Multidimensional explanations and future perspectives on the limited efficacy of immunotherapy in prostate cancer

Abstract

As immunotherapy continues to push the envelope, it has had transformative success in malignancies such as melanoma and lung cancer. However, in contrast to these cancers, implementing immunotherapy in prostate cancer (PCa) still presents considerable difficulties. PCa itself is not sensitive to immunotherapy. The low response rate of PCa to immunotherapy cannot be attributed to a single mechanism. Instead, it results from the interplay of multiple adverse factors. These include the tumor’s inherently low immunogenicity and the highly immunosuppressive properties of its tumor microenvironment. Taken together, these features create a “perfect storm” that severely limits the efficacy of immunotherapy. In this review, we comprehensively assess the latest advances in PCa immunotherapy, encompassing cancer vaccines, immune checkpoint inhibitors (ICIs), chimeric antigen receptor T cell (CAR-T) therapy, and various combination regimens. We also summarize their limited efficacy observed in clinical practice to date. Furthermore, we explore the underlying mechanisms contributing to the limited effectiveness of immunotherapy in PCa, with a focus on intrinsic molecular features, the immunosuppressive microenvironment, and key signaling pathways. Through an in-depth review of previous studies, we aim to provide a theoretical foundation and strategic guidance to enhance the effectiveness of immunotherapy for PCa and to facilitate the development and translation of more targeted and effective immunotherapeutic interventions.

INTRODUCTION

Prostate cancer (PCa) is the most common malignancy affecting men and the second most commonly diagnosed cancer worldwide.1 Early-stage PCa is typically localized with a relatively low disease burden. Patients generally have a good prognosis with standard treatments, which include radical prostatectomy, radiotherapy, androgen deprivation therapy, novel endocrine therapies, and chemotherapy. The 5-year survival rate for localized PCa is reported to be close to 100%.2 However, PCa develops resistance to conventional treatments over time, and most patients eventually progress to castration-resistant prostate cancer (CRPC), which is characterized by high heterogeneity and aggressiveness. Lack of prompt treatment can lead to disease progression and death.3 Therefore, identifying more effective strategies to delay disease progression and improve patient survival is an urgent priority.

With ongoing research in immunotherapy, favorable outcomes have been achieved for several tumors, including melanoma and lung cancer, marking a major breakthrough in cancer treatment.4,5 By harnessing the host’s immune system to recognize and eliminate tumor cells, immunotherapy is reshaping the conventional cancer treatment paradigms. For example, combining pembrolizumab and nivolumab can increase survival in patients with melanoma by nearly threefold.⁶ However, immunotherapy continues to face challenges in PCa. Various immunotherapeutic approaches, including immune checkpoint inhibitors (ICIs), therapeutic vaccines, and chimeric antigen receptor T cell (CAR-T) therapy, have been explored in clinical trials for PCa. Most have failed to demonstrate efficacy in PCa comparable with that in other cancers.7,8,9 Possibly because of the specific tumor microenvironment (TME) of PCa. PCa is widely considered to be an “immunologically cold” tumor with an immunosuppressive tumor immune microenvironment (TIME) and a limited antitumor immune response.10 Therefore, it is important to improve our knowledge of PCa immune phenotypes and the factors hindering the effectiveness of immunotherapy.

The weak immunogenicity of PCa may be attributable to low tumor mutational burden (TMB), insufficient expression of programmed death ligand 1 (PD-L1), and impaired antigen presentation.11,12,13 Furthermore, the TME of PCa harbors multiple immunosuppressive cells, including tumor-infiltrating lymphocytes (TILs), tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and cancer-associated fibroblasts (CAFs).14,15,16 These cells cooperate to establish an immunosuppressive milieu that further impedes the efficacy of immunotherapy. This article systematically reviews the main immunotherapeutic strategies and key clinical advances in the treatment of PCa, explores the reasons for the limited efficacy of current immunotherapies, and suggests research directions for the development of better-targeted and more efficient combination immunotherapy strategies.

IMMUNOTHERAPY FOR PROSTATE CANCER: LIMITED EFFICACY TO DATE

Immunotherapy offers advantages over conventional treatments for a range of malignant tumors, including melanoma, with markedly extended overall survival (OS).17,18,19 However, clinical trials of immunotherapies for PCa have been largely disappointing; many studies, including those of sipuleucel-T, prostate-specific antigen-targeted poxvirus vaccine (PROSTVAC), granulocyte–macrophage colony-stimulating factor (GM-CSF), gene transduced autologous tumor vaccine (GVAX), pembrolizumab, ipilimumab, and various combination regimens, have either demonstrated benefit only in selected subpopulations or been terminated for futility (Table 1).

Table 1.

Clinical trial of immunotherapy for prostate cancer

Study population	Treatment	Phase	Patient (n)	Outcome	Clinical registration number	Study status	Reference
mCRPC	Sipuleucel-T	III	512	Sipuleucel-T prolongs survival in male patients with mCRPC, greater efficacy in asymptomatic or mildly symptomatic CRPC patients	NCT00065442	Completed	23
mCRPC	PROSTVAC	III	1297	The clinical trial was terminated early due to limited efficacy	NCT01322490	Completed	28
CRPC	GVAX	III	626	The clinical trial was terminated early due to limited efficacy	NCT00133224	Terminated	30
mCRPC	Pembrolizumab + olaparib	III	793	Combination therapy fails to improve rPFS and OS in unscreened mCRPC patients	NCT03834519	Completed	43
mCRPC	Pembrolizumab + enzalutamide	III	1251	The trial was terminated due to futility and more and more severe AEs were seen in the combination group	NCT04191096	Active	44
mCRPC	Ipilimumab	III	602	Ipilimumab showed no significant difference in OS in mCRPC patients compared with placebo and 9 patients died of treatment-related AEs	NCT01057810	Completed	61
mCRPC	Ipilimumab	III	799	Ipilimumab failed to improve OS in patients with mCRPC	NCT00861614	Completed	62
mCRPC	Atezolizumab + enzalutamide	III	759	In the planned biomarker subgroup analysis, longer rPFS was observed with atezolizumab	NCT03016312	Completed	47
mCRPC	Durvalumab + tremelimumab	II	52	Durvalumab alone failed to observe an OR compared to 19.4% in the combination therapy group	NCT02788773	Completed	49
mCRPC	Durvalumab + olaparib	II	17	This combination regimen has shown some antitumor activity in patients harboring mutations in the DDR gene, but efficacy remains limited in the overall patient population	NCT02484404	Active	50
NEPC/AVPC	Avelumab	II	15	The clinical trial was terminated early due to limited efficacy	NCT03179410	Completed	53
mCRPC	Avelumab + SABR	II	31	The combination was safe and well tolerated, with half of the patients benefiting from this combination therapy	ACTRN12618000954224	Completed	54
mCRPC	CAR-T	I	18	Three patients had PSA reductions of 30% or more, with isolated instances of reductions of approximately 98%, but one patient died of treatment-related sepsis	NCT03089203	Active	69
mCRPC	Ipilimumab + radiotherapy	III	799	A small proportion of long-term surviving patients were able to benefit from the combination therapy, but there was no significant difference in the overall OS data analysis compared to the control group	NCT03016312	Completed	73
mCRPC	DCVAC/PCa + docetaxel	III	1182	DCVAC/PCa combined with docetaxel does not prolong OS in mCRPC patients	NCT02111577	Completed	83
mCRPC	Pembrolizumab + docetaxel	III	1030	Pembrolizumab combined with docetaxel failed to improve OS in mCRPC patients and nine patients died of treatment-related AEs	NCT03834506	Completed	45

ACTRN: Australian New Zealand clinical trials registry number; AE: adverse event; AVPC: aggressive variant prostate cancer; CAR-T: chimeric antigen receptor T cell; CRPC: castration-resistant prostate cancer; DCVAC/PCa: dendritic cell vaccine for prostate cancer; DDR: DNA damage repair; GVAX: gene transduced autologous tumor vaccine; mCRPC: metastatic castration-resistant prostate cancer; NEPC: neuroendocrine prostate cancer; NCT: National Clinical Trial; OR: objective response; OS: overall survival; PCa: prostate cancer; PD-1: programmed death-1; PD-L1: programmed death ligand-1; PROSTVAC: prostate-specific antigen-targeted poxvirus vaccine; PSA: prostate-specific antigen; rPFS: radiographic progression-free survival; SABR: stereotactic ablative body radiotherapy

A dendritic cell-based vaccine

PCa has long been at the forefront of cancer vaccine research, primarily because it expresses targetable tissue-specific antigens.20 Sipuleucel-T is the first vaccine for PCa to be approved by the U.S. Food and Drug Administration (FDA). Its mechanism of action involves ex vivo activation of the patient’s antigen-presenting cells using a recombinant fusion protein (PA2024).21 PA2024 is a recombinant fusion protein composed of prostatic acid phosphatase, a prostate tumor-associated antigen, and GM-CSF. Upon reinfusion, the activated antigen-presenting cells elicit a prostatic acid phosphatase-specific T cell-mediated immune response that enables the immune system to recognize and target PCa cells.22 In the InforMing the PAthway of COPD Treatment (IMPACT) study, sipuleucel-T increased median OS in patients with metastatic CRPC (mCRPC) by approximately 4.1 months. Notably, sipuleucel-T did not produce significant changes in disease-specific markers (e.g., prostate-specific antigen [PSA] levels) or tumor size in patients with CRPC,23,24 suggesting that sipuleucel-T primarily extends survival through immune activation rather than directly reducing tumor burden. It should be noted that although sipuleucel-T is approved for patients with early-stage CRPC, its efficacy in more advanced or symptomatic CRPC has yet to be evaluated.

A viral vector-based vaccine

PROSTVAC is a recombinant viral vector vaccine engineered to express PSA in host cells, thereby directing immune cells to selectively target PSA-expressing PCa cells.25 PROSTVAC also carries three co-stimulatory molecules that can activate a powerful immune response in T cells. These modalities synergize to precisely target and eradicate PCa cells, thereby having the intended therapeutic effect.26 In early clinical trials, PROSTVAC did not improve progression-free survival (PFS) in patients with mCRPC but extended their OS by 8 months.27 Ultimately, the Phase III study showed almost no survival advantage for PROSTVAC over placebo (34.4 months vs 34.3 months) and was terminated early.28 This represents a major setback, indicating that generating PSA-specific T cell responses alone is insufficient to slow the progression of advanced PCa.

A whole-cell tumor vaccine

GVAX is a whole-cell vaccine engineered by genetic modification. Derived from irradiated PCa cells, GVAX is genetically engineered to secrete human GM-CSF. The vaccine leverages these modified cancer cells to present multiple tumor-associated antigens while continually releasing GM-CSF to recruit dendritic cells, enhance antigen presentation, and elicit robust T cell-mediated antitumor immunity. Before entering Phase II trials, GVAX had shown an excellent safety profile and strong immunogenicity.29 Two Phase III clinical trials were then launched to evaluate GVAX as immunotherapy in patients with mCRPC. Both these studies were terminated prematurely because of insufficient efficacy or excessive toxicity.30 Multiple factors have limited the efficacy of GVAX, including the restricted potency of a single immunostimulatory factor, obstacles to surmounting tumor immune evasion, and a lack of target specificity. Furthermore, non-negligible toxicities have been observed in a subset of patients during clinical trials, suggesting that GVAX-induced immune activation may trigger nonspecific inflammation or immune-related adverse events, further limiting its translational potential.31

The results of the clinical trials to date indicate that therapeutic cancer vaccines have limited efficacy in patients with PCa. Their efficacy is often inadequate because of the immunosuppressive TME, immune tolerance, and lack of effective biomarker-based patient selection. However, research on these vaccines has laid the groundwork for immunotherapy in PCa and encouraged investigations into transforming the “cold” TIME.

Anti-programmed cell death protein 1 (PD-1)/PD-L1 therapies

Targeting PD-1/ PD-L1 or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) with immune checkpoint blockade antibodies has produced significant clinical benefits in various malignancies by reactivating T cells that eliminate tumor cells.32,33,34 Several studies have also evaluated the effects of ICIs in PCa. Unfortunately, monotherapy with ICIs has shown limited efficacy in unselected patients with PCa.

PD-1 is an immune checkpoint receptor expressed on T cells, B cells, macrophages, and other immune cells. By binding to its ligands PD-L1 and programmed cell death 1 ligand 2 (PD-L2), PD-1 plays an essential role in modulating excessive immune activation. However, tumor cells can exploit this pathway by expressing PD-L1 or PD-L2 to engage PD-1 and suppress immune cell activity, thereby facilitating immune evasion.35 Pembrolizumab targets PD-1, blocking its interaction with PD-L1 and PD-L2, thereby reversing T cell inhibition and restoring T cell proliferation, cytotoxicity, and production of cytokines to enhance antitumor immunity.36 Expression of PD-L1 is typically lower in PCa than that in melanoma or lung cancer, which limits the efficacy of PD-1/PD-L1 inhibitors in PCa.37 Nevertheless, some success has been achieved with ICIs. Pembrolizumab elicits a marked therapeutic response in cases of mCRPC characterized by mismatch repair deficiency (dMMR) or high microsatellite instability (MSI-H)38 and is presently the only ICI approved by the FDA for PCa, with its use confined to MSI-H or dMMR tumors. Given the limited efficacy of monotherapy, current studies are exploring combination treatment strategies. Clinical studies of pembrolizumab have focused mainly on its combination with commonly used therapeutic agents, aiming to improve patient survival and overcome tumor immune tolerance. The KEYNOTE-365 study assessed pembrolizumab combined with standard therapy for mCRPC (i.e., abiraterone, enzalutamide, and olaparib), and early results demonstrated encouraging antitumor efficacy and acceptable safety profiles.39,40,41,42 However, subsequent studies have raised questions about the efficacy of these combinations. In KEYLYNK-010, a large Phase III clinical trial of pembrolizumab plus olaparib in patients with mCRPC, combination treatment only extended OS by 1.2 months and radiographic PFS by 0.2 months in comparison with standard therapy, and the study was terminated.43 Similarly, in the Phase III KEYNOTE-991 study, the addition of pembrolizumab to enzalutamide did not benefit patients with metastatic hormone-sensitive PCa and was stopped.44 Moreover, the recently published KEYNOTE-921 trial demonstrated that pembrolizumab in combination with docetaxel did not improve clinical outcomes in mCRPC.45 The clinical results of the KEYNOTE-921 and KEYNOTE-991 trials ultimately demonstrated that adding pembrolizumab to a standard first-line treatment regimen did not have a clinical benefit in patients with PCa.44,45 These findings challenge the earlier optimistic expectations for first-line combination therapy strategies.

In addition to targeting PD-1, immune responses can also be reactivated by targeting its ligand, PD-L1. Atezolizumab achieves this by targeting PD-L1 and blocking its interaction with PD-1, thereby relieving functional suppression of T cells.46 Atezolizumab, which inhibits PD-L1, has also undergone clinical trials for PCa within the scope of ICI research. Atezolizumab in combination with enzalutamide was recently assessed in a Phase III clinical trial. However, in unselected patients, adding atezolizumab did not enhance the efficacy of enzalutamide. Not only did OS not improve, but radiographic PFS and time to PSA progression did not show any benefit from combination therapy.47 This study was ultimately terminated for futility. These findings underscore the challenges faced when using current immunotherapy strategies in the treatment of PCa, which is an archetypal “immune-cold” tumor.

Like atezolizumab, durvalumab restores T cell-mediated immune activity by targeting PD-L1 and blocking its interaction with PD-1.48 Durvalumab has emerged as an important agent in PCa immunotherapy research, particularly in combination therapy strategies. A Phase II trial in patients with mCRPC found no objective response when durvalumab was administered alone and an objective response rate of 19.4% in patients who received durvalumab in combination with tremelimumab, suggesting that dual immune checkpoint inhibition may have antitumor activity in specific patients.49 Another Phase II trial evaluated the efficacy of durvalumab combined with olaparib in patients with mCRPC. This regimen was predicated on the notion that DNA damage induced by poly(ADP-ribose) polymerase (PARP) inhibition would increase tumor immunogenicity, thereby potentiating the immune response. Although this combination had measurable antitumor activity in patients harboring DNA damage response and repair gene mutations, its efficacy remained limited in the overall patient population.50 These findings highlight the need to select patient populations based on molecular features and precisely match immunotherapy combinations.

Avelumab has a mechanism of action similar to that of atezolizumab and durvalumab. However, unlike other PD-L1 inhibitors, avelumab retains an intact fragment crystallizable (Fc) region, enabling antibody-dependent cellular cytotoxicity, which is an additional mechanism contributing to its antitumor activity.51,52 Research on avelumab in PCa has primarily focused on specific patient subgroups. This is because early clinical trials of avelumab in unselected patients with PCa did not show satisfactory efficacy, with significant responses observed only in patients with MSI-H features.53 Concurrently, research on avelumab shifted from monotherapy toward combination approaches. A subsequent Phase II trial assessed the effectiveness of avelumab in conjunction with stereotactic ablative radiotherapy in patients with treatment-resistant mCRPC. Disease control was maintained for 6 months or more in about half of the patients in that study.54 Radiotherapy can induce immunogenic cell death and enhance tumor antigen exposure, thereby producing synergistic effects with ICIs.55 This finding provides important clinical evidence for developing strategies that combine radiotherapy and immunotherapy.

In summary, ICIs have shown limited efficacy in unselected patients with PCa. However, for patients with specific molecular features, some treatment combinations can yield better therapeutic responses. The relevant studies highlight the importance of patient stratification and individualized immunotherapy for PCa. The current guidelines for treatment of PCa do not include ICIs in standard therapy, considering them only for patients positive for biomarkers such as MSI-H and dMMR. Identifying more precise biomarkers and optimizing combination treatment strategies will be key to achieving breakthroughs in immunotherapy for PCa.

Anti-CTLA-4 therapies

Ipilimumab is a monoclonal antibody that targets CTLA-4, effectively preventing its interaction with cluster of differentiation 80 (CD80) and cluster of differentiation 86 (CD86), which enhances T cell-mediated immune responses against tumors.56 Ipilimumab was the first ICI to demonstrate a significant survival benefit in melanoma and the first to be approved by the FDA.57 Its efficacy was subsequently confirmed in several other malignant tumors.58,59,60 However, responses to immunotherapy vary according to the type of tumor. Multiple clinical trials have evaluated ipilimumab in PCa, but none have achieved the expected efficacy. Compared with placebo, high-dose ipilimumab administered post-chemotherapy did not improve OS.61 Another trial found no significant difference in survival following palliative radiotherapy for bone metastases in mCRPC between patients who received ipilimumab and those who received a placebo.62 Overall, the clinical trial data indicate that ipilimumab has limited efficacy in PCa when administered as monotherapy. Future strategies should consider combining ipilimumab with PD-1/PD-L1 inhibitors to achieve dual checkpoint blockade and enhance its antitumor effects.

CAR-T therapies

In CAR-T therapy, T cells are genetically modified to express chimeric antigen receptors targeting defined tumor-associated antigens.63 This approach has achieved breakthroughs in hematologic malignancies, particularly acute lymphoblastic leukemia and certain types of lymphoma, significantly improving long-term patient survival.64,65 However, extending this success to solid tumors like PCa remains challenging.66 Prostate-specific membrane antigen-targeted CAR-T cells have been tested in early-stage trials.67,68 In a Phase I trial of prostate-specific membrane antigen-targeted CAR-T therapy, approximately 30% of patients with mCRPC experienced a reduction in PSA of over 30%, with reductions of up to 98% in some cases.69 However, toxicity was substantial, with nearly half of the patients experiencing high-grade cytokine release syndrome and some dying from treatment-related sepsis. The highly suppressive tumor milieu appears to compromise the activity of CAR-T cells in PCa, limiting their effectiveness.

Immunotherapy combined with radiotherapy

Radiation to the site of a tumor has been confirmed to boost infiltration of T cells, which may assist in overcoming immune resistance.70 Synergistic effects have been observed in preclinical models of melanoma and breast cancer when stereotactic ablative radiotherapy is combined with PD-1 inhibitors. The mechanism is related to enhanced tumor antigen presentation.71 A recent clinical trial in patients with lung cancer demonstrated that the addition of radiotherapy to pembrolizumab extended PFS by 4.6 months and OS by 10.5 months beyond that achieved by pembrolizumab alone, significantly improving clinical outcomes.72 Based on these preclinical and clinical findings, combining immunotherapy with radiotherapy can be considered a promising approach. Another recent study evaluated the efficacy and safety of avelumab in combination with radiotherapy in patients with mCRPC. More than 50% of patients achieved durable disease control. Notably, patients with predominantly lymph node soft tissue disease derived more sustained clinical benefit from the combination therapy.54 However, this trial was only a Phase II investigation of avelumab used alongside radiotherapy, and whether this combination has definitive clinical efficacy requires confirmation in larger Phase III trials. Another Phase III study has evaluated the outcomes of ipilimumab following radiotherapy in patients with mCRPC. After a follow-up of up to 2.4 years, only 29 patients survived in the placebo group, while 49 patients survived in the ipilimumab group. Although these findings appeared encouraging, the final analysis of OS did not reveal a significant difference between the ipilimumab and placebo groups. Furthermore, the study demonstrated that only a minority of patients could potentially benefit from this combined regimen.73

In summary, the studies reported to date have not confirmed a significant improvement in OS from ICIs combined with radiotherapy. However, some findings suggest that this strategy may afford durable disease control and clinical benefits for patients with specific subtypes of mCRPC, such as those with soft tissue metastases or radiotherapy-sensitive characteristics.54

Immunotherapy combined with androgen receptor pathway inhibitors (ARPIs)

For most mCRPC patients, ARPIs remain the preferred first-line treatment.74 AR signaling is a key driver of mCRPC progression, and ARPIs such as enzalutamide and abiraterone inhibit this pathway through different mechanisms, significantly improving patient survival.75,76 Furthermore, enzalutamide is known to increase the number of natural killer (NK) cells and decrease the creation of MDSCs.77 This may help to improve the immune microenvironment in patients with PCa, allowing more patients to benefit from immunotherapy. Clinical trials of enzalutamide in combination with ICIs have now been completed. Although preclinical studies showed that enzalutamide has clear immunomodulatory effects, clinical trials have indicated no significant improvement in OS for patients with CRPC.47 Therefore, simply adding ICI therapy to an AR pathway inhibitor regimen may not be sufficient to benefit patients with mCRPC.

Immunotherapy combined with chemotherapy

Docetaxel is the standard first-line treatment for mCRPC, particularly when other treatments have failed or the disease has progressed.78 Docetaxel activates the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) signaling pathway in PCa, indirectly inducing an interferon response by regulating this pathway.79 Activation of interferon enhances infiltration of T cells, contributing to an improved TIME. Docetaxel can also increase the expression levels of PD-1 and PD-L1, making mice responsive again to PD-1 inhibitors.79 Docetaxel combined with immunotherapy can enhance the antitumor immune response through multiple mechanisms, making it a potential combination strategy for improving the efficacy of immunotherapy.80,81,82 However, subsequent clinical trials that investigated docetaxel combined with immunotherapy have generally failed to meet expectations. Dendritic cell-based immunotherapy (DCVAC)/PCa is an active dendritic-cell-based immunotherapy that boosts the body’s immune response to a tumor. A study that evaluated the impact of using docetaxel alongside DCVAC/PCa in patients with mCRPC found that the median OS in the combination therapy group was 0.4 months shorter than that in the docetaxel group.83 Although the combination therapy demonstrated good tolerability and safety, it did not extend OS and was even slightly inferior to docetaxel alone. The study also found no significant difference in any secondary efficacy measure, including radiographic PFS and time to PSA progression, indicating that DCVAC/PCa combined with docetaxel is ineffective in mCRPC.83 Furthermore, according to recently published data from KEYNOTE-921, patients with mCRPC did not benefit from combination therapy using pembrolizumab and docetaxel. Compared with standard treatment, the combination only improved OS and radiographic PFS by 0.6 months and 0.3 months, respectively.45 Moreover, this combination was associated with more severe toxicity and adverse reactions.

The results of the recent clinical trials suggest that most patients with PCa do not achieve durable remission with immunotherapy and that immunotherapy may only be effective in patients with mild symptoms or specific disease subtypes. This limitation not only reflects the unique TME of PCa but also highlights the complexity of immune escape mechanisms. Detailed evaluation of the factors that limit the effectiveness of immunotherapy in PCa will contribute to the improvement of current approaches and advance the development of more efficient combination treatments.

FACTORS CONTRIBUTING TO IMMUNOTHERAPY RESISTANCE

Some intrinsic features of PCa cells and their antigens limit the effectiveness of immunotherapy. Compared with cancers that have higher immunogenicity, such as melanoma and lung cancer, prostate tumors exhibit characteristics including low TMB, low PD-L1 expression, and deficiencies in antigen presentation (Figure 1). These features greatly limit the role of immunotherapy in PCa. Meanwhile, the TME in PCa is a critical factor limiting the effectiveness of immunotherapy. Even when immune cells are activated or delivered to the patient, they must function within a highly immunosuppressive environment (Figure 2). Elucidating the underlying mechanisms driving this immunosuppressive microenvironment is crucial to improving the efficacy of immunotherapy in PCa.

Figure 1.

Intrinsic factors in prostate cancer cells that synergistically reduce the effectiveness of immunotherapy. One of the hallmarks of PCa is a low TMB, resulting in a scarcity of neoantigens and impaired antigen presentation by APCs, which further contributes to insufficient recruitment and activation of CD8⁺ T cells. This creates an immunologically “cold” tumor microenvironment that limits T cell recognition and cytotoxicity. Additionally, many prostate tumors display low or heterogeneous PD-L1 expression, which diminishes the efficacy of PD-1/PD-L1 checkpoint blockade in reversing T cell exhaustion and restoring effective antitumor responses, which may limit the efficacy of anti-PD-1/PD-L1 therapies. Furthermore, defects in MHC-I antigen presentation prevent tumor-associated antigens from being displayed on the cancer cell surface, meaning cytotoxic T lymphocytes discriminate malignant cells from normal cells, thereby undermining effective T cell-mediated cytotoxicity. PCa: prostate cancer; TMB: tumor mutational burden; APCs: antigen-presenting cells; CD8⁺ T cells: CD8⁺ T lymphocytes; MHC-I: major histocompatibility complex class I; PD-1: programmed cell death protein 1; PD-L1: programmed cell death ligand 1; TCR: T cell receptor.

Figure 2.

Key immunosuppressive networks in the prostate cancer microenvironment. The immunosuppressive microenvironment of PCa is characterized by the enrichment of immunosuppressive cell populations, including Tregs and M2-polarized TAMs, accompanied by a marked deficiency of activated CD8⁺ T cells. (1) T cells within PCa tissues exhibit high expression of exhaustion markers such as PD-1, LAG-3, and TIM-3, with significantly impaired cytotoxicity. (2) MDSCs secrete immunosuppressive cytokines including IL-6, VEGF, CCL20, and IL-23, which not only inhibit CD8⁺ T cell activity but also promote Treg recruitment, angiogenesis, and therapeutic resistance in PCa. (3) M2-type TAMs are enriched in PCa tissues and suppress CD8⁺ T cell function while facilitating Tregs accumulation through the release of immunoregulatory factors such as IL-10 and TGF-β. (4) CAFs remodel the extracellular matrix to create a physical barrier that hinders T cell tumor cell interactions. In addition, CAFs secrete cytokines such as TGF-β and IL-6, which attenuate T cell activity. They also catalyze adenosine production, which further suppresses T cell function, upregulates PD-L1 expression, and enhances MDSC infiltration, reinforcing the immunosuppressive tumor microenvironment. AR: androgen receptor; CAFs: cancer-associated fibroblasts; CCL20: C–C motif chemokine ligand 20; CD8⁺ T cells: CD8⁺ T lymphocytes; ECM: extracellular matrix; LAG-3: lymphocyte activation gene-3; MDSCs: myeloid-derived suppressor cells; MHC-I: major histocompatibility complex class I; M2: M2 macrophage; NK cell: natural killer cell; PCa: prostate cancer; PD-1: programmed cell death protein 1; PD-L1: programmed cell death ligand 1; IL-6: interleukin-6; IL-10: interleukin-10; TIM-3: T cell immunoglobulin and mucin-domain containing-3; TAM: tumor-associated macrophage; TCR: T cell receptor; TGF-β: transforming growth factor-β; TILs: tumor-infiltrating lymphocytes; Tregs: regulatory T cells; VEGF: vascular endothelial growth factor; ↓: decrease; ↑: increase.

Low TMB

When tumors have a high TMB, they typically produce more novel antigens that the immune system can recognize, thereby activating a powerful T cell response.84 In contrast, PCa generally has a low TMB. The average TMB in PCa is approximately 0.9 mutations per Mb, which is markedly lower than the TMB observed in immunologically “hot” tumors, such as lung cancer (about 7.2 mutations per Mb) and melanoma (about 13.5 mutations per Mb).85 The ability of the immune system to identify tumor antigens is restricted by a low TMB, complicating the distinction between tumor cells and normal tissue and facilitating immune evasion. However, there is an important exception in PCa, namely, a subset of patients with dMMR or MSI-H phenotypes.86 Their tumors typically have a significantly elevated TMB, which can elicit a stronger immunogenic response. Across multiple types of cancer, dMMR/MSI-H status has been confirmed as a biomarker of benefit from PD-1 inhibitors. Studies in PCa have similarly shown that these patients can achieve survival benefits from anti-PD-1 therapies.38,87,88 Although dMMR/MSI-H PCa constitutes only a minor proportion of advanced cases, the notable clinical responses in these patients have highlighted the promise of immunotherapy for PCa and driven the advancement of precision treatment strategies guided by biomarker-based classification.

Low PD-L1 expression

PD-L1 expression levels are generally low in PCa, with only about 25% of PCa tissues showing positive PD-L1 expression.89 Low PD-L1 expression suggests that tumor cells lack the ability to mediate immune evasion through PD-L1. However, in the context of immunotherapy, low PD-L1 expression also means that ICIs are less able to activate an effective antitumor immune response, making it a key factor limiting their efficacy. PD-L1 expression is not solely determined by intrinsic tumor properties but can be dynamically regulated under immune selection pressure. During immune interventions, such as activation of T cells, tumor cells can induce upregulation of PD-L1 to counter an immune attack.90 Increased expression of PD-L1 may reflect a strong antecedent immune reaction in the TME, indicating that targeting the PD-1/PD-L1 interaction could “unlock” this dormant immunity and achieve therapeutic efficacy. In contrast, persistently low PD-L1 expression in PCa suggests that the body is unable to mount an effective and sustained immune response, which likely explains the low rates of response to ICIs.91 Notably, PD-L1 expression is significantly elevated in neuroendocrine prostate cancer (NEPC), with studies reporting positive expression rates of up to 46%.92 Although NEPC is relatively rare in patients with advanced PCa, PD-L1 expression is higher in these patients than in those with other subtypes, suggesting that individuals with NEPC are more likely to benefit from immunotherapy that targets PD-L1. Although the underlying reasons cannot be explained at present, this phenomenon provides important insights for further research into the relationship between expression of PD-L1 and the efficacy of immunotherapy in PCa.

Defective antigen presentation machinery

The main function of major histocompatibility complex class I (MHC-I) is to present tumor antigens to CD8⁺ T cells, which in turn activate the cytotoxic activity of these cells. Like various other tumor cells, PCa cells frequently evade immune recognition by downregulating the expression of MHC-I molecules.93 Reduced MHC-I levels prevent T cells from recognizing tumor cells, ultimately impairing the overall effectiveness of the immune system. Reports indicate that activation of the androgen receptor (AR) signaling pathway suppresses expression of MHC-I, whereas inhibition of this pathway can upregulate MHC-I and enhance the immune response.94 Phase III clinical trials have shown that the combination of enzalutamide and immunotherapy does not result in a substantial improvement in clinical outcomes compared with enzalutamide monotherapy. However, mechanistic and preclinical studies indicate that androgen receptor inhibition can modulate tumor immunogenicity, including upregulation of MHC-I expression. Consequently, androgen receptor inhibitors remain a promising therapeutic strategy for prostate cancer.47

Abnormal signal transduction pathways lead to abnormal immune microenvironments

In PCa, abnormal immune microenvironments are closely associated with disruptions in multiple signal pathways, including those for the AR, phosphoinositide-3 kinase/protein kinase B (PI3K/AKT), wingless/integrated (Wnt), and Notch pathways. These pathways not only act on PCa cells but also regulate the functional state of immune cells, collectively shaping an immunosuppressive TME, which hinders effective treatment (Figure 3).

Figure 3.

Aberrant signal transduction pathways cooperatively remodel prostate cancer and its microenvironment. Binding of AR to APOE accelerates AR protein degradation, relieving repression of MHC-I expression and thereby enhancing antigen presentation and CD8⁺ T cell-mediated cytotoxicity. Conversely, within CD8⁺ T cells, endogenous AR has been reported to suppress Ifng transcription and upregulates USP18, leading to sustained TAK1 dephosphorylation and reduced NF-κB activity; these changes together promote an immunosuppressive phenotype and impair effector function. Hyperactivation of the PI3K/Akt pathway not only accelerates tumor cell proliferation, limits CD8⁺ T cell infiltration, and skews TAMs toward the immunosuppressive M2 phenotype. Factors such as CXCL14 and LOX further reinforce M2 polarization via Wnt signaling. Notch signaling exerts a dual effect: it promotes proliferation and drug resistance in AR-positive PCa cells, while concurrently upregulating MHC-I and IFN-γ to facilitate immune effector cell infiltration. Taken together, dysregulation of these pathways contributes to therapeutic resistance and to an immunologically “cold” tumor microenvironment in prostate cancer, representing a major obstacle to effective immunotherapy. AKT: protein kinase B; APOE: apolipoprotein E; AR: androgen receptor; CXCL14: C-X-C motif chemokine ligand 14; ICI: immune checkpoint inhibitor; IFN-γ/Ifng: interferon-gamma; LOX: lysyl oxidase; MHC-I: major histocompatibility complex class I; M0: M0 macrophage; M1: M1 macrophage; M2: M2 macrophage; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; P: phosphorylation; PI3K: phosphoinositide 3-kinase; TAM: tumor-associated macrophage; TAK1: transforming growth factor-β-activated kinase 1; USP18: ubiquitin-specific peptidase 18; Wnt: wingless/integrated; ↓: decrease.

The AR signaling pathway is central to the regulation of the genesis and development of PCa. Currently, several first-line treatment strategies can target this pathway and exert antitumor effects. The AR not only drives tumor proliferation, metastasis, and acquired resistance but also influences tumor-related immune regulation. CD8⁺ T cells contain open chromatin regions associated with interferon-gamma (Ifng) and granzyme B (Gzmb). Upon activation of T cell receptor signaling, these regions rapidly induce expression of Ifng and Gzmb, which mediate effective antitumor immune responses. However, the AR can also be endogenously expressed in T cells and bind directly to the Ifng promoter region, suppressing its transcriptional activity. This leads to impaired functioning of CD8⁺ T cells and loss of their ability to produce IFN-γ, thereby weakening their potential for immune clearance.95 Other research has demonstrated that suppression of AR signaling upregulates MHC-I expression in PCa cells, enhancing tumor antigen presentation and promoting T cell-mediated cytotoxicity.94 Apolipoprotein E (APOE) is a protein that is widely involved in lipid transport, metabolism, and regulation of immune function.96 Elevated APOE levels have been associated with a poor response to AR-directed treatments in PCa because of direct interaction between APOE and AR, which enhances ubiquitination of the AR and proteasome-mediated turnover. Furthermore, elevated expression of APOE correlates strongly with increased levels of immune checkpoint molecules, including PD-1 and PD-L1. In mouse models, combined blockade of APOE and PD-L1 significantly enhances infiltration of CD8⁺ T cells into tumors and inhibits recruitment of MDSCs, improving the efficacy of ICIs.97 At the molecular level, the AR is not only regulated by upstream signals but also participates in immune regulation by modulating downstream effector molecules. Ubiquitin specific peptidase 18 (USP18), a deubiquitinating enzyme and direct AR target in T cells, removes ubiquitin from transforming growth factor-β (TGF-β)-activated kinase 1, preventing its phosphorylation and activation. Blockade of the activity of TGF-β-activated kinase 1 inhibits nuclear factor kappa-B (NF-κB) signaling, which promotes an immunosuppressive phenotype.98 Beyond its established role as a treatment target in PCa, AR signaling influences the intricate immune microenvironment of prostate tumors, positioning it as a promising avenue for further immunotherapeutic strategies.

Excessive PI3K/AKT signaling is a well-established driver of oncogenesis, disease progression, and treatment failure. In PCa, the PI3K/AKT pathway is more strongly activated in advanced refractory cases of CRPC. This observation not only underscores the close relationship between activation of the PI3K/AKT pathway and progression of PCa, but also highlights the critical need for inhibitors of this pathway in the treatment of the disease.99 Ipatasertib, a highly selective AKT kinase inhibitor, has shown promise in the treatment of PCa.100 In a Phase III study, median radiographic PFS increased from 16.5 months in patients with phosphatase and tensin homolog (PTEN)-deficient mCRPC who received placebo plus abiraterone to 18.5 months in those who received ipatasertib plus abiraterone.101 This finding highlights the PI3K/AKT pathway as a promising therapeutic target for molecular subtypes of PCa characterized by high resistance and limited treatment options. Beyond its ability to inhibit the proliferation of tumor cells by suppression of the PI3K/AKT pathway, ipatasertib also contributes to remodeling of the TIME in PCa. Ipatasertib has been reported to reduce infiltration of MDSCs effectively while promoting accumulation of CD8⁺ T cells in the body, thereby enhancing tumor responsiveness to ICIs.102 Furthermore, certain immune regulatory factors exert immunosuppressive effects by mediating the AKT pathway. The interleukin (IL)-1 receptor antagonist is a key anti-inflammatory factor that has recently been found to regulate PD-L1 expression directly and to activate the AKT pathway, inducing polarization of TAMs to the immunosuppressive M2 phenotype.103 This mechanism further impairs the function of immune effector cells, promotes immune evasion, and consequently limits the effectiveness of immunotherapy. The AKT signaling pathway plays a dual role in driving PCa progression and establishing an immunosuppressive microenvironment. Targeting this pathway may not only directly inhibit tumor cell activity but also relieve immunosuppression, thereby enhancing the response to immunotherapy. Therefore, combining AKT inhibitors with standard treatment regimens or immunotherapy may represent a novel precision strategy for treating PCa, particularly for PTEN-deficient subtypes.

The Wnt signaling pathway has an important role in driving the growth and progression of cancer. While its regulatory effects in the immune system remain incompletely elucidated, evidence from multiple malignancies confirms that the Wnt pathway influences the differentiation and polarization of TAMs.104 Early research showed that activation of Wnt/β-catenin signaling in the TME of lung cancer induces TAMs to transition from a tumoricidal M1 state to an immunosuppressive M2 state, illustrating its importance in the modulation of the TAM phenotype and immune evasion.105 Recent studies in PCa have further expanded our understanding of this mechanism. Hybrid endothelial-osteoblast-like cells are formed during the transdifferentiation of PCa-induced endothelial cells into osteoblast-like cells. These hybrid cells secrete various cytokines, including Wnts, C-X-C motif chemokine ligand 14 (CXCL14), and lysyl oxidase, which activate the Wnt pathway and drive polarization of TAMs to the M2 phenotype, thereby contributing to the immunosuppressive microenvironment in PCa.106 Combined use of Wnt pathway inhibitors can block the polarization of TAMs to the M2 phenotype at the molecular level, which alleviates the immunosuppressive state. Given the role of the Wnt pathway in the initiation and progression of PCa and the modulation of the immune microenvironment, developing drugs that target the Wnt pathway and combining them with standard or immunotherapy treatments may be a promising therapeutic approach.

The Notch signaling pathway primarily functions to maintain tissue homeostasis and promote normal embryonic development. Abnormal activation or regulatory imbalance in this pathway has been widely recognized as playing an important role in the growth of various malignant tumors.107 Aberrant activation of the Notch signaling pathway enhances tumor proliferation in AR-positive PCa and promotes its resistance to standard treatment strategies.108,109,110,111 However, in NEPC, activation of this pathway inhibits neuroendocrine differentiation, upregulates expression of MHC-I, enhances activity in the interferon signaling pathway, and promotes tumor infiltration by immune effector cells.112 These immune-related changes suggest that Notch signaling can shift PCa from an “immune-cold” phenotype to a more immunoreactive “immune-hot” state, potentially enhancing the response to immunotherapy. On the one hand, the Notch signaling pathway promotes tumor progression and resistance to treatment; on the other, it can remodel the immune microenvironment and enhance the efficacy of immunotherapy. These seemingly contradictory phenomena reflect the complexity and context-dependence of functions in the Notch pathway. Notch is not a purely oncogenic or tumor-suppressive pathway; its functions may vary depending on tumor subtype and microenvironmental context. Therefore, rational modulation of Notch signaling to achieve its immunostimulatory effects in specific contexts, particularly in NEPC, may represent an innovative strategy to enhance the efficacy of immunotherapy in PCa.

Sparse and functionally suppressed T cell infiltration

TILs predominantly comprise CD8⁺ cytotoxic T cells and CD4⁺ helper T cells, with smaller subsets of B cells and NK cells. Fully functional TILs can specifically recognize tumor-associated antigens and mediate effective cytotoxic responses, with their abundance and activity closely linked to the prognosis and the response to immunotherapy.113,114 However, the pronounced “immune-cold” phenotype of PCa, characterized by low infiltration of TILs and an exhausted functional state, significantly limits the efficacy of immunotherapy.115,116 PCa tissues are typically enriched with immunosuppressive cell populations, including regulatory T cells (Tregs) and M2-type TAMs, while activated CD8⁺ T cells are notably scarce. This predominance of immunosuppressive cell populations further aggravates the compromised antitumor immune response. Immunoprofiling reveals that TILs in PCa are more functionally impaired than those in typical “immune-hot” tumors, such as melanoma and non-small cell lung cancer. In PCa, infiltrating CD8⁺ T cell populations are not only scarce but also have significantly reduced cytotoxic scores, indicating impaired effector function. Furthermore, T cells in PCa tissues express high levels of exhaustion markers, such as PD-1, lymphocyte activation gene-3 (LAG-3), and T cell immunoglobulin domain and mucin domain-3 (TIM-3), with exhaustion levels significantly exceeding those in normal prostate tissues, further intensifying the immunosuppressive nature of the TME.117 Notably, even in low-grade PCa, patterns of TIL infiltration resemble those of high-grade PCa, including signs of early exhaustion, which suggests that an immunosuppressive microenvironment is established early in the progression of PCa.118

Within the TME, Tregs maintain immune homeostasis by releasing inhibitory cytokines that curtail the proliferation and activation of effector T cells. A high presence of Tregs in PCa is strongly associated with tumor growth, immune system evasion, and resistance to immunotherapy.119 Therefore, to improve the outcomes of immunotherapy, reducing levels of Tregs or inhibiting their activity has been identified as a potential strategy for PCa. N-cadherin, a key inducer of epithelial–mesenchymal transition (EMT), was initially shown to promote invasion and metastasis of PCa cells by activating EMT pathways.120 However, emerging evidence indicates that N-cadherin is involved in more than cell motility; it is also crucial for immune escape. EMT triggered by N-cadherin increases the expression of checkpoint molecules like PD-L1 and indoleamine 2,3-dioxygenase 1 (IDO-1) in various cancers, strengthening the immunosuppressive effects of the tumor.121 Recent research in PCa has confirmed the key role of N-cadherin in immune evasion, demonstrating that its expression promotes upregulation of PD-L1 and drives recruitment and expansion of Tregs. Conversely, knockout of N-cadherin significantly reduces infiltration of Tregs and partially reverses the immunosuppressive TME.122 These findings suggest that targeting N-cadherin could help overcome resistance of PCa to immunotherapy. Moreover, forkhead box P3 (FOXP3), as the central transcription factor of Tregs, is crucial for maintaining the immunosuppressive function of these cells. Targeting the expression or activity of FOXP3 has emerged as a key strategy for weakening the function of Tregs. Notably, entinostat, a class I histone deacetylase inhibitor, has been shown to significantly reduce expression of FOXP3 in Tregs, thereby reducing their immunosuppressive activity and enhancing the antitumor effects of ICIs.123 Although clinical application of this method in PCa is in its infancy, it offers new perspectives and potential targets for enhancing the effectiveness of immunotherapy in PCa.

Abundant MDSCs

MDSCs are a population of immature myeloid cells recognized for their potent immunosuppressive properties and important role in regulating immune homeostasis.124 In PCa, MDSCs are significantly enriched in tumor tissues and peripheral blood, and their accumulation is closely associated with disease progression and the response to immunotherapy.125 The initial research found no significant difference in the numbers of Tregs between patients with PCa and healthy individuals; however, Tregs isolated from cases with PCa have since been found to have significantly increased inhibitory capacity.126 MDSCs release various immunosuppressive factors, including IL-6, vascular endothelial growth factor receptor (VEGFR), and arginase. These cytokines impede the correct functioning of CD8⁺ T cells and NK cells, promoting the growth of tumor cells and inhibiting immune responses.127 Furthermore, there is close immunological crosstalk between MDSCs and Tregs. Studies have shown that MDSCs can recruit Tregs by secreting the chemokine C-C motif chemokine ligand 20 (CCL20), which acts via the C-C motif chemokine receptor 6 (CCR6) receptor. Together, they synergistically induce exhaustion of CD8⁺ T cells, reinforcing the immunosuppressive TME.117 Notably, MDSCs are involved in the formation of a drug-resistant phenotype in PCa, in addition to playing an important role in immune escape. Researchers have found that MDSC-derived IL-23 activates the AR signaling pathway in PCa cells, inducing resistance in the context of androgen deprivation therapy and reducing its efficacy.16 The above studies suggest that MDSCs play multiple roles in immunomodulation and therapeutic resistance in PCa, constructing an immunosuppressive barrier and promoting tumor survival and adaptive evolution through multiple mechanisms. Targeting MDSCs or interfering with their associated signaling pathways, in combination with standard treatments, may substantially improve the efficacy of immunotherapy in PCa.

M2-polarized TAMs

TAM is critical for maintaining tissue homeostasis, eliminating pathogens, and facilitating the initial immune response.128 However, within the TME, TAMs are often reprogrammed by tumor cells into pro-tumorigenic phenotypes that support the development and progression of tumors, making them one of the key drivers of immunosuppression in PCa.129 The local microenvironment promotes differentiation of tumor-infiltrating macrophages into either M1-like macrophages, which have antitumor and pro-inflammatory activity, or M2-like macrophages, which have protumor activity and suppress the immune response.130 A study has shown that tissues with advanced PCa are often enriched with M2-like TAMs that express immunosuppressive gene signatures. A high level of infiltration by M2-like TAMs is strongly correlated with unfavorable patient outcomes and diminished efficacy of immunotherapy.131 M2-type TAMs reduce the toxicity of CD8⁺ T cells by secreting immunosuppressive factors such as IL-10 and TGF-β. They also promote the recruitment of Tregs, and the two complement each other, contributing to inhibitory microenvironment.132 Moreover, TAMs within the TME upregulate immune checkpoint proteins such as PD-L1, which bind to receptors on T cells and inhibit their activation. This mechanism further impairs the antitumor immune response and contributes to resistance against ICIs.133 A recent single-cell RNA sequencing study has identified a TAM subset with elevated levels of secreted phosphoprotein 1 (SPP1) transcripts (SPP1^hi-TAM), which is significantly enriched during the progression of PCa. This subset significantly enhances adenosine signaling pathways, inhibits the function of T cells, and is essential in the mediation of immunosuppression.134 TAMs have an important role in forming the immunosuppressive environment of PCa and aiding resistance to immunotherapy. These processes include the release of inflammatory substances, control of immune checkpoints, and activation. Targeting TAMs or their associated functional pathways, including inhibition of M2 polarization, blocking PD-L1 expression, and disrupting adenosine signaling, could overcome the current limitations of immunotherapy in PCa.

Dual immunoregulatory roles of CAFs and stromal barriers

CAFs play a crucial role in establishing and maintaining the highly immunosuppressive TME in PCa. Recent studies have identified two main subtypes of CAFs in PCa, namely, extracellular matrix-associated CAFs (ECM-CAFs) and lymphocyte-associated CAFs (Lym-CAFs).135 ECM-CAFs enhance collagen deposition and mediate extracellular matrix remodeling, creating a physical barrier that impedes the contact between effector T cells and tumor cells, thereby intensifying immune exclusion. In addition to spatially restricting immune cell infiltration, CAFs actively regulate the immune microenvironment by secreting various cytokines. For instance, Lym-CAFs secrete chemokines such as chemokine ligand 9 (CXCL9), chemokine ligand 10 (CXCL10), and chemokine ligand 11 (CXCL11), which recruit and activate CD8⁺ T cells, thereby bolstering antitumor immune responses.135 However, this subtype is typically underrepresented in an immunosuppressive TIME. The transcription factor yes-associated protein 1 (YAP1), in addition to regulating the proliferation of PCa through the Hippo signaling pathway, regulates CAF phenotypic shifts in the TME to affect the response of tumor cells to immunotherapy. Inhibiting YAP1 can reprogram ECM-CAFs into Lym-CAFs, thereby enhancing CD8⁺ T cell infiltration and penetration, and significantly improving responses to ICIs.135 By releasing multiple immunosuppressive mediators, CAFs further potentiate tumor immune escape. In particular, CAFs secreted TGF-β and IL-6, which drive tumor growth while inhibiting cytotoxic T lymphocyte and NK cell activity. Concurrently, CAFs upregulate CD39 and CD73 expression, facilitating the production of adenosine, which acts as an immunosuppressive signal to dampen T cell and NK cell responses. It also induces local hypoxia, which upregulates immune checkpoint ligands such as PD-L1 and promotes the infiltration of MDSCs, further reinforcing the immunosuppressive microenvironment.136,137 Recent studies have also identified a special subtype of CAFs rich in iron, known as ferrum iron cancer-associated fibroblasts (Ferro-CAFs). Ferro-CAFs promote the recruitment of TAMs and MDSCs by secreting chemokines such as CCL2, colony stimulating factor 1 (CSF1), and CXCL1.138 This further suppresses CD8⁺ T cell function and promotes tumor immune evasion. Targeting the heme oxygenase 1 (Hmox1)/iron/lysine demethylase 6b (Kdm6b) signaling axis to modulate Ferro-CAF function can effectively alleviate the immunosuppressive state they induce, offering a new therapeutic target for PCa immunotherapy.138

Overall, the limited efficacy of immunotherapy in PCa is not only due to the lack of effective immune activation signals, but more importantly, because even when immune cells reach the tumor site, they are often rendered ineffective by multiple CAF-mediated immunosuppressive mechanisms. This further highlights the important clinical value of targeting CAF functions and their associated signaling pathways to reshape the TIME and enhance the efficacy of combined immunotherapy.

DISCUSSION AND PERSPECTIVES

Immunotherapy has significantly changed the treatment prospects for cancers like lung cancer and melanoma. However, the clinical efficacy of immunotherapy is very limited in PCa. This review systematically summarizes the main immunotherapeutic strategies explored to date in PCa, including cancer vaccines, ICIs, CAR-T cell therapy, and various combination regimens, and discusses the intrinsic and extrinsic mechanisms of immune resistance in PCa. The limited efficacy of PCa immunotherapy is not dominated by individual factors; rather, it is more like a “perfect storm” of unfavorable factors. These factors include intrinsic tumor features, such as low TMB and inadequate antigen presentation, as well as a profoundly immunosuppressive TME dominated by Tregs, MDSCs, TAMs, and CAFs. These factors highlight a need to counteract these mechanisms for effective engagement of the immune system and promotion of antitumor activity in PCa, providing a theoretical framework for crafting more potent immunotherapy methods.

Given the profound immunosuppressive microenvironment in PCa, current research is focused on strategies that target key immune tolerance mechanisms to overcome the barriers to effective immunotherapy. Among these, immunosuppressive cell populations such as Tregs and MDSCs represent important therapeutic targets. Mogamulizumab is a humanized anti-CCR4 monoclonal antibody that has been approved for the treatment of CCR4⁺ T cell leukemia and lymphoma. Studies in bladder cancer models have shown that mogamulizumab can selectively deplete Tregs by specifically binding to CCR4.139 In PCa, mogamulizumab significantly reduces the number of FOXP3⁺ Tregs, while having no significant effect on CD8⁺ cytotoxic T cells or CD4⁺ helper T cells.140 Selective depletion of Tregs offers a novel therapeutic strategy to improve the immunosuppressive microenvironment of PCa and enhance responses to immunotherapy. MDSCs are another key cellular component that shapes the immunosuppressive microenvironment in PCa. Prostaglandin E receptor 4 (PTGER4) is highly expressed in various immune cells, and its inhibitor, YY001, suppresses the differentiation of MDSCs and diminishes their immunosuppressive function, enhancing T cell cytotoxicity and synergizing with PD-1 inhibitors to boost antitumor efficacy.141,142 Furthermore, preclinical studies have shown that targeting elevated adenosine levels in PCa can restore the cytotoxicity of T cells within the tumor. A Phase I clinical trial that combined an adenosine inhibitor with a PD-1 inhibitor has recently been completed.143 The results of this trial demonstrated favorable safety and tolerability, paving the way for Phase II and III clinical studies.144 Based on these studies, interventions targeting immunosuppressive cell populations may provide a research direction for reshaping the immune microenvironment of PCa and open up new avenues for improving the immune response to PCa treatment.

Notably, effective antitumor immune responses rely not just on remodeling the immunosuppressive microenvironment but more critically on the ability of the immune system to recognize tumor antigens. As mentioned earlier, PCa cells often evade immune surveillance by downregulating antigen presentation or through other mechanisms, thereby limiting the immune response. Therefore, while targeting immunosuppressive cells such as Tregs and MDSCs or reducing elevated adenosine levels can partially restore immune responsiveness, the absence of effective tumor recognition continues to limit the efficacy of targeted therapies. A recently developed oncolytic virus, Newcastle disease virus-genetically tailored (NDV-GT), incorporates porcine genes to induce expression of xenogeneic glycan antigens in tumor cells, enabling precise immune recognition and triggering a potent hyperacute rejection response. NDV-GT has demonstrated a disease control rate of 90% in patients with various treatment-refractory solid tumors.145 Current evidence suggests that the antitumor immune mechanisms of NDV-GT are not restricted to a specific type of cancer. Given its precise targeting and remarkable efficacy in hepatocellular carcinoma, which is a prototypical immunologically “cold” tumor, NDV-GT is also expected to be effective in PCa, which is also an “immune-cold” tumor.

In addition to exploring new therapeutic strategies, the outcomes of current clinical trials also warrant careful consideration. Most Phase III clinical trials of immunotherapy have shown no survival benefit in unselected PCa populations, but post hoc analyses of several studies have indicated that patients with dMM or MSI-H tumors and certain immunologically defined subgroups may derive meaningful clinical benefits from immunotherapy. For example, PCa with homologous recombination deficiency, such as breast cancer 2, early onset (BRCA2) mutation, has increased genomic instability. There is evidence suggesting a synergistic effect between PD-1 inhibitors and PARP inhibitors. Combined therapy has shown a significantly higher objective response (OR) rate in patients with BRCA2-mutated mCRPC in comparison with those without BRCA2 mutations.146 This finding suggests that DNA-damaging agents may enhance tumor antigenicity, making tumors more responsive to immunotherapy. These observations strongly suggest that the success of future PCa immunotherapy depends not only on improved combination strategies but also on tailoring these combinations to specific PCa subgroups. Consequently, developing reliable predictive biomarkers to determine precisely which patients will benefit most from immunotherapy is essential for overcoming the current challenges with this treatment method. Although PCa remains largely refractory to current immunotherapy approaches, the understanding of its unique immune landscape is rapidly expanding, providing a scientific basis for developing more effective immunotherapies. Combining immunotherapy with standard treatments or other agents, as well as developing more precise biomarkers for patient stratification, will be key to unlocking the full potential of immunotherapy in PCa. With deeper mechanistic insights and more precise patient selection, it is conceivable that immunotherapy-based strategies will ultimately become an integral part of treatment for PCa.

AUTHOR CONTRIBUTIONS

SSF drafted the original manuscript. YMC contributed to drafting the manuscript and performed the visualization. WDC contributed to visualization. ZHS and JY supervised the study. MX performed the formal analysis. PW supervised the study and contributed to reviewing and revising the manuscript. All authors read and approved the final manuscript.

COMPETING INTERESTS

All authors declare no competing interests.