenicity of vaccines (102-104). As research progresses, individualized new antigen vaccines are expected to become a significant breakthrough in the field of immunotherapy, offering hope and a boon to a greater number of patients.

Strengths and limitations

While literature analyses indicate a marked growth in prostate cancer immunotherapy research (with an average annual growth exceeding 25%), a notable disparity persists between the output of basic research and the efficiency of clinical translation. Using CAR-T therapy as a paradigm, despite a 35% annual increase in related publications [2020–2024], immune suppressive mechanisms within the solid tumor microenvironment (e.g., TGF-β-mediated T-cell exhaustion) and heterogeneity in target expression (15–30% of patients with mCRPC exhibit PSA-MDA negativity) have resulted in a lack of approved agents in this field—starkly contrasting with the seven CAR-T therapies approved for hematologic malignancies (102,105).

Currently, combination strategies have emerged as a focus to break this impasse. The KEYNOTE-199 trial confirmed that anti-PD-1 monotherapy achieved only a 5% ORR in mCRPC, whereas radiotherapy combined with dual ICIs (nivolumab + ipilimumab) increased ORR to 25% via in situ antigen release (CheckMate 650 trial). In patients with homologous recombination repair deficiency (HRD), the combination of PARP inhibitors and ICIs extended progression-free survival by 8.3 months (PROfound subgroup analysis). However, mechanistic studies on combination therapies account for merely 12% of the total literature, underscoring structural delays in translational medicine research (106,107). Three groundbreaking clinical trials are garnering attention: the INSITU trial (NCT05534373) investigates the sensitizing effect of intratumoral cryoablation on PD-1 efficacy; the PRINCE trial (NCT03905925) examines whether IL-15 agonists combined with PSMA-targeted radiotherapy can improve survival; and the PROVEN personalized neoantigen vaccine (NCT04382898), which utilizes RNA sequencing to customize treatment regimens, has shown early success in inducing T-cell responses in 8 of 12 patients (108,109).

Looking forward, competitive focus will center on biopsy-free liquid biopsy-driven therapies (as exemplified by the PlasmaMATCH trial, which achieved over 90% sensitivity in detecting HRR mutations via ctDNA testing) and AI-assisted antigen design (e.g., the DeepPrimeVax platform, which reduces neoantigen prediction time to 72 hours) (110,111). Notably, however, only 3% of current literature addresses cost analyses. For instance, the 177Lu-PSMA regimen costs up to $150,000, while CAR-T therapy exceeds $500,000. Such exorbitant expenses risk rendering these innovative therapies “privileges of the affluent,” impeding their widespread clinical adoption (112,113).

Conclusions

The purpose of this study is to summarize the application of immunotherapy in the treatment of prostate cancer and to review the related literature. Immunotherapy drugs are summarized in the following table (Table 6). However, it is not without its limitations. Firstly, the collected literature data may not be comprehensive enough because it is limited to papers and comments selected using a limited set of search terms in the WoSCC database. Secondly, due to time constraints, we may not fully reflect the academic value of recent high-quality literature, particularly those with a low citation rate. Thirdly, although breakthrough words, co-citation analysis, and other statistical methods are employed, the results may not fully represent the consensus of scholars in this field. Fourthly, for publications involving multiple authors, it is challenging to accurately evaluate each author’s contribution, especially when relying on a single and difficult-to-quantify indicator (such as author order). Fifthly, the instability of the author’s affiliation has brought significant challenges in bibliometric analysis. Finally, because this study was conducted in early 2025, papers published in early 2025 could not be included, although this omission may have little impact on the research results. Despite these limitations, this study provides a valuable macro perspective for this field and offers useful guidance for future research.

Acknowledgments

We are grateful for the assistance of all those who contributed to this study.

Footnote

Reporting Checklist: The authors have completed the BIBLIO reporting checklist. Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-414/rc

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-414/prf

Funding: This study was supported by the Youth and Middle-aged Scientific Research Fund of Affiliated Hospital of Qinghai University (No. ASRF-2022-YB-05).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-414/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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