Guangqiang Hu
Zeng Li1,2†- 1Department of Urology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- 2Department of Urology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, China
Prostate cancer (PCa), the most prevalent malignancy among male genitourinary cancers, is distinguished by its immunologically ”cold” phenotype with persistently high incidence and mortality. Radical prostatectomy and radiotherapy represent the current standard of care for localized prostate cancer. However, recurrence or progression occurs frequently, and advanced or metastatic disease is common at initial presentation. Recent progress in cancer immunotherapy reveals that modulation of immune responses represents an effective strategy for enhancing antitumor activity. Programmed Cell Death Protein 1 and Programmed Cell Death Ligand 1 (PD-1/PD-L1) inhibitors, which restore T-cell function and remodel the tumor immune microenvironment, have achieved clinical success in melanoma, lymphoma and non-small-cell lung cancer. Although their efficacy as monotherapy in PCa remains limited and optimal patient selection criteria are lacking, emerging evidence suggests that combination immunotherapy regimens may offer clinically significant benefits. This review critically evaluates current clinical trial outcomes involving PD-1/PD-L1 inhibitors for prostate cancer and outlines priority directions for future investigation.
1 Introduction
Prostate cancer (PCa) continues to represent both the most frequently diagnosed cancer and the second primary cause of cancer-specific death among males in Europe and the United States (1, 2). Global epidemiological trends demonstrate a marked increase in PCa burden, with cases (+116.11%), deaths (+108.94%), and disability-adjusted life years (+98.25%) all nearly doubling between 1990 and 2019 (3). Projected annual incidence shows 299,010 cases (29% of male cancers) alongside 35,250 deaths (the third among male cancer deaths) in 2024 (2). By 2025 (4), these estimates will climb to 313,780 cases (30%) and 35,770 deaths. Current trajectories suggest global annual incidence will surpass 2.9 million cases by 2040 (5), underscoring a critical public health concern. Standard treatments for advanced PCa—androgen deprivation therapy (ADT) (6), radiotherapy (7), and chemotherapy (8)—frequently fail due to rapid drug resistance and limited long-term survival improvements. Immune evasion is promoted by immunosuppressive signals transmitted throught the PD-1/PD-L1 axis, a pivotal immune checkpoint. Although PD-1/PD-L1 inhibitors demonstrate clinical efficacy in certain solid tumors, their utility in PCa remains unclear. This review consolidates existing findings on the immune microenvironment, immune escape mechanisms, PD-1/PD-L1-targeted immunotherapy, and clinical implementation challenges (Figure 1). The goal is to evaluate therapeutic limitations and explore future research opportunities in cancer immunotherapy.
Figure 1. Overview diagram of the review. This paper is structured as follows: the immune microenvironment, immune escape mechanisms, PD-1/PD-L1-targeted immunotherapy, clinical challenges, and therapeutic prospects in prostate cancer.
2 The immune microenvironment within prostate cancer tumors
PCa incidence increases at an annual rate of 3%, making it the most prevalent cancer among men worldwide, with nearly half of cases diagnosed at advanced stages (2, 9, 10). A distinct tumor microenvironment is a notable feature observed across multiple forms of PCa. The immune scoring system classifies solid tumors as either immunologically active "hot tumors"—such as melanoma, lymphoma, and liver cancer—or as immune-privileged "cold tumors," based on an evaluation of tumor-infiltrating lymphocyte density, functional status, and inflammatory characteristics within both the tumor core and the invasive margin (11, 12). PCa exemplifies a heterogeneous “cold tumor”, exhibiting minimal T-cell infiltration and low tumor mutation burden (TMB) (13). Primary lesions show mutation rates below 1mut/Mb, contrasting with metastatic lesions that may reach 4mut/Mb (14, 15). This limited TMB reduces neoantigen generation, leaving PCa devoid of potent immunogenic targets. The PCa tumor microenvironment contains immune effector cells such as CD8+ cytotoxic T lymphocytes, natural killer (NK) cells, neutrophils, B cells, and proinflammatory M1 macrophages (16), but immunosuppressive populations like myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) predominate (17, 18). Immunosuppressive cytokines—notably IL-10, IL-35, and TGF-β—directly inhibit T-cell activation and cytotoxic function (19).
MDSCs constitute a heterogeneous cell population, typically categorized into polymorphonuclear (PMD-MDSCs) and monocytic (M-MDSCs) subtypes, which exhibit potent immunosuppressive capabilities. These cells can suppress NK cells, macrophages, and effector T cells, while also promoting the expansion of Tregs and enhancing their immunosuppressive function (20–22).Tregs, a subset of CD4se cells with immunosuppressive functions, facilitate tumor immune evasion by directly suppressing effector T cell activity, secreting immunosuppressive cytokines such as IL-10, reducing T cell metabolic activity, and inhibiting antigen-presenting cell function through contact-dependent mechanisms (22–24). Clinical evidence (25–29) indicates that MDSCs and Tregs are enriched in advanced PCa tissues and are associated with disease progression and poor prognosis. MDSCs and Tregs form a stable “immunosuppressive hub” through chemokine-mediated recruitment and functional cross-reinforcement. For instance, MDSCs secrete chemokine ligand 22 (CCL22), which recruits Tregs to the tumor microenvironment by binding to chemokine receptor 4 (CCR4) on Treg surfaces (21). Transforming growth factor-β (TGF-β) secreted by Tregs upregulates the expression of arginase-1 (Arg-1) and indoleamine 2,3-dioxygenase (IDO) in MDSCs by activating the Smad3 pathway. Both Arg-1 and IDO inhibit T cell receptor expression and induce T cell apoptosis via their metabolites. In co-culture experiments, Treg-conditioned medium enhanced Arg-1 and IDO activity in MDSCs, an effect that could be blocked by TGF-β neutralizing antibodies (22). Further analysis of clinical samples revealed that patients with co-enrichment of MDSCs and Tregs had a significantly lower response rate to docetaxel combined with ADT compared to those without co-enrichment (18% vs. 45%) (30).
Single-cell transcriptome analyses demonstrate reduced expression of T-cell cytotoxicity-related genes alongside marked elevation of exhaustion markers (e.g., TIM-3 and PD-1) in PCa tissues relative to melanoma (31). Tumor cells further impair T-cell transendothelial migration by suppressing adhesion molecules such as ICAM-1 and VCAM-1 (32). Patients with metastatic castration-resistant prostate cancer (mCRPC) undergoing novel endocrine therapies (abiraterone or enzalutamide) show decreased peripheral blood T-cell counts (33), while exhibiting elevated circulating proportions of Tregs, M2-polarized macrophages, and MDSCs (34, 35).
In the immune microenvironment of PCa, MDSCs and Tregs form a synergistic immunosuppressive network through a triple interaction of “chemoattractants-cytokines-metabolites”: On one hand, TGF-β, secreted by tumor cells and Tregs binds to TGF-βRII on the surface of MDSCs, activating Smad2/3 phosphorylation and upregulating the expression of Arg-1 and CCL22, thereby enhancing the metabolic suppression mediated by MDSCs (36). TGF-β can also promote the differentiation of naive CD4+ T cells into Foxp3+ Tregs via a Smad4-dependent pathway (22). On the other hand, IL-23 secreted by MDSCs induces the differentiation of CD4+ T cells into Th17 cells by activating the STAT3 pathway; IL-17 secreted by Th17 cells binds to IL-17R on the surface of Tregs, activating the NF-κB pathway and upregulating the expression of Foxp3 and CTLA-4, thereby maintaining Treg stability and enhancing their function (30, 37). Additionally, MDSCs and Tregs can cooperatively generate adenosine through CD39/CD73, collectively suppressing CD8+ T cells (37).
PCa establishes a unique TME through diverse genomic mechanisms: mCRPC tissues frequently carry somatic or germline mutations in DNA repair genes, such as BRCA1/2 alterations, CDK12 inactivation, and RB1 shallow deletions, with homologous recombination defects occurring in 20%–25% (38). PTEN and TP53 aberrations appear in 25% of primary tumors and 60% of mCRPC cases (14, 15, 39, 40). CDK12 is a key gene for DNA repair, which is involved in cell cycle progression and transcription elongation (41). Loss-of-function mutations in this gene are often characterized by increased focal tandem duplications, elevated gene fusion events, and higher tumor neoantigen burden (42).
Functionally, NK cells in prostate cancer patients exhibit suppression and exhaustion, characterized by the expression of markers such as PD-1 and TIM-3 and the downregulation of activation receptors like NKG2D; this leads to a reduction in both cytotoxic activity and cytokine secretion (43, 44). Hypoxia, acidity, and metabolic waste accumulation in the TME can trigger NK cell dysfunction; TGF-β secreted by tumor cells can downregulate the expression of NK cell activation receptors, thereby impairing their ability to recognize tumor cells (45, 46). Additionally, PD-1 binding to PD-L1 inhibits both NK cell degranulation and IFN-γ secretion, activates SHP phosphatase, and suppresses phosphorylation within the PI3K–AKT pathway, thereby blocking the cytotoxic function of NK cells (47).Blocking PD-L1 enhances the anti-tumor activity of NK cells and increases tumor clearance rates (48), although some models rely on T cell cooperation. In the PD-L1 high-expressing lung cancer cell line H441 (49), avelumab combined with NK cells induced approximately 46.4% antibody-dependent cellular cytotoxicity (ADCC) lysis. Simultaneously blocking the PD-L1 and TGF-1 pathways (50) further enhances immune cell infiltration; the dual-target inhibitor M7824, at doses exceeding 1 mg/kg, fully occupies PD-L1 receptors and neutralizes all TGF-β isoforms (TGF-β1, β2, and β3) in plasma. Combined blockade of B7-H3 and PD-L1 (10), elimination of MDSCs in the tumor microenvironment (46), and blockade of TIGIT (51) (T cell immunoglobulin and ITIM domain protein) can all partially restore NK cell activity and function.
Dysregulated AR signaling, including AR amplification and AR-V7 expression, persists under androgen-deprived conditions; AR-V7 not only constitutively activates AR signaling pathways but also suppresses antigen presentation, thereby reinforcing an immunosuppressive state (52). AR-V7, a splice variant of the AR, constitutively activates AR signaling under low androgen conditions or in the presence of AR antagonists. It can also bind directly to androgen response elements in the PD-L1 promoter and enhance PD-L1 transcription (53–55). AR-V7 blockade (55) suppresses prostate tumor growth in mice and eradicates intraosseous tumor cells. Clinical evidence (52) indicates that although nivolumab plus ipilimumab shows limited overall efficacy in unselected AR-V7-positive mCRPC, a subset of patients (23.3%) achieved sustained progression-free survival exceeding 24 weeks, suggesting a potentially responsive subgroup. This effect may be attributable to DNA repair deficiencies that elevate tumor mutational burden and thereby potentiate responses to immunotherapy. These interconnected mechanisms perpetuate an immune-hormonal vicious cycle.
Metastatic lesion single-cell transcriptome analysis (56) demonstrates increased CD8+ T lymphocyte, NK cell, and monocyte infiltration in metastases relative to primary tumors, suggesting compensatory immune activation. Despite this response, downregulated Major Histocompatibility Complex I molecules (MHC I) expression and impaired interferon signaling pathways—including defective STAT1 phosphorylation (57, 58)—promote immune evasion, immunosuppression, and tumor immune inertia in PCa (Figure 2), characteristic of a “cold tumor” phenotype.
Figure 2. Prostate cancer immune microenvironment. This figure illustrates the distinct tumor microenvironment in prostate cancer. Despite the presence of immune effector cells, immunosuppressive cells predominate and coexist with elevated levels of immunosuppressive cytokines. This milieu facilitates tumor immune evasion, ultimately culminating in disease progression.
3 The PD-1/PD-L1 checkpoint and immune suppression in prostate cancer
The limited efficacy of PD-1/PD-L1 blockade in PCa – despite the immune checkpoint inhibitors (ICI) therapy’s transformative impact on solid tumors – highlights the imperative to delineate PCa’s distinct immune evasion mechanisms. The PD-1/PD-L1 checkpoint axis transduces immunosuppressive signals that compromise antitumor immunity. Structurally, PD-1 possesses: (i) an extracellular IgV-like ligand-binding domain, (ii) a transmembrane region, and (iii) an intracellular domain with an embedded immunoreceptor tyrosine-based inhibitory motif (59). This receptor regulates T-cell function by modulating apoptosis and acts as a pivotal negative immune regulator (60). Tissue-specific PD-1 expression patterns reveal abundant presence in peripheral memory T cells but negligible levels in monocytes, dendritic cells, NK cells and B cells (59, 61, 62). Under normal physiological conditions, this system preserves immune homeostasis by curbing excessive activation (63). Phosphorylated tyrosine residues within the PD-1 intracellular domain function as docking sites that recruit SHP-1 and SHP-2 phosphatases (64).
Within the TME, PD-L1 serves as the predominant immunosuppressive ligand, constitutively expressed on both malignant cells and key immune populations including dendritic cells, macrophages, and T lymphocytes (65). The PD-L1 topology includes extracellular IgV and IgC domains (responsible for PD-1 engagement), a transmembrane helix, and a truncated cytoplasmic tail without known signaling functionality (66). The recruitment of SHP-2 by ligated PD-1 disrupts proximal TCR and CD28 signaling, thereby inhibiting T-cell effector functions including proliferation, cytotoxicity, and cytokine secretion (67–69).
In PCa, epigenetic modifiers and signal transducers can regulate the expression of PD-1/PD-L1 through multi-level pathways, shape the immune microenvironment, and thereby promote tumor immune escape. Specifically: p300/CBP can directly activate PD-L1 transcription through H3K27ac (70); IL30 indirectly upregulates PD-L1 expression through the STAT1/STAT3 pathway (71); histone deacetylases (72) and ARID1A (the core subunit of the SWI/SNF complex) (73) inhibit PD-L1 expression through negative regulatory pathways (when they are deficient, the tumor’s immune escape ability is significantly enhanced); DNA methylation (74) (e.g., GSTP1, i.e., glutathione S-transferase Pi1, whose promoter is methylated; and RARβ2, i.e., retinoic acid receptor β2, whose promoter is methylated) can indirectly upregulate PD-L1 expression through the NF-κB and Wnt/β-catenin signaling pathways, respectively; EZH2 (histone methyltransferase) inhibitors (75) can activate the dsRNA-STING-IFN pathway, increase the secretion level of IFN-γ and thereby induce PD-L1 expression. In addition, it is worth noting that the ketogenic diet (76) can also upregulate PD-L1 expression to a certain extent.
The PD-1/PD-L1 checkpoint axis mediates immune evasion to facilitate PCa progression. In Pten conditional knockout mouse models of PCa (77), compared to IL-17RC knockout and lean controls, both IL-17RC wild-type and obese mice demonstrated substantial co-upregulation of PD-1 and PD-L1 in prostate tumor tissues. These findings imply that PD-1/PD-L1 pathway activation may contribute to tumor aggressiveness and immune resistance in PCa. Notably, granulocyte-macrophage colony-stimulating factor vaccination that blocked PD-1 activated CD8+ T cells but failed to eliminate tumors completely, coinciding with increased PD-L1 expression (78). This demonstrates how tumors adaptively resist immune surveillance by upregulating PD-L1. Clinical evidence further links PD-L1 expression to disease progression, as dendritic cells from mCRPC patients showed elevated PD-L1 levels (79). Analysis of mCRPC patients circulating tumor cells (CTCs) (80) revealed PD-L1 protein in over 50% of CTCs, PD-L1 mRNA overexpression in 48% of patients, and both PD-L1-positive and -negative CTCs in 37.5% of cases, highlighting tumor heterogeneity. Longitudinal data (81) revealed that PD-L1 positivity in CTCs increased from 40% at initial diagnosis to 70% after treatment as PCa transitioned from hormone-sensitive to castration-resistant stages, mirroring disease aggressiveness. Histological examination of 220 radical prostatectomy specimens demonstrated PD-1 and PD-L1 expression in only 1.5% and 0.5% of benign tissues, respectively, compared to 7.7% and 13.2% in tumor tissues (82). Among mCRPC cases, PD-L1 expression reached 32.1% (83). While methodological differences and tumor heterogeneity account for some variability across studies, the consensus confirms progressive PD-1/PD-L1 upregulation during PCa advancement (84, 85).
PCa cells hijack the PD-1/PD-L1 axis to orchestrate a multifaceted immunosuppressive network enabling immune evasion (Figure 3). A key mechanism involves the phosphorylation of PD-1’s immunoreceptor tyrosine-based switch motif, which facilitates SHP-1/SHP-2 binding and consequent dampening of antitumor T-cell signaling (86). This cascade impairs T-cell function through multiple mechanisms: it disrupts TCR–pMHC–CD8 interactions and thereby compromises antigen recognition (87); activates PTEN to suppress the TCR-mediated PI3K/AKT pathway, limiting T-cell proliferation (88); amplifies STAT3-mediated negative feedback, which reduces NK cell responsiveness (89); and suppresses PKCδ activation, diminishing effector molecule production (90).Consequently, T cells within the TME become functionally impaired. PD-L1 expression not only mediates immune evasion but also directly modulates tumor aggressiveness, as demonstrated by AKT-mTOR inhibitor studies showing reduced migration, invasion, and growth rates of DU-145 and PC-3 cells in murine models (91). The regulation of PD-1/PD-L1 in PCa extends beyond established signaling cascades, involving multifaceted crosstalk between genomic, metabolic, and immunomodulatory factors. ATM overexpression in CRPC elevates PD-L1 levels (92), while IL-6, IL-17 and TNF-α enhance PD-L1 expression via JAK/STAT3, NF-κB and AKT-dependent pathways (92, 93). The PD-L1 regulatory network integrates intrinsic factors, such as ATM mutations and PTEN loss, extrinsic stimuli like IFN-γ and epigenetic modifications, which together establish a multifaceted immunosuppressive program. This network synergizes with the prostate cancer microenvironment to promote immune escape (94).
Figure 3. PD-1/PD-L1 checkpoint-mediated immunosuppressive mechanism. Prostate cancer cells subvert antitumor immunity by targeting the PD-1/PD-L1 axis, thereby impairing TCR-CD28 co-stimulatory interactions. This disruption dysregulates critical signaling pathways—including PI3K/AKT and RAS-MEK-ERK cascades—while suppressing secretion of effector molecules such as IFN-γ. Consequently, T cells exhibit restricted proliferative capacity, functional exhaustion, and acquired chemoresistance.
To improve the immunosuppressive properties of “cold tumors” in PCa, researchers have conducted multiple explorations, specifically including STING agonist intervention, oncolytic virus application, and other tumor microenvironment remodeling strategies. Among these, STING (stimulator of interferon genes) serves as a key molecule in the cytoplasmic DNA sensing pathway, and its core function is to induce the production of interferons and pro-inflammatory cytokines by activating the downstream TBK1-IRF3 signaling axis, thereby initiating anti-tumor immune responses. Current research highlights several key mechanisms: (1) CDK4/6 inhibitors such as palbociclib (95) alleviate suppression of the STING–TBK1–IRF3 pathway via TBK1 or RB1 dephosphorylation; combined with STING agonists like diABZI, they markedly enhance T cell infiltration into tumors, converting immunologically “cold” tumors to “hot” ones. RNA-seq analysis of DU145 and C4–2 cells treated with palbociclib for 24 hours revealed significant activation of the cytosolic DNA-sensing pathway, cytokineingallyon receptor interactions, and Toll-like receptor signaling; in a murine RM-1 xenograft model, tumor volumes were significantly smaller following combination treatment with palbociclib and diABZI compared to monotherapies (n=5, p<0.001), with elevated infiltration of CD4+ and CD8+ T cells (n=3, p<0.001). (2) Mitochondrial DNA (mtDNA) released by senescent tumor cells (96) activates the cGAS–STING pathway in PMN-MDSCs, augmenting their immunosuppressive capacity. Specifically, tumor cells induced into senescence via OIS, PICS, or TIS release mtDNA through voltage-dependent anion channels (VDACs); this mtDNA is packaged into extracellular vesicles (EVs) and selectively internalized by PMN-MDSCs within the tumor microenvironment. Subsequent activation of the cGAS–STING pathway in PMN-MDSCs amplifies NF-κB signaling via the STING–PERK axis, ultimately enhancing immunosuppressive activity. (3) Induction of immunogenic cell death (ICD) in tumor cells via chemotherapy, radiotherapy, or physical interventions (97, 98) promotes the release of damage-associated molecular patterns (DAMPs), activating the cGAS–STING–IFN pathway and facilitating the conversion of cold tumors to hot ones. Pathological evaluation of patient samples (97) revealed substantial T cell enrichment in tumor tissues post-chemotherapy, with significantly higher densities of CD3+, CD4+, and CD8+cells in treated compared to untreated groups (P = 0.0057, 0.031, and 0.031, respectively).
Oncolytic viruses are a class of viruses that can selectively infect and kill tumor cells while stimulating the body’s specific anti-tumor immune response, and their core function lies in breaking tumor immune tolerance and remodeling the “cold” TME. A review of relevant research results shows that: the MG1-Maraba oncolytic virus (99) (carrying the STEAP vaccine) can effectively break tumor immune tolerance and realize the remodeling of the “cold” TME; reovirus (100) can target prostate cancer cells with activated Ras signaling and induce antigen-specific anti-tumor immune responses; when radiotherapy (101) is used in combination with VSV-IFNb (vesicular stomatitis virus-interferon β fusion virus), it can effectively overcome the viral resistance of tumor cells and induce long-term anti-tumor immune memory mediated by CD8+ T cells. In addition, the MG1-GFP oncolytic virus exhibits potent killing activity against human-derived prostate cancer cells (DU145, PC3, LNCaP) and mouse-derived prostate cancer cells (TRAMP-C1, TRAMP-C2); among them, TRAMP-C2 cells are highly sensitive to MG1-GFP at a low multiplicity of infection; in the study of clinical samples, 90% of patients’ biopsy samples can be effectively infected by MG1-GFP, and the yield of the virus in tumor cells is significantly higher than the initial input amount (99).
Besides the aforementioned strategies, other effective approaches for remodeling the “cold tumor” microenvironment of prostate cancer also include: inhibiting YAP1 (102) can transform the functional phenotype of cancer-associated fibroblasts, promote CD8+ T cell infiltration, and thereby enhance the efficacy of anti-PD-1 therapy; mRNA nanoparticles (103) can restore the expression of PTEN in tumor cells, induce immunogenic cell death (ICD) and systemic immune activation, while reducing the infiltration of immunosuppressive cells in the TME; targeting IRE1α (104) can achieve the remodeling of the TME, which is specifically manifested by a reduction in the number of Tregs and TAMs, an increase in the infiltration of CD8+ T cells and NK cells, and thereby exerts a synergistic effect with anti-PD-1 antibodies to effectively inhibit tumor growth.
4 PD-1/PD-L1 expression landscape in prostate cancer
Accumulating clinical evidence establishes that PD-1/PD-L1 expression levels independently predict treatment resistance, disease progression, and adverse prognosis in PCa. A retrospective analysis of 51 prostatectomy patients who underwent pelvic lymph node dissection revealed that PD-L1 positivity-defined as tumor cell staining in at least 1% of cells-correlated with shorter metastasis-free survival and a fourfold increased risk of distant metastasis relative to PD-L1-negative cases (105). Multivariate Cox regression analysis identified PD-L1 overexpression as an independent prognostic biomarker, associated with both elevated serum PSA levels and higher rates of surgical margin positivity (106).
PD-L1 expression patterns and clinical implications in PCa have been extensively investigated. Both primary PCa and CRPC exhibit PD-L1 expression, which correlates with poor prognostic indicators including higher Gleason scores, increased Ki-67 index, elevated PSA levels, and aggressive tumor behavior (107). Analysis of untreated prostatectomy specimens revealed PD-L1 positivity in 13.8% of localized prostate cancer cases, increasing to 26.5% in tumors with Gleason pattern 4–5; neoadjuvant therapy did not significantly alter expression levels (106). Patients with mCRPC exhibited substantially higher PD-L1 positivity (32.1%) than those with primary prostate cancer (7.7%), indicating progressive upregulation during disease progression (108). TCGA RNA sequencing data revealed complex interactions between PD-1/PD-L1 signaling, tumor purity, and immune infiltration patterns (72). Immunohistochemical studies (109) detected increased PD-L1 expression in perineural tissue, and showed an inverse relationship with CD8+ T cell density. Despite their demonstrated efficacy in melanoma, lung cancer, lymphoma, and hepatocellular carcinoma (110), PD-1/PD-L1 checkpoint inhibitors continue to show limited effectiveness in PCa. Addressing this therapeutic gap requires more comprehensive analysis of clinical trial outcomes, clarification of resistance mechanisms, and development of improved combination strategies.
This article summarizes (Table 1) and systematically analyzes recent research findings on the regulation of PD-1/PD-L1 expression in PCa. The analysis reveals that PD-L1 is highly expressed in enzalutamide-resistant PCa cell lines, such as C4-2B MDVR and PC-3, where it strongly correlates with enhanced immune evasion by tumor cells. Treatment with NRP2–28 in vitro effectively reduces PD-L1 expression and augments T cell-mediated antitumor immunity. Additionally, RelB drives PD-L1 expression via the NF-κB signaling pathway, leading to suppression of T cell immune function.
Table 1. PD-1/PD-L1 immunohistochemistry assay characteristics and pathologic associations in prostate cancer.
Based on the available data, combining agents that inhibit PD-L1 expression and enhance anti-tumor immune responses—such as NRP2 or RelB inhibitors—with existing regimens may further improve therapeutic efficacy in prostate cancer. These studies, however, possess notable limitations: while each confirms the significance of PD-1/PD-L1-mediated immune escape in prostate cancer progression, they vary in their specific research emphases. Furthermore, they generally lack comparative data on drug administration sequences, making it impossible to assess how sequencing affects clinical outcomes. Existing research also omits efficacy evaluations in special populations, including elderly patients and those with hepatic impairment. Consequently, the optimal drug sequence for these populations remains to be established through subsequent studies.
5 Clinical exploration of PD-1/PD-L1 targeted immunotherapy for prostate cancer
Clinically, over ten PD-1 antibodies and three PD-L1 antibodies are currently approved for treating various cancers. However, PD-1/PD-L1 inhibitors exhibit limited efficacy in PCa clinical trials, likely attributable to the tumor’s “cold” immunological phenotype.
5.1 PD-1/PD-L1 immune checkpoint inhibitor monotherapy for prostate cancer
As core immune checkpoint inhibitors (ICIs), PD-1/PD-L1 inhibitors significantly improve clinical outcomes in diverse malignancies by disrupting tumor immune evasion. Their safety profiles and toxicity patterns, however, show substantial variability. Although these agents hold therapeutic potential for solid tumors including PCa, clinical trials report persistently low objective response rates, highlighting the urgent need to investigate resistance mechanisms and optimize treatment strategies.
5.1.1 Toxicity profiles of PD-1/PD-L1 inhibitors
Overall, PD-1/PD-L1 inhibitors cause fewer adverse events (AEs) than cytotoxic chemotherapy and maintain a favorable safety profile even when AE rates increase in combination regimens (128, 129). Compared with CTLA-4 inhibitors, PD-1/PD-L1 agents are associated with lower AE frequencies; within the class, PD-1 inhibitors generally report slightly higher AE rates than PD-L1 inhibitors (130).
PD-1/PD-L1 blockade is efficacious in tumor immunotherapy but can trigger AEs because checkpoint inhibition may induce systemic immune overactivation, resulting in autoimmune-like reactions across multiple organs. The liver, gastrointestinal tract, skin, lungs, and endocrine system are most frequently affected (131, 132). The most common nonspecific AEs include fatigue, diarrhea, and pruritus (133). Across anti-PD-1, anti-PD-L1 monotherapies, and combination regimens, reported fatigue incidence ranges from 12% (134) to 71% (135); nearly 70% of patients receiving PD-1/PD-L1 inhibitors experience immune-related adverse events (irAEs), and the incidence approaches universality with combination therapy (131). Cutaneous irAEs are predominant (136, 137), most commonly presenting as lichenoid eruptions (25%) and maculopapular rash (18%).
Representative safety datasets are consistent with this profile. In a pooled analysis of 576 nivolumab-treated patients, any-grade AEs occurred in 71%, grade 3–4 events in 10%, and no treatment-related deaths were observed; most complications resolved spontaneously within weeks (138). A separate nivolumab study reported AEs in 47.3%, primarily grade 1–2 with fatal outcomes remaining exceptional (139). In contrast, the IMbassador250 trial documented AEs in 96.5% of participants (grade 3–4 in 54.3%, grade 5 in 4.3%) and serious AEs in 36.4% (140).
A comprehensive analysis of publicly available data on PD-1/PD-L1 inhibitor monotherapy in PCa demonstrates that PD-1 inhibitors (pembrolizumab, nivolumab; n = 319) (118, 139, 141) were associated with frequent adverse events including gastrointestinal toxicities (nausea, diarrhea, decreased appetite), skin and subcutaneous tissue disorders (maculopapular rash, pruritus, rash), and systemic conditions (fatigue, asthenia, weight loss). Similarly, PD-L1 inhibitors (atezolizumab, avelumab; n = 59) (142–144) commonly induced gastrointestinal toxicities (nausea, decreased appetite, colitis), dermatological manifestations (pruritus, rash, severe cutaneous reactions), and systemic symptoms (fatigue, arthralgia, infusion-related reactions). Fatigue, thyroid dysfunction (hyperthyroidism/hypothyroidism), and gastrointestinal disturbances (nausea, decreased appetite) were observed with both drug classes, with most cases being grade 1–2 in severity. While dermatological AEs (pruritus, rash) occurred frequently, ≥grade 3 reactions were generally uncommon (mostly <2%). Overall, PD-1 inhibitors exhibited higher rates of ≥grade 3 severe adverse events compared to PD-L1 inhibitors. Notably, fatal adverse events (e.g., pneumonitis, sepsis) were occasionally reported in PD-1 inhibitor studies but were not documented in PD-L1 inhibitor trials. Conversely, infusion-related reactions occurred more frequently with PD-L1 inhibitors than with PD-1 inhibitors.
According to the ASCO guideline, irAEs should be graded and managed with organ-specific attention: grade 1–2 toxicities usually do not require treatment interruption; grade 3–4 toxicities warrant permanent discontinuation and intensified immunosuppression. Myocarditis or myasthenia gravis requires escalation of care within 48 hours, whereas most endocrine toxicities rarely necessitate discontinuation (145). Multiple studies suggest that manageable irAEs correlate with better efficacy, and corticosteroid-based toxicity control does not necessarily blunt antitumor activity; upon careful reassessment, re-challenge with PD-1/PD-L1 inhibitors may be appropriate in selected cases (146, 147).
In clinical practice, a combination of baseline assessment and dynamic monitoring is recommended, routinely including complete blood count, endocrine function, and pulmonary evaluation (148). A meta-analysis across cancer types revealed that the median time to onset of irAEs ranges from 2.2 to 14.8 weeks, with severe (ever events typically occurring later; endocrine events require the longest recovery time. Follow-up frequency should be tailored based on the specific onset window and recovery pattern of each irAE (149). Throughout the treatment course, continuous patient and family education is essential, maintaining a high level of vigilance for any new symptoms (145). For PCa patients, special attention should be paid to long-term issues such as hypoandrogenism symptoms and fertility (148).
5.1.2 Clinical trials of PD-1/PD-L1 inhibitor monotherapy for prostate cancer
As key ICIs, PD-1/PD-L1 inhibitors demonstrate therapeutic promise yet face clinical challenges in PCa management. The commonly used agents—nivolumab and pembrolizumab (PD-1 antibodies) and atezolizumab (PD-L1 antibody)—operate through similar mechanisms but exhibit distinct response profiles and efficacy patterns in PCa treatment.
Nivolumab (150, 151) demonstrates high PD-1 binding affinity on T cells, inducing their activation and subsequent tumor cell apoptosis through T cell-mediated cytotoxicity. In a single-arm, multicenter phase II trial (139) involving 38 mCRPC patients, nivolumab treatment yielded a PSA50 response rate (≥50% PSA decline) of merely 10.5% (4 patients), with an overall objective response rate of 26%. A phase I study (152) of nivolumab in 17 mCRPC patients reported no objective responses.
Pembrolizumab (153), a humanized anti-PD-1 monoclonal antibody, augments T cell-mediated antitumor immunity through PD-1/PD-L1 axis blockade. This immunotherapeutic agent demonstrates efficacy across multiple malignancies, including melanoma (154), non-small cell lung cancer (155), and lymphoma (156). Graff (157) conducted a phase II trial evaluating pembrolizumab in mCRPC, observing PSA reductions below 0.1 ng/ml in 3 of 10 treated patients. The KEYNOTE-028 trial (141) enrolled PD-L1-positive patients, with pembrolizumab treatment yielding stable disease in 8 of 23 participants and median PFS and OS durations of 3.5 and 7.9 months, respectively.
Atezolizumab, a humanized IgG1 monoclonal antibody, prevents T cell exhaustion through PD-L1 blockade mediated by antibody-dependent cellular cytotoxicity (158). In a phase Ia trial of 35 mCRPC patients (142), RECIST 1.1 criteria identified one partial responder, while a second patient met the immune-related response criteria. This review synthesizes published clinical trial data on PD-1/PD-L1 inhibitor monotherapy for prostate cancer (Table 2).
Table 2. Therapeutic potential of PD-1/PD-L1 inhibitors for prostate cancer.
5.2 Combination therapies involving PD-1/PD-L1 inhibitors for prostate cancer
As mentioned above, PD-1/PD-L1 inhibitors demonstrate clinical efficacy against multiple tumor types, but their effectiveness in PCa remains limited. Growing insights into immunotherapy’s regulatory mechanisms have driven increasing interest in combination treatment strategies. Current approaches integrate immunotherapy with ADT, radiotherapy, chemotherapy, or other immunotherapeutic agents (Table 3, for more detailed information, please refer to the Supplementary Material).
Table 3. Combined therapeutic approaches involving PD-1/PD-L1 inhibitors and other modalities for prostate cancer.
Although ADT, radiotherapy, and chemotherapy are all conventional treatment modalities for prostate cancer, some patients still experience disease progression during treatment. Current research data indicate that the occurrence of ADT resistance (27, 183–186) is significantly associated with abnormalities in the AR pathway (including low AR activity, upregulation of AR-V7, and inhibition of AR target genes caused by CHD1 deletion), abnormal regulation of myeloid cells (elevated neutrophil-to-lymphocyte ratio (NLR), enrichment of CXCL1/2/8, and infiltration of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs)), and activation of the protein stabilization axis (KIF15-USP14-AR/AR-V7). Notably, reduced AR pathway activity is a necessary condition for resistance to AR signaling inhibitors (186); in addition, PMN-MDSCs can promote resistance to AR signaling inhibitors by activating AR-V7 (27), while KIF15 can enhance the resistance of tumor cells to enzalutamide by stabilizing the protein levels of AR/AR-V7 (184).
The mechanism of radiotherapy resistance (187–190) is closely associated with the high expression of metabolic markers (GLS1, LDHA), upregulation of stem cell-related markers (ALDH1A1), activation of DNA repair genes (PLK3), and high-risk status of CAF-related gene signatures (BCRFS/MFS signatures). Specifically, GLS1 inhibitors can significantly enhance the radiosensitivity of PCa cells (187); high expression of ALDH1A1 is closely associated with bone metastasis of PCa and post-radiotherapy recurrence risk (190); meanwhile, CAF-related gene signatures have high predictive efficacy for post-radiotherapy biochemical recurrence and distant metastasis (188).
Chemotherapy resistance (115, 191, 192) (with docetaxel and cisplatin resistance as the main research objects) occurs in association with intestinal microbiota dysbiosis (enrichment of Proteobacteria), activation of the inflammatory signaling axis (LPS-NF-κB-IL6-STAT3), abnormalities of the metabolic regulatory axis (circARHGAP29-IGF2BP2/c-Myc-LDHA), and dysregulation of the epigenetic regulator (WDR5). Among these, STAT3 inhibitors can increase the apoptosis rate of docetaxel-resistant cells by 2–3 folds (191); silencing circARHGAP29 can effectively reverse the resistance of tumor cells to docetaxel (192); while WDR5 inhibitors can enhance the sensitivity of cells to cisplatin by downregulating the expression of the DNA repair gene (XRCC2) (115).
The mechanisms of immunotherapy resistance (28, 193–196) involve tumor suppressor gene deletion (e.g., PTEN deletion leading to a “cold tumor” phenotype in tumors), abnormal transcription factor regulation (FOXA1 inhibiting the IFN signaling pathway), activation of chromatin effectors (Pygo2-Kit-Ido1 axis), and myeloid cell abnormalities (enrichment of SPP1hi-TAMs). Regarding specific mechanisms, SPP1hi-TAMs can inhibit the anti-tumor function of CD8+ T cells through the adenosine-A2AR pathway (28); while Pygo2 inhibitors can reverse immune checkpoint inhibitor resistance by enhancing the infiltration of cytotoxic T lymphocytes in tumor tissues (195).
5.2.1 PD-1/PD-L1 inhibitor therapy combined with ADT for prostate cancer
Androgen receptor (AR) signaling plays a critical role in driving PCa initiation and progression, thereby establishing AR signaling as a principal therapeutic target. This pathway modulates T-cell function through PTPN1 transcriptional activation while suppressing Th1 cell activity via JAK/STAT pathway downregulation (100). As the cornerstone treatment for metastatic PCa, ADT remodels tumor immune infiltration (197), potentially enhancing PD-1/PD-L1 inhibitor sensitivity (198).
The KEYNOTE-199 trial (199) demonstrated that pembrolizumab combined with enzalutamide in mCRPC yielded a 22% PSA response rate, a 51.1% disease control rate for bone-only metastases, and a median OS of 20.8 months. Phase II studies (199) and the KEYNOTE-365 trial (129) later corroborated the antitumor activity of this regimen. However, the IMbassador250 trial (140) found no significant benefit in OS, PFS, or PSA progression time from adding atezolizumab to enzalutamide, except among patients with high CD8 T-cell infiltration and PD-L1 expression, who showed improved progression-free survival. Investigators have also explored alternative strategies to conventional ADT combinations, such as bipolar androgen therapy. In the COMBAT trial, nivolumab paired with cyclic testosterone modulation achieved a 40% PSA50 response rate (18/45), with median OS reaching 24.4 months and radiographic PFS (rPFS) lasting 5.6 months (182).
5.2.2 PD-1/PD-L1 inhibitor therapy combined with radiotherapy for prostate cancer
Radiotherapy remains a cornerstone treatment for diverse tumor types. By damaging tumor cell DNA and inducing cell death, it modifies the TME while increasing immunogenicity through enhanced release of tumor-associated antigens and upregulation of tumor suppressor proteins and cytokines (200–202). These effects collectively stimulate both adaptive and innate immune responses. Current radiotherapy approaches primarily comprise external beam radiotherapy and targeted radionuclide therapy, distinguished by their dosimetric characteristics.
Radium-223 (203), an alpha-emitting radionuclide, induces DNA double-strand breaks and targets tumor-associated osteoblasts by mimicking calcium-phosphorus complexes, ultimately altering the PCa microenvironment. In mCRPC patients receiving pembrolizumab combination therapy (166), median OS and rPFS reached 16.9 and 6.1 months, respectively, versus 16.0 and 5.7 months with radiotherapy alone. The immune cell infiltration profiles did not differ significantly between treatment groups.
177Lu-PSMA-617 combines the beta-emitting radionuclide Lutetium-177 with PSMA-617, a high-affinity ligand targeting prostate-specific membrane antigen (PSMA) (204),. In mCRPC patients, Aggarwal et al. (167) reported improved therapeutic outcomes when this agent was paired with pembrolizumab. Administering pembrolizumab 28 days after 177Lu-PSMA-617 treatment produced optimal results, with 56% (14/25) of patients showing objective responses (>50% PSA reduction), a median PFS of 6.9 months, and an OS extending to 28.2 months. Another study examined the efficacy of stereotactic ablative radiotherapy (SABR) combined with avelumab (a PD-L1 inhibitor) (180).
5.2.3 PD-1/PD-L1 inhibitor therapy combined with chemotherapy for prostate cancer
Chemotherapy remains a cornerstone of tumor treatment, primarily through tumor cell destruction that releases antigens and damage-associated molecular patterns. This process activates dendritic cells, enhancing antigen cross-presentation and triggering specific immune responses (205). Concurrently, chemotherapy diminishes immunosuppressive cell populations, including MDSCs and Tregs (206, 207). It also stimulates CXCL10 production within tumor tissues, a chemokine that recruits T cells and potentiates tumor-infiltrating lymphocyte activity through its dual chemotactic and immunomodulatory functions (208). As a steroidal antimitotic agent, docetaxel exerts its apoptotic effects by binding β-tubulin and disrupting microtubule dynamics during cell division (97).
In the CheckMate 9KD trial, nivolumab plus docetaxel was administered to patients with mCRPC (128). The combination achieved an ORR of 40.0% among 84 treated patients, with a median time to response of 2.0 months. The median response duration was 7.0 months, and median rPFS stood at 9.0 months. Median OS reached 18.2 months.
The KEYNOTE-921 trial investigated pembrolizumab plus docetaxel (161, 209) in mCRPC patients. Of the 1030 randomized participants, 515 were treated with the pembrolizumab-docetaxel combination. The ORR was 33.5%, with a median response duration of 6.3 months. Median rPFS survival reached 8.6 months, while the OS was 19.6 months. Previous studies have also examined pembrolizumab combined with platinum-based chemotherapy (170) for small cell or neuroendocrine PCa.
5.2.4 Other combinatorial immunotherapy approaches for prostate cancer
The limited efficacy of monotherapy with immune checkpoint inhibitors has driven research toward combination approaches. CTLA-4, primarily expressed on activated T cells and regulatory T cells, suppresses T cell activity through mechanisms such as PI3K-Akt pathway inhibition and CD80/CD86 degradation (210). In the CheckMate 650 trial (173), nivolumab combined with ipilimumab achieved a 10.0% objective response rate, 6.7% complete response rate, and 13.3% disease control rate, with a median rPFS of 3.8 months in mCRPC patients previously treated with chemotherapy.
Comparative analysis of different combination regimens reveals that for patients with mCRPC progressing after enzalutamide, the sequence of pembrolizumab combined with enzalutamide yields a significantly higher PSA response rate than other combinations; its mechanism-checkpoint blockade plus ADT-may enhance antitumor immune activity and improve overall efficacy. However, among mCRPC patients who have received no more than two prior lines of metastatic therapy, this combination should be avoided due to both reduced efficacy and increased side effects, including a higher incidence of grade 2–3 immune-related adverse events.
To improve the clinical outcomes of immunotherapy while minimizing toxicity, researchers are investigating novel combination therapies, including pembrolizumab with docetaxel and prednisone (162) as well as nivolumab and ipilimumab paired with enzalutamide (52). Although ORR and survival times show improvement, treatment-related AEs remain a growing concern. These findings offer robust clinical evidence to advance precision immunotherapy for PCa and inform future personalized combination approaches.
6 Current challenges and future perspectives
The development of ICIs targeting the PD-1/PD-L1 axis has expanded therapeutic options for advanced PCa, although clinical outcomes continue to demonstrate limited efficacy. As a “cold tumor,” PCa demonstrates robust immune resistance, resulting in significantly poorer responses to PD-1/PD-L1 inhibitors compared to those observed in lung cancer (211), melanoma (212), squamous cell carcinoma (213), or hepatobiliary and colorectal malignancies (214). To enhance ICI efficacy, overcoming this resistance is imperative. Current strategies integrate ICIs with conventional treatments like ADT, radiotherapy, or chemotherapy, as well as emerging modalities such as alternative checkpoint inhibitors, cancer vaccines, and targeted therapies. While these combinations can amplify antitumor immunity, they frequently exacerbate treatment-related toxicities, underscoring the need for more refined patient selection. Major challenges involve managing overlapping adverse effects, establishing optimal dosing sequences, and mitigating irAEs arising from dual checkpoint blockade. Future studies should address these constraints through rigorously designed clinical trials.
First, PCa immune evasion arises from a complex regulatory network spanning multiple pathways. The JAK–STAT and PI3K–AKT–mTOR cascades directly modulate PD-L1 expression, while metabolic reprogramming and epigenetic modifications synergistically promote immune escape (215, 216). These insights inform the development of targeted immunotherapies. However, the substantial interpatient and intratumoral heterogeneity of PCa limits one-size-fits-all approaches. Tumor heterogeneity further compounds complexity in an already heterogeneous patient population (217). A single biomarker (e.g., PSA, an individual gene mutation, or a solitary imaging feature) is insufficient to predict responses to combination therapies; integrating multi-omics data—including genomics, transcriptomics, proteomics, radiomics, and clinical information—enables a more comprehensive evaluation of patient responses, improves predictive accuracy, and supports effective screening for immunotherapy-based combination regimens (218–220). For example, a predictive model based on macrophage-related marker genes (221) has demonstrated potential in guiding the precise selection of combination therapies, enabling the prediction of responses to ICIs, identifying chemotherapy-sensitive subgroups, and assisting in the combined application of targeted drugs. Future studies should prioritize predictive model development through integrated multi-omics analyses of genomic, transcriptomic, and proteomic profiles.
Second, clinical consensus is lacking on optimal timing and sequencing of immunotherapy. Emerging evidence suggests that initiating ICIs during the metastatic hormone-sensitive PCa (mHSPC) phase may improve outcomes, but confirmation is needed. For advanced disease, clinicians must carefully integrate immunotherapy with standard modalities (e.g., ADT, taxane-based chemotherapy, radiotherapy) (178). Robust response assessment systems and dynamic monitoring remain priorities, including identification of precise biomarkers (174, 222) such as CDK12 biallelic inactivation (CDK12i). A multicenter retrospective study (223) involving 52 cases of CDK12-mutated PCa (including 27 cases with biallelic mutations) reported a median post-metastasis survival of 3.9 years during follow-up, with 63% of patients progressing to CRPC within three years. Additionally, 79% of patients exhibited a tandem duplication signature, and those with a higher degree of tandem duplication dispersion had worse survival outcomes (HR = 2.8, P = 0.01). In contrast, a prospective study (172) found that most patients with biallelic inactivation of CDK12 did not respond to treatment.
Third, the interplay between the TME and immunotherapy remains incompletely characterized, impeding rational design of combinations. As a “cold” tumor, PCa responds poorly to PD-1/PD-L1 inhibitors largely due to an immunosuppressive TME. This suppression reflects the coordinated actions of Tregs, MDSCs, and inhibitory cytokines (e.g., IL-10, TGF-β), which collectively blunt T cell–mediated antitumor immunity. Systematic mapping of stromal–immune crosstalk using single-cell sequencing and organoid co-culture models would advance mechanistic understanding. Improved drug-delivery systems (224) capable of overcoming microenvironmental barriers may enhance the effectiveness of combined ADT, radiotherapy, and chemotherapy.
Fourth, a more comprehensive biomarker system is needed to improve treatment selection. PD-L1 expression and TMB have limited predictive value in PCa (174). Liquid-biopsy assessment of PD-L1/AR-V7 co-expression in CTCs (225) provides real-time readouts of immune-evasion dynamics. Circulating microbiome DNA (cmDNA) (226), a bone metastasis-related gene prognostic index derived from single-cell sequencing of CTCs (227), and blood-based TMB assays (228) all show promise in distinguishing patients from healthy individuals, predicting immunotherapy benefit and durability, and complementing dynamic monitoring of circulating tumor DNA (ctDNA) mutation profiles. Liquid biopsy facilitates dynamic monitoring in PCa immunotherapy through several key mechanisms: firstly, by tracking immune checkpoint expression and evasion mechanisms:pyg, as the shift from PD-L1 to B7-H3 dominance on CTCs following PD-1 inhibitor therapy, indicating adaptive resistance and the need for target adjustment (81); ctDNA-based detection of MSI-H status also demonstrates high concordance with tissue testing (86% sensitivity, 99.5% specificity), supporting patient selection for immune checkpoint inhibitors (229). Secondly, it captures genomic heterogeneity and the evolution of resistant clones; serial next-generation sequencing can trace temporal changes in resistant populations (230). Thirdly, it assists in treatment response prediction and prognostic stratification: AR-V7 positivity in CTCs is associated with significantly shorter progression-free survival under AR pathway inhibitor treatment (1.4 vs. 6.0 months) (231), predicts resistance to AR-targeted therapies (232), and blood-based MSI-H status is significantly correlated with progression-free survival in advanced disease (228). Nevertheless, liquid biopsy remains constrained by insufficient assay standardization, limited prospective validation, and high costs. An integrated model combining genomic markers, immune microenvironment profiling, and metabolomic signatures could yield a quantifiable system for therapeutic-outcome prediction.
Fifth, multi-center studies incorporating population-specific data are needed to generate robust, generalizable evidence. Global initiatives (e.g., CheckMate 650, KEYNOTE-365) have begun addressing racial and regional disparities via multinational collaboration. Establishing STROBE-compliant real-world databases with standardized RECIST v1.1 + PCWG3 composite criteria and interoperable data-sharing platforms would raise research quality. Particular attention should focus on TME dynamics during castration resistance, with adaptive trial designs used to validate novel biomarkers. Ultimately, advances in PCa immunotherapy will require integration of mechanistic discovery, biomarker development, and clinical validation to elevate immunotherapy from a supplementary option to a cornerstone of precision oncology, thereby improving survival outcomes.
7 Summary
Although prostate cancer is generally classified as an immunologically “cold” tumor demonstrating a poor response to conventional immunotherapeutic approaches, PD-1/PD-L1 inhibitors manifest significant antitumor activity through three distinct mechanisms: (1) blockade of T-cell inhibitory signaling pathways, (2) enhancement of T-cell activation, and (3) reduction of tumor immune evasion. Nevertheless, the clinical efficacy of PD-1/PD-L1 inhibitor monotherapy in prostate cancer patients persists at suboptimal levels, which may be partially explained by the characteristically low PD-L1 expression levels observed in prostate cancer. Combined therapeutic approaches appear more promising for enhancing patient outcomes. Further research should elucidate the underlying immunotherapeutic mechanisms in PCa and explore innovative treatment modalities. Subsequent investigations must focus on refining the efficacy-to-safety ratio of immunotherapy while evaluating its synergistic potential with existing therapies to optimize clinical results.
Author contributions
GH: Conceptualization, Data curation, Visualization, Writing – original draft. ZL: Writing – original draft, Conceptualization, Data curation. YC: Data curation, Visualization, Writing – original draft. HL: Supervision, Writing – review & editing. SZ: Conceptualization, Funding acquisition, Supervision, Writing – review & editing.
Funding
The author(s) declared that financial support was received for this work and/or its publication. This research was supported by the Natural Science Foundation of Sichuan Science and Technology Agency(No. 2024NSFSC0699).
Conflict of interest
The authors declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Supplementary material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2025.1664587/full#supplementary-material
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Keywords: prostate cancer, PD-1/PD-L1, immune microenvironment, immunotherapy, combined therapy
Citation: Hu G, Li Z, Chen Y, Liao H and Zhou S (2025) Advances in the application of PD-1/PD-L1 immunotherapy for prostate cancer: a review. Front. Immunol. 16:1664587. doi: 10.3389/fimmu.2025.1664587
Received: 12 July 2025; Accepted: 04 November 2025; Revised: 01 September 2025;
Published: 19 December 2025.
Edited by:
Stefano Cavalieri, Fondazione IRCCS Istituto Nazionale dei Tumori, ItalyReviewed by:
Xinpei Deng, Sun Yat-sen University Cancer Center (SYSUCC), ChinaIk-Hwan Han, Kyung Hee University, Republic of Korea
Copyright © 2025 Hu, Li, Chen, Liao and Zhou. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Hong Liao, bGlhb2hvbmcxMzFAMTYzLmNvbQ==; Shukui Zhou, amFja3RlbkBhbGl5dW4uY29t
†These authors have contributed equally to this work