Therapeutic potential of cytokine-induced killer cell therapy for renal cell carcinoma and prostate cancer.

Introduction

The treatment landscape for renal cell carcinoma (RCC) has rapidly evolved, with immune checkpoint inhibitors (ICIs) and targeted therapies now forming the backbone of management for advanced or metastatic disease. Combination regimens incorporating immune checkpoint inhibitors and tyrosine kinase inhibitors have demonstrated improved progression-free and overall survival compared with sunitinib in phase III clinical trials [ 1 ]. Additionally, adjuvant immunotherapy with pembrolizumab following nephrectomy has been shown to reduce the risk of recurrence in high-risk localized RCC, marking a shift toward the use of immunotherapy in earlier stages of the disease [ 2 ]. These advances highlight the central role of immunotherapy in the modern treatment of RCC.

Despite these encouraging developments, significant clinical challenges remain, including the absence of reliable predictive biomarkers to guide immunotherapy selection, variability in patient responses, and limited therapeutic options for those who progress after ICI-based regimens. These limitations underscore the urgent need for more personalized treatment strategies, refined molecular profiling, and the identification of novel therapeutic targets to improve long-term outcomes for patients with RCC.

The treatment of metastatic castration-sensitive prostate cancer (mCSPC) and metastatic castration-resistant prostate cancer (mCRPC) has also advanced significantly with the incorporation of androgen receptor pathway inhibitors (ARPIs) and combination systemic therapies. For mCSPC, clinical trials have shown that adding apalutamide or enzalutamide to androgen deprivation therapy (ADT) significantly improves OS and delays disease progression [ 3 , 4 ]. For mCRPC, novel therapeutic agents such as 177 Lu-PSMA-617 and PARP inhibitors have expanded available treatment options [ 5 , 6 ]. However, several clinical challenges persist: most patients ultimately develop resistance to ARPIs, and treatment efficacy in patients without actionable mutations or PSMA expression remains suboptimal. These gaps emphasize the necessity for more individualized therapeutic approaches and the exploration of novel combination strategies to further prolong survival. Although immunotherapy has transformed the management of multiple solid tumors, its clinical impact in prostate cancer has been comparatively modest. Unlike renal cell carcinoma, prostate cancer has generally shown limited responsiveness to immune checkpoint inhibition in unselected patient populations. Clinical benefit from immune checkpoint inhibitors has largely been confined to molecularly defined subsets, such as tumors with microsatellite instability-high (MSI-H), mismatch repair deficiency (dMMR), or high tumor mutational burden. Beyond these rare subgroups, prostate cancer is widely regarded as an immunologically “cold” tumor, characterized by low neoantigen load, limited baseline immune infiltration, and a suppressive tumor microenvironment [ 7 ]. Mechanistic analyses and translational studies have suggested that these features contribute to primary resistance to immunotherapy and restrict durable antitumor immune activation. Accordingly, current research efforts have increasingly focused on combination strategies and adoptive cellular immunotherapies as potential approaches to overcome immune resistance in prostate cancer.

Over the past decade, immunotherapy has revolutionized cancer treatment and established clinical efficacy in both solid and hematological malignancies. ICIs have provided remarkable clinical benefits, particularly in tumors with a high mutational burden. Among various immunotherapeutic approaches, adoptive cellular immunotherapy represents a rapidly advancing field defined by the extraction, modification, and reinfusion of autologous or allogeneic immune cells for therapeutic purposes [ 8 ]. The first clinically effective adoptive cellular immunotherapy was reported in 1979 as allogeneic hematopoietic stem cell transplantation [ 9 ]. After decades of development, several forms of adoptive cell immunotherapy have emerged as promising cancer treatments, including lymphokine-activated killer (LAK) cells, cytokine-induced killer (CIK) cells, tumor-infiltrating lymphocytes (TILs), T cell receptor (TCR)-engineered T cells, and chimeric antigen receptor (CAR) T cells [ 10 ].

Adoptive cell immunotherapy can be classified according to its cellular source, cellular composition, and in vitro processing method. In terms of source, immune cells can be derived from peripheral blood or resected tumor tissues, either as autologous cells from the patient or as allogeneic off-the-shelf products from donors. In terms of composition, adoptively transferred immune cells may include αβ T cells, γδ T cells, NK cells, macrophages, and dendritic cells (DCs). Each product contains varying proportions of immune cell subsets (for example, the CD3⁺:CD56⁺ T cell ratio), with differences in expansion capacity, differentiation state, and exhaustion level. Regarding in vitro processing, isolated immune cells may undergo simple ex vivo expansion (as in LAK cells, CIK cells, or bulk TILs), enrichment for anti-tumor specificity (as in neoantigen-reactive TILs), or genetic modification (as in TCR-engineered T cells, CAR T cells, CAR NK cells, and CAR macrophages).

CAR T-cell therapy has demonstrated impressive clinical efficacy in B cell-derived hematologic malignancies. To date, six CAR T-cell therapies have been approved by the U.S. Food and Drug Administration (FDA): four targeting CD19-positive leukemias and lymphomas, and two directed against the B-cell maturation antigen (BCMA) expressed in multiple myeloma [ 11 ]. However, the toxicity and complexity associated with CAR T-cell production continue to limit its large-scale clinical application. Major obstacles include cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), tumor lysis syndrome (TLS), off-target or off-tumor toxicity (OTOT), and the high cost and labor-intensive manufacturing process [ 12 ].

To overcome these challenges, alternative cell therapy platforms have been developed, among which CIK cells have shown great promise. Compared to CAR T cells, CIK cells exhibit broad antitumor activity, simpler preparation, lower cost, and a more favorable safety profile. In this review, we summarize the current progress and therapeutic applications of CIK cell therapy in cancer treatment, with particular focus on its emerging role in RCC and prostate cancer (PCa). To maintain a focused narrative and clearly delineate the scope of this review, the manuscript is structured to progress from general concepts to disease-specific applications. We first introduce the fundamental biological characteristics and cytotoxic mechanisms of CIK cells as a distinct adoptive cellular immunotherapy platform. This is followed by a concise overview of clinical experience with CIK-based therapies across multiple malignancies, intended to provide contextual background relevant to RCC and prostate cancer rather than a comprehensive pan-cancer survey. The core of this review then focuses on renal cell carcinoma and prostate cancer, two urological malignancies with distinct immunological profiles. For renal cell carcinoma, we discuss the clinical rationale and emerging evidence supporting CIK-based strategies, particularly in adjuvant and combination settings. In contrast, the prostate cancer section emphasizes the biological and immunological challenges that limit clinical translation, drawing primarily from preclinical and translational studies. Finally, we integrate these observations to highlight where rational combination strategies may enhance the therapeutic potential of CIK cells in each disease context.

Methods: literature search strategy

This narrative review was based on a comprehensive literature search of PubMed and related databases up to Month Year. The search strategy included combinations of keywords such as “cytokine-induced killer cells,” “CIK,” “renal cell carcinoma,” “prostate cancer,” “immunotherapy,” and “adoptive cell therapy.” Priority was given to peer-reviewed clinical studies, prospective trials, and relevant translational or preclinical studies that were directly related to RCC or prostate cancer. Reference lists of key articles were also manually screened to identify additional relevant studies. Given the narrative nature of this review, no formal risk-of-bias assessment or quantitative meta-analysis was performed.

Mechanistic insights and functional characteristics of CIK cells

In 1991, Schmidt-Wolf and Negrin established an optimized LAK cell culture system that successfully achieved the in vitro expansion of CIK cells for the first time. Their study demonstrated that CIK cells exhibited a markedly stronger proliferative capacity and higher cytotoxic activity in both in vivo and in vitro settings compared with conventional LAK cells [ 13 ]. CIK cells are a heterogeneous and polyclonal population of CD3⁺CD56⁺ T cells that share phenotypic and functional characteristics with natural killer (NK) cells. They can be efficiently expanded from multiple sources, including peripheral blood, bone marrow, and umbilical cord blood, using a stepwise stimulation protocol that involves the timed addition of interferon-γ (IFN-γ), anti-CD3 monoclonal antibodies, and interleukin-2 (IL-2) [ 14 – 16 ]. The most distinctive feature of CIK cells lies in their potent and broad cytotoxicity, enabling the lysis of both hematologic [ 13 , 16 , 17 ] and solid [ 18 – 23 ] tumor cells without the need for prior antigen exposure or priming.

Unlike conventional T cells that recognize tumor antigens presented by major histocompatibility complex (MHC) class I molecules, CIK cells, particularly the CD3⁺CD56⁺ subset, possess dual T-cell (CD3⁺) and NK-like (CD56⁺) properties. This dual phenotype allows them to exert cytotoxicity through MHC-independent mechanisms. A key pathway involves the natural killer group 2 member D (NKG2D) receptor, which recognizes stress-induced ligands such as the UL16-binding protein family (ULBP1-6) and MHC class I-related molecules A and B (MICA/B) expressed on tumor cells [ 24 – 26 ]. This NKG2D-mediated recognition bypasses the need for MHC restriction and enables CIK cells to effectively target tumor cells with low or absent MHC class I expression, a common immune evasion mechanism in cancer.

Engagement of NKG2D with its ligands initiates downstream signaling cascades that trigger the release of cytolytic granules containing perforin and granzymes. These effector molecules induce target cell apoptosis through caspase activation and DNA fragmentation [ 27 – 29 ]. In addition to direct tumor cell killing, CIK cells secrete a spectrum of pro-inflammatory cytokines, including IFN-γ, TNF-α, and IL-2, which promote the recruitment and activation of other immune cells within the tumor microenvironment. IFN-γ, in particular, enhances antigen presentation and increases the immunogenicity of tumor cells, thereby amplifying antitumor responses through a secondary, bystander effect [ 30 , 31 ].

Moreover, CIK cells express several adhesion molecules and chemokine receptors that facilitate their migration and accumulation at tumor sites. These include lymphocyte function-associated antigen 1 (LFA-1; CD11a/CD18) [ 32 ] and chemokine receptors such as CXCR3 and CCR5 [ 33 ], which mediate effective trafficking toward chemokine gradients within the tumor microenvironment. Through this coordinated interplay of cytotoxic effector mechanisms, cytokine secretion, and tumor-directed migration, CIK cells exhibit robust and sustained antitumor activity. As a novel form of adoptive cellular immunotherapy, CIK therapy demonstrates favorable therapeutic potential for patients who are resistant to conventional treatments and represents a valuable platform for integration with next-generation immunotherapies.

Clinical applications of CIK cell therapy in cancer

CIK cell therapy, a form of adoptive cell immunotherapy, has evolved from promising preclinical research into multiple clinical trials across a variety of malignancies. It possesses three fundamental characteristics that underpin its therapeutic potential. First, CIK cells exhibit dual functionality, representing a distinct population that combines CD3⁺ T-cell and CD56⁺ NK-cell phenotypes, thus integrating both adaptive and innate immune properties. Second, they exert non-MHC-restricted cytotoxicity, as CIK cells recognize and eliminate malignant cells independently of MHC restriction through engagement of the NKG2D activating receptor, which binds to stress-induced ligands expressed on tumor cells. This mechanism allows CIK cells to overcome a common immune evasion pathway exploited by many cancers. Third, they demonstrate a favorable safety profile compared with more complex immunotherapies such as CAR-T therapy, with adverse events that are generally mild and transient, most commonly low-grade fever, and a low incidence of CRS. Evidence from randomized controlled trials and meta-analyses suggests that CIK cell-based therapies, when combined with standard treatment modalities, have been associated with improved clinical outcomes and survival in several cancer types, including non-small cell lung cancer [ 34 ], hepatocellular carcinoma [ 35 ], colorectal cancer [ 36 ], breast cancer [ 37 ], gastric cancer [ 38 ], esophageal cancer [ 39 ], nasopharyngeal carcinoma [ 40 ], and malignant gliomas [ 41 ]. However, the magnitude of benefit varies substantially across tumor types, study designs, and patient populations, reflecting considerable heterogeneity among the available studies. These findings collectively support the utility of CIK cell therapy as a valuable adjuvant or combination treatment approach, and the following sections discuss its applications in two major urological malignancies: RCC and PCa.

CIK cell therapy in renal cell carcinoma

RCC poses significant therapeutic challenges, particularly in advanced or metastatic stages. Although targeted therapies such as tyrosine kinase inhibitors (TKIs) and ICIs have improved prognosis, drug resistance and immune-related adverse events remain major obstacles. Even with immune checkpoint inhibition, long term outcomes in advanced renal cell carcinoma remain heterogeneous. In previously treated advanced or metastatic RCC, nivolumab monotherapy has been associated with a median overall survival of approximately 22 months in phase III clinical trials. Longer term follow up analyses across different risk groups and study populations have reported five year overall survival rates ranging from approximately 8% to 28% [ 42 ]. CIK therapy presents a novel strategy to potentiate antitumor responses and improve clinical outcomes. Preclinical studies have demonstrated that CIK cells exert potent cytotoxic activity against RCC cell lines through non-MHC-restricted mechanisms. Yang et al. showed that IL-15 and IL-2 stimulation enhances the cytotoxicity of CIK cells in both in vitro and in vivo RCC models, significantly suppressing tumor growth in xenograft mice without detectable systemic toxicity [ 43 ]. These results suggest that CIK therapy could serve as an effective adjuvant immunotherapy after nephrectomy.

Clinical efficacy of CIK therapy in renal cell carcinoma

A prospective clinical study comparing autologous CIK therapy with subcutaneous IL-2 plus IFN-α-2a in 148 patients with metastatic clear cell RCC demonstrated that patients treated with CIK therapy achieved significantly prolonged progression-free survival (12 vs. 8 months, P = 0.024) and OS (46 vs. 19 months, P < 0.001), with a notably higher three-year survival rate of 61% compared with 23% in the control group [ 44 ]. Similarly, a retrospective analysis involving 410 post-surgical metastatic RCC patients revealed that DC-CIK therapy significantly outperformed IFN-α therapy, resulting in superior three-year OS ( P = 0.0116) and progression-free survival ( P = 0.0212) [ 45 ]. In the same study, DC-CIK treatment also reduced recurrence rates ( P = 0.0418) and achieved a markedly higher three-year disease-free survival rate (96.7% vs. 57.7%) compared with patients who did not receive adjuvant therapy. Importantly, no severe adverse effects were observed, underscoring the favorable safety profile of this therapeutic approach. Collectively, these findings suggest that CIK-based immunotherapy may be associated with signals of disease control and favorable tolerability in selected RCC settings; however, heterogeneity in study design, patient selection, and treatment era necessitates cautious interpretation of reported survival outcomes.

It should be noted that the progression-free survival and overall survival values reported in this review are derived from heterogeneous studies conducted across different treatment eras, patient populations, and clinical settings. Many of the included CIK or DC-CIK studies were performed prior to the widespread adoption of contemporary immune checkpoint inhibitor-based regimens and therefore relied on historical control arms that are no longer representative of current standards of care. In addition, substantial variability exists among studies with respect to eligibility criteria, disease stage, risk stratification, endpoint definitions, and subsequent lines of therapy. Several reports are retrospective or single-center in nature and may be subject to selection bias and unmeasured confounding. Consequently, direct cross-trial comparison of survival outcomes and P -values should be interpreted with caution, and the reported efficacy signals should be viewed as hypothesis-generating rather than definitive evidence of comparative clinical benefit.

Combination strategies in renal cell carcinoma

CIK cells combined with dendritic cells (DC-CIK therapy)

The bidirectional interaction between DCs and CIK cells leads to enhanced immune activation. Coculture significantly upregulates DC costimulatory and antigen-presenting molecules and increases interleukin-12 (IL-12) secretion, thereby amplifying the cytotoxicity of CIK cells [ 46 ]. A randomized controlled trial involving 137 patients with localized or locally advanced RCC evaluated postoperative immunotherapy using tumor lysate-pulsed DCs combined with CIK cells [ 47 ]. Patients treated with DC-CIK therapy exhibited significantly reduced metastasis and recurrence rates ( P < 0.01) and improved OS ( P < 0.01) compared with those receiving standard care, supporting its efficacy as an adjuvant immunotherapy in early- and mid-stage RCC.

CIK cells combined with surgery (adjuvant therapy)

Adjuvant administration of CIK cells following nephrectomy improves clinical outcomes in localized RCC. In a small clinical study, 20 patients with stage I/II disease were randomized to receive autologous CIK cells or standard follow-up. The CIK group demonstrated longer disease-free survival (32.2 vs. 21.6 months, P = 0.032) and elevated peripheral immune activation, reflected by increased CD3⁺, CD8⁺, and CD3⁺CD56⁺ lymphocyte counts, with no severe adverse events [ 48 ]. A separate analysis of 29 metastatic RCC patients treated with CIK therapy showed an objective response rate (ORR) of 13.8%, and higher circulating myeloid-derived suppressor cells (MDSCs) were associated with poorer outcomes [ 49 ]. A prospective randomized trial including 122 RCC patients (60 operable, 62 inoperable) found that DC-CIK treatment significantly improved three-year DFS (96.7% vs. 57.7%) in operable cases and extended both overall survival (OS) and progression-free survival (PFS) in inoperable patients ( P = 0.0116 and P = 0.0212) [ 45 ]. Similarly, a large-scale study of 410 patients compared DC-CIK immunotherapy ( n = 154) with IFN-α therapy ( n = 256) after radical or partial nephrectomy. In patients with stages I, II, and IV RCC, as well as in those with well or moderately differentiated tumors, DC-CIK therapy significantly improved OS, DFS, and PFS ( P < 0.01) [ 50 ]. Immunologically, the therapy enhanced cytotoxic T-cell activity, increased CD3⁺CD56⁺ effector cells, and reduced recurrence, particularly in high-risk patients. These results suggest that DC-CIK adjuvant immunotherapy effectively prolongs survival and reduces relapse after nephrectomy, with excellent tolerability.

CIK cells combined with conventional therapy (interleukin-2 or interferon-α or surgery)

A meta-analysis of seven trials including 385 RCC patients demonstrated that combining CIK therapy with conventional therapy significantly improved pooled complete and partial response rates ( P < 0.0001) and enhanced one-year and three-year OS ( P = 0.0002 and P < 0.0001, respectively) [ 51 ]. The combination also maintained a favorable safety profile, without an increase in severe adverse events. These findings highlight the potential of integrating CIK therapy with conventional therapy to potentiate antitumor immunity, although study heterogeneity and small sample sizes remain limitations.

CIK cells combined with targeted therapies (TKIs such as Sunitinib or Sorafenib)

In a cohort of 34 patients with metastatic RCC post-nephrectomy, combination therapy using Sunitinib or Sorafenib with DC-CIK immunotherapy ( n = 19) yielded superior outcomes compared with monotherapy ( n = 15) [ 52 ]. After a median follow-up of 19.5 months, the combination group achieved longer PFS (28.0 vs. 11.0 months, P = 0.03) and higher three-year OS (57.1% vs. 28.6%). These results suggest that TKIs may debulk tumors and sensitize residual disease to immune attack by CIK cells, though larger prospective studies are warranted to confirm this synergy.

CIK cells combined with immune checkpoint inhibitors

Recent evidence indicates strong potential for CIK therapy in combination with ICIs and targeted agents. A phase II study evaluated axitinib plus low-dose pembrolizumab-activated autologous DC-CIK therapy in 43 metastatic RCC patients [ 53 ]. The combination achieved a disease control rate of 25.6% (95% CI 13.5–41.2%) with a median PFS of 14.7 months (95% CI 11.16–18.3), and toxicity remained manageable. Another investigation combined pazopanib ( n = 9) or axitinib ( n = 7) with PD-1-activated DC-CIK cell immunotherapy as neoadjuvant treatment for locally advanced RCC [ 54 ]. After a median 2.1-month regimen, the median tumor volume reduction reached 42.3% (IQR: 19.37–66.78%, P = 0.0002), and all patients became eligible for surgery. No perioperative immune-related complications were reported, suggesting feasibility and safety in the neoadjuvant setting. Furthermore, a single-center study in 29 metastatic RCC patients refractory to targeted therapy demonstrated encouraging clinical activity for autologous CIK therapy combined with anti-PD-1 agents (nivolumab or pembrolizumab), achieving an ORR of 41.4%, CR of 24.1%, PR of 17.2%, median DFS of 15.0 months, and OS of 37 months [ 55 ]. These findings suggest that combining adoptive CIK therapy with checkpoint blockade may represent a biologically rational and clinically feasible multimodal strategy; however, the available evidence is derived mainly from early-phase or single-center studies, and definitive conclusions regarding survival benefit require validation in larger prospective trials.

Summary and future perspectives

It is important to note that much of the clinical evidence supporting CIK or DC-CIK therapy in renal cell carcinoma originates from studies conducted prior to the widespread adoption of current first-line immune checkpoint inhibitor and tyrosine kinase inhibitor combination regimens. Many of these studies employed historical control arms such as interferon-α (IFN-α) or IL-2, were retrospective or single-center in design, and involved heterogeneous patient populations with limited or unclear risk stratification. Consequently, direct comparison of survival outcomes across studies, particularly in relation to contemporary treatment standards, should be interpreted with caution. Accordingly, Table 1 summarizes key clinical studies together with their study design characteristics, patient selection, control arms, principal efficacy signals, and reported safety outcomes, to facilitate balanced interpretation of the available evidence. Adoptive cell immunotherapies have transformed the treatment landscape of RCC and continue to evolve alongside ICIs and TKIs. CIK cells, characterized by their non-MHC-restricted cytotoxicity and easy expansion from peripheral blood, provide a practical and safe cellular platform. Early-phase clinical studies indicate that CIK therapy is generally well tolerated and may improve disease control when used as adjuvant or combination therapy in selected RCC settings. Ongoing research explores integrating CIK cells with checkpoint inhibitors, targeted agents, or other immune modalities to enhance antitumor efficacy within the immunosuppressive RCC microenvironment [ 56 – 59 ]. Together, these advances suggest that CIK therapy represents a versatile and promising adjunctive strategy for personalized immunotherapy in renal malignancies.

CIK cell therapy in prostate cancer

Compared with renal cell carcinoma, the clinical evidence supporting CIK cell therapy in prostate cancer remains limited. Most available data are derived from preclinical and translational studies, while robust prospective clinical trial evidence is currently lacking. PCa remains the second most frequently diagnosed malignancy and the fifth leading cause of cancer-related mortality among men worldwide. Despite remarkable advances in therapeutic strategies, the prognosis for advanced disease remains poor. For men with metastatic castration-sensitive prostate cancer (mCSPC), median overall survival varies substantially depending on disease burden, patient population, and treatment regimen. Earlier cohorts treated with androgen deprivation therapy alone generally reported shorter median OS, whereas more recent phase III trials incorporating combination strategies with androgen receptor pathway inhibitors and/or docetaxel have reported median OS extending beyond 30 months, with five-year OS rates approaching 50% [ 60 ]. Once the disease progresses to the mCRPC stage, even the most effective combination therapies yield only a median OS of 11 to 15 months, a five-year OS rate of approximately 30%, and an incidence of adverse effects exceeding 10% [ 5 ]. Moreover, although a wide range of treatments are available for prostate cancer, spanning from localized interventions to advanced systemic therapies, disease progression to metastatic castration-resistant prostate cancer (mCRPC) continues to pose a major clinical challenge with limited survival benefits [ 61 – 63 ]. Although the field of onco-immunology has revolutionized cancer treatment, its clinical impact on PCa remains limited. To date, the U.S. FDA has approved only two immunotherapies for prostate cancer: sipuleucel-T (Provenge), indicated for asymptomatic or minimally symptomatic mCRPC [ 64 ], and pembrolizumab (Keytruda), which is restricted to genetically defined subgroups such as MSI-H, dMMR, or TMB-H prostate cancers [ 65 ]. Despite limited clinical success, immunotherapy in PCa remains a rapidly evolving and promising field. The inherently “cold” immune phenotype of prostate tumors, characterized by low neoantigen expression, limited immune cell infiltration, and an immunosuppressive tumor microenvironment, represents a key barrier. These immunological characteristics are primarily based on mechanistic and preclinical observations and do not yet translate into confirmed clinical resistance to adoptive cellular immunotherapy. However, ongoing research aims to convert these “cold” tumors into “hot,” immune-responsive phenotypes through novel combination regimens and cellular immunotherapies. Among these, dendritic cell activated cytokine-induced killer (DC-CIK) cells have gained attention for their potent non-MHC-restricted cytotoxicity, cytokine secretion, and synergistic immune-modulating properties. Despite these theoretical advantages, several tumor- and microenvironment-related factors may still limit the efficacy of CIK-based immunotherapy in prostate cancer. First, inefficient trafficking and infiltration of adoptively transferred CIK cells into prostate tumor sites may restrict effective tumor engagement, particularly in poorly inflamed lesions. Second, the prostate tumor microenvironment is enriched with immunosuppressive myeloid populations, including myeloid-derived suppressor cells and tumor-associated macrophages, which may dampen CIK activation and cytotoxic function through cytokine- and metabolite-mediated mechanisms. Third, heterogeneous or low-level expression of stress-induced ligands relevant to NKG2D signaling on prostate cancer cells may further constrain CIK-mediated tumor recognition and killing. Together, these CIK-specific barriers may partially explain the limited clinical translation observed to date, despite encouraging preclinical activity.

DC-CIK cell therapy has shown emerging promise in the treatment of prostate cancer, particularly by targeting cancer stem-like cells (CSCs), which are known to be resistant to conventional androgen deprivation therapies. In a preclinical study by Wang et al., dendritic cells were pulsed with peptides derived from prostate CSC-associated antigens, including CD44 and EpCAM, and used to activate CIK cells [ 66 ]. The resulting DC-CIK cells exhibited significantly enhanced cytotoxicity against prostate CSCs in vitro and produced potent antitumor effects in mouse xenograft models. This therapeutic approach effectively suppressed tumor growth, prolonged survival, and demonstrated the potential to overcome treatment resistance by directly targeting CSC populations. These findings suggest that CIK-based immunotherapy may represent a potential strategy to address tumor recurrence and therapeutic resistance in prostate cancer, primarily at the preclinical level.

Although current treatments for early-stage PCa are relatively effective, advanced malignancies continue to present major challenges, including recurrence, metastasis, and resistance to chemotherapy and radiotherapy. Cytotoxic T lymphocytes play a critical role as effector cells in antitumor immunity and may offer a preclinical avenue for enhancing treatment efficacy in advanced disease. In a study by Shen et al., combining adoptive T-cell therapy (including γδ T cells and CIK cells) with chemoradiotherapy using docetaxel and radiotherapy significantly enhanced cytotoxicity against metastatic PC-3 prostate cancer cells, which are known for docetaxel resistance [ 67 ]. The combination therapy markedly reduced tumor cell viability and increased apoptosis rates compared with either modality alone, indicating a strong synergistic effect. This enhanced efficacy may result from chemoradiotherapy-induced tumor stress and upregulation of immune-activating ligands, which render cancer cells more vulnerable to immune attack. These findings suggest a potential multimodal therapeutic strategy that may help address chemoresistance in metastatic PCa through immune modulation and combined treatment, although clinical validation remains limited.

In another study investigating both in vivo and in vitro models, researchers assessed the immunological impact of DC-CIK co-culture using a PC-3 prostate cancer rat model [ 68 ]. Compared with chemotherapy or monotherapy with either DCs or CIK cells, the DC-CIK combination significantly enhanced CIK proliferation between days 12 and 20 and markedly increased the secretion of IL-12 and IFN-γ, two cytokines crucial for robust antitumor immunity. Flow cytometry revealed elevated frequencies of CD3⁺CD56⁺ and CD8⁺ effector cells and a reduction in CD45RA⁺ markers, indicating enhanced activation and differentiation. Importantly, the cytotoxic activity of DC-CIK cells against PCa targets was significantly higher at various effector-to-target ratios (10:1, 20:1, 50:1; P < 0.05), accompanied by a notable reduction in tumor volume and larger necrotic areas in treated rats. Body weight remained stable throughout treatment, confirming a favorable safety profile. These data support the potential of DC-CIK co-culture to strengthen immune effector function and improve therapeutic efficacy in prostate cancer models.

Nevertheless, the prostate tumor microenvironment and androgen receptor (AR) signaling appear to influence the efficacy of CIK-based immunotherapy. A recent preclinical study reported that AR activity modulates the sensitivity of prostate cancer cells to CIK-mediated cytotoxicity [ 69 ]. Specifically, pretreatment of AR-positive prostate cancer cell lines (LNCaP and C4-2) with either AR agonists, such as R1881 or dihydrotestosterone (DHT), or the AR antagonist enzalutamide resulted in a marked reduction in CIK-induced tumor cell apoptosis and overall lysis. In addition, conditioned media derived from AR ligand-treated prostate cancer cells suppressed CIK proliferation, suggesting that hormonal modulation may alter tumor immunogenicity and impair immune effector function. Collectively, these observations indicate that AR signaling may influence tumor-CIK interactions at the cellular level. However, it is important to emphasize that these findings are derived exclusively from in vitro or preclinical models. At present, no clinical evidence demonstrates that androgen deprivation therapy compromises the therapeutic efficacy of CIK-based immunotherapy in patients. Accordingly, the impact of hormonal manipulation on CIK function should be regarded as hypothesis-generating, and extrapolation to clinical outcomes should be made with caution. Consideration of hormonal regulation may nevertheless be relevant when designing future combination strategies integrating CIK therapy with androgen receptor-targeted treatments. The key preclinical and translational findings of CIK-based immunotherapy in prostate cancer are summarized in Table 2 .

CIK cells thus represent a promising immunotherapeutic option in prostate cancer owing to their non-MHC-restricted cytotoxicity, cytokine-mediated immune enhancement, and favorable safety profile. While clinical applications remain in the early investigational stage, future research should focus on improving therapeutic efficacy, overcoming tumor immune evasion, and optimizing combination strategies. Potential avenues include combining CIK therapy with ICIs such as anti-PD-1 antibodies to reverse T-cell exhaustion, incorporating radioligand therapies like 177Lu-PSMA-617 to increase tumor immunogenicity, and reassessing the concurrent use of AR antagonists, given emerging evidence that such agents may impair CIK cell cytotoxicity. Continued translational and clinical studies are warranted to refine these multimodal immunotherapeutic strategies and enhance their applicability in advanced prostate cancer.

Conclusions and future perspectives

CIK cell therapy represents an emerging form of adoptive cellular immunotherapy with a favorable safety profile, practical feasibility, and broad antitumor activity reported in multiple studies involving both RCC and PCa. In RCC, CIK and DC-CIK therapies have been associated with improved survival outcomes, delayed recurrence, and prolonged progression-free survival in both adjuvant and metastatic settings. Clinical studies have confirmed their ability to enhance immune effector activation, reduce relapse rates after nephrectomy, and produce synergistic effects when used with conventional treatments such as targeted therapy, chemotherapy, and ICIs. Similarly, in PCa, preclinical and translational evidence suggests that CIK-based immunotherapy effectively suppresses tumor growth, enhances cytotoxic T-cell responses, and may help address therapeutic resistance, particularly when combined with chemoradiotherapy or immune checkpoint blockade. However, challenges such as tumor-induced immunosuppression, the influence of androgen receptor signaling, and the need for optimized treatment protocols remain critical barriers to clinical translation.

Future research should focus on refining the manufacturing and standardization of CIK cell products, identifying predictive biomarkers of response, and developing combination strategies that enhance therapeutic synergy. Rational integration of CIK therapy with modern immunotherapies, targeted agents, and radioligand treatments holds strong potential to amplify antitumor efficacy. In addition, incorporating CIK therapy into precision medicine frameworks guided by tumor immunogenomic profiling and individualized immune signatures may further improve patient outcomes. Large-scale multicenter clinical trials are warranted to validate efficacy, optimize dosing schedules, and define the most effective clinical settings for CIK-based regimens. Ultimately, the combination of safety, immunological potency, and compatibility with other therapeutic modalities positions CIK cell therapy as a promising frontier in personalized oncology for RCC, PCa, and other solid tumors.

Acknowledgements

This work was partially supported by the National Science and Technology Council, Taiwan (Grant Nos. NSTC 113-2314-B-075B-011 and NSTC 114-2314-B-075B-017), the Ministry of Health and Welfare, Taiwan (Grant No. 11310), and Taoyuan General Hospital, Taiwan (Grant Nos. PTH114001, PTHTM114001, and PTH114002).

Authors’ contributions

I-Ta Lee and Chih-Hung Chiang conceived and designed the review. Yung-Li Wang and Thi Thuy Tien Vo performed the literature search and drafted the manuscript. Jian-Hua Hong, Chao-Yuan Huang, and Wei-Ju Lee contributed to data interpretation, critical revision, and manuscript editing. Chih-Hung Chiang supervised the project and secured funding. All authors read and approved the final version of the manuscript.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Yung-Li Wang and Thi Thuy Tien Vo contributed equally to this work.

References

1. Motzer RJ, Powles T, Burotto M, Escudier B, Bourlon MT, Shah AY, Suárez C, Hamzaj A, Porta C, Hocking CM, Kessler ER, Gurney H, Tomita Y, Bedke J, Zhang J, Simsek B, Scheffold C, Apolo AB, Choueiri TK. Nivolumab plus cabozantinib versus sunitinib in first-line treatment for advanced renal cell carcinoma (CheckMate 9ER): long-term follow-up results from an open-label, randomised, phase 3 trial. Lancet Oncol. 2022;23:888–98.

2. Choueiri TK, Tomczak P, Park SH, Venugopal B, Ferguson T, Chang YH, Hajek J, Symeonides SN, Lee JL, Sarwar N, Thiery-Vuillemin A, Gross-Goupil M, Mahave M, Haas NB, Sawrycki P, Gurney H, Chevreau C, Melichar B, Kopyltsov E, Alva A, Burke JM, Doshi G, Topart D, Oudard S, Hammers H, Kitamura H, Bedke J, Perini RF, Zhang P, Imai K, Willemann-Rogerio J, Quinn DI, Powles T. KEYNOTE-564 Investigators. Adjuvant pembrolizumab after nephrectomy in renal-cell carcinoma. N Engl J Med. 2021;385:683–94.

3. Chi KN, Agarwal N, Bjartell A, Chung BH, Pereira de Santana Gomes AJ, Given R, Juárez Soto Á, Merseburger AS, Özgüroğlu M, Uemura H, Ye D, Deprince K, Naini V, Li J, Cheng S, Yu MK, Zhang K, Larsen JS, McCarthy S, Chowdhury S. TITAN Investigators. Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med. 2019;381:13–24.

4. Armstrong AJ, Szmulewitz RZ, Petrylak DP, Holzbeierlein J, Villers A, Azad A, Alcaraz A, Alekseev B, Iguchi T, Shore ND, Rosbrook B, Sugg J, Baron B, Chen L, Stenzl A. ARCHES: a randomized, phase III study of androgen deprivation therapy with enzalutamide or placebo in men with metastatic hormone-sensitive prostate cancer. J Clin Oncol. 2019;37:2974–86.

5. Sartor O, de Bono J, Chi KN, Fizazi K, Herrmann K, Rahbar K, Tagawa ST, Nordquist LT, Vaishampayan N, El-Haddad G, Park CH, Beer TM, Armour A, Pérez-Contreras WJ, DeSilvio M, Kpamegan E, Gericke G, Messmann RA, Morris MJ, Krause BJ. VISION Investigators. Lutetium-177-PSMA-617 for metastatic castration-resistant prostate cancer. N Engl J Med. 2021;385:1091–103.

6. de Bono J, Mateo J, Fizazi K, Saad F, Shore N, Sandhu S, Chi KN, Sartor O, Agarwal N, Olmos D, Thiery-Vuillemin A, Twardowski P, Mehra N, Goessl C, Kang J, Burgents J, Wu W, Kohlmann A, Adelman CA, Hussain M. Olaparib for metastatic castration-resistant prostate cancer. N Engl J Med. 2020;382:2091–102.

7. Rizzo A, Mollica V, Cimadamore A, Santoni M, Scarpelli M, Giunchi F, Cheng L, Lopez-Beltran A, Fiorentino M, Montironi R, Massari F. Is there a role for immunotherapy in prostate cancer? Cells. 2020;9:2051.

8. Waldman AD, Fritz JM, Lenardo MJ. A guide to cancer immunotherapy: from T cell basic science to clinical practice. Nat Rev Immunol. 2020;20:651–68.

9. Weiden PL, Flournoy N, Thomas ED, Prentice R, Fefer A, Buckner CD, Storb R. Antileukemic effect of graft-versus-host disease in human recipients of allogeneic-marrow grafts. N Engl J Med. 1979;300:1068–73.

10. Wendel P, Reindl LM, Bexte T, Künnemeyer L, Särchen V, Albinger N, Mackensen A, Rettinger E, Bopp T, Ullrich E. Arming immune cells for battle: a brief journey through the advancements of T and NK cell immunotherapy. Cancers (Basel). 2021;13:1481.

11. Cappell KM, Kochenderfer JN. Long-term outcomes following CAR T cell therapy: what we know so far. Nat Rev Clin Oncol. 2023;20:359–71.

12. Zhang Y, Qin D, Shou AC, Liu Y, Wang Y, Zhou L. Exploring CAR-T cell therapy side effects: mechanisms and management strategies. J Clin Med. 2023;12:6124.

13. Schmidt-Wolf IG, Negrin RS, Kiem HP, Blume KG, Weissman IL. Use of a SCID mouse/human lymphoma model to evaluate cytokine-induced killer cells with potent antitumor cell activity. J Exp Med. 1991;174:139–49.

14. Sharma A, Schmidt-Wolf IGH. 30 years of CIK cell therapy: recapitulating the key breakthroughs and future perspective. J Exp Clin Cancer Res. 2021;40:388.

15. Cappuzzello E, Sommaggio R, Zanovello P, Rosato A. Cytokines for the induction of antitumor effectors: The paradigm of Cytokine-Induced Killer (CIK) cells. Cytokine Growth Factor Rev. 2017;36:99–105.

16. Lu PH, Negrin RS. A novel population of expanded human CD3 + CD56+ cells derived from T cells with potent in vivo antitumor activity in mice with severe combined immunodeficiency. J Immunol. 1994;153:1687–96.

17. Dalla Pietà A, Cappuzzello E, Palmerini P, Ventura A, Visentin A, Astori G, Chieregato K, Mozzo V, Perbellini O, Tisi MC, Trentin L, Visco C, Ruggeri M, Sommaggio R, Rosato A. Innovative therapeutic strategy for B-cell malignancies that combines obinutuzumab and cytokine-induced killer cells. J Immunother Cancer. 2021;9:e002475.

18. Cappuzzello E, Tosi A, Zanovello P, Sommaggio R, Rosato A. Retargeting cytokine-induced killer cell activity by CD16 engagement with clinical-grade antibodies. Oncoimmunology. 2016;5:e1199311.

19. Sangiolo D. Cytokine induced killer cells as promising immunotherapy for solid tumors. J Cancer. 2011;2:363–8.

20. Sangiolo D, Martinuzzi E, Todorovic M, Vitaggio K, Vallario A, Jordaney N, Carnevale-Schianca F, Capaldi A, Geuna M, Casorzo L, Nash RA, Aglietta M, Cignetti A. Alloreactivity and anti-tumor activity segregate within two distinct subsets of cytokine-induced killer (CIK) cells: implications for their infusion across major HLA barriers. Int Immunol. 2008;20:841–8.

21. Sommaggio R, Cappuzzello E, Dalla Pietà A, Tosi A, Palmerini P, Carpanese D, Nicolè L, Rosato A. Adoptive cell therapy of triple negative breast cancer with redirected cytokine-induced killer cells. Oncoimmunology. 2020;9:1777046.

22. Fayyaz F, Yazdanpanah N, Rezaei N. Cytokine-induced killer cells mediated pathways in the treatment of colorectal cancer. Cell Commun Signal. 2022;20:41.

23. Capellero S, Erriquez J, Melano C, Mesiano G, Genta S, Pisacane A, Mittica G, Ghisoni E, Olivero M, Di Renzo MF, Aglietta M, Sangiolo D, Valabrega G. Preclinical immunotherapy with Cytokine-Induced Killer lymphocytes against epithelial ovarian cancer. Sci Rep. 2020;10:6478.

24. López-Soto A, Huergo-Zapico L, Acebes-Huerta A, Villa-Alvarez M, Gonzalez S. NKG2D signaling in cancer immunosurveillance. Int J Cancer. 2015;136:1741–50.

25. Wu X, Sharma A, Oldenburg J, Weiher H, Essler M, Skowasch D, Schmidt-Wolf IGH. NKG2D engagement alone is sufficient to activate cytokine-induced killer cells while 2B4 only provides limited coactivation. Front Immunol. 2021;12:731767.

26. Verneris MR, Karimi M, Baker J, Jayaswal A, Negrin RS. Role of NKG2D signaling in the cytotoxicity of activated and expanded CD8 + T cells. Blood. 2004;103:3065–72.

27. Trapani JA, Jans P, Smyth MJ, Froelich CJ, Williams EA, Sutton VR, Jans DA. Perforin-dependent nuclear entry of granzyme B precedes apoptosis, and is not a consequence of nuclear membrane dysfunction. Cell Death Differ. 1998;5:488–96.

28. Ramírez-Labrada A, Pesini C, Santiago L, Hidalgo S, Calvo-Pérez A, Oñate C, Andrés-Tovar A, Garzón-Tituaña M, Uranga-Murillo I, Arias MA, Galvez EM, Pardo J. All about (NK cell-mediated) death in two acts and an unexpected encore: initiation, execution and activation of adaptive immunity. Front Immunol. 2022;13:896228.

29. Tibbs E, Cao X. Emerging canonical and non-canonical roles of Granzyme B in health and disease. Cancers (Basel). 2022;14:1436.

30. Lee YY, Luo SC, Lee CH, Tang CL, Shen CC, Cheng WY, Yang YC, Yang MY, Yen CM. Optimizing tumor-associated antigen-stimulated autologous dendritic cell and cytokine-induced killer cell coculture to enhance cytotoxicity for cancer immunotherapy in manufacturing. BMC Immunol. 2023;24:14.

31. Ying Li CM, Li R, Drew P, Price T, Smith E, Maddern GJ, Tomita Y, Fenix K. Clinical application of cytokine-induced killer (CIK) cell therapy in colorectal cancer: Current strategies and future challenges. Cancer Treat Rev. 2024;122:102665.

32. Urlaub D, Höfer K, Müller ML, Watzl C. LFA-1 activation in NK cells and their subsets: influence of receptors, maturation, and cytokine stimulation. J Immunol. 2017;198:1944–51.

33. Zou Y, Liang J, Li D, Fang J, Wang L, Wang J, Zhang J, Guo Q, Yan X, Tang H. Application of the chemokine-chemokine receptor axis increases the tumor-targeted migration ability of cytokine-induced killer cells in patients with colorectal cancer. Oncol Lett. 2020;20:123–34.

34. Rosero ID, Ramírez-Vélez R, Lucia A, Martínez-Velilla N, Santos-Lozano A, Valenzuela PL, Morilla I, Izquierdo M. Systematic review and meta-analysis of randomized, controlled trials on preoperative physical exercise interventions in patients with non-small-cell lung cancer. Cancers (Basel). 2019;11:944.

35. Guo H, Meng Y, Peng J, Yang X. Post-operative adjuvant immunotherapy with cytokine-induced killer and dendritic cells for hepatocellular carcinoma: A systematic review and meta-analysis. Asian J Surg. 2023;46:2433–6.

36. Li CMY, Tomita Y, Dhakal B, Li R, Li J, Drew P, Price T, Smith E, Maddern GJ, Fenix KA. Use of cytokine-induced killer cell therapy in patients with colorectal cancer: a systematic review and meta-analysis. J Immunother Cancer. 2023;11:e006764.

37. Jiang Y, Qiu J, Ye N, Xu Y. Current status of cytokine-induced killer cells and combination regimens in breast cancer. Front Immunol. 2025;16:1476644.

38. Hu G, Zhong K, Wang S, Wang S, Ding Q, Xu F, Chen W, Cheng P, Huang L. Cellular immunotherapy plus chemotherapy ameliorates survival in gastric cancer patients: a meta-analysis. Int J Clin Oncol. 2020;25:1747–56.

39. Yuan X, Zhang AZ, Ren YL, Wang XL, Jiang CH, Yang L, Liu CX, Liang WH, Pang LJ, Gu WY, Li F, Hu JM. Cytokine-induced killer cells/dendritic cells and cytokine-induced killer cells immunotherapy for the treatment of esophageal cancer: A meta-analysis. Med (Baltim). 2021;100:e24519.

40. Zhao JJ, Zhou S, Chen CL, Zhang HX, Zhou ZQ, Wu ZR, Liu Y, Pan QZ, Zhu Q, Tang Y, Xia JC, Weng DS. Clinical effect of adjuvant cytokine-induced killer cells immunotherapy in patients with stage II-IVB nasopharyngeal carcinoma after chemoradiotherapy: A propensity score analysis. J Cancer. 2018;9:4204–14.

41. Regmi M, Wang Y, Liu W, Dai Y, Liu S, Ma K, Lin G, Yang J, Liu H, Wu J, Yang C. From glioma gloom to immune bloom: unveiling novel immunotherapeutic paradigms-a review. J Exp Clin Cancer Res. 2024;43:47.

42. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Drilon A, Wolchok JD, Carvajal RD, McHenry MB, Hosein F, Harbison CT, Grosso JF, Sznol M. Five-year survival and correlates among patients with advanced melanoma, renal cell carcinoma, or non-small cell lung cancer treated with nivolumab. JAMA Oncol. 2019;5:1411–20.

43. Yang Y, Wang RQ, Zhong YM, Meng MY, Zhao YY, Yang LR, Li L, Hou ZL. Efficacy of enhanced cytokine-induced killer cells as an adjuvant immunotherapy for renal cell carcinoma: preclinical and clinical studies. J Healthc Eng. 2021;2021:5709104.

44. Liu L, Zhang W, Qi X, Li H, Yu J, Wei S, Hao X, Ren X. Randomized study of autologous cytokine-induced killer cell immunotherapy in metastatic renal carcinoma. Clin Cancer Res. 2012;18:1751–9.

45. Zhao X, Zhang Z, Li H, Huang J, Yang S, Xie T, Huang L, Yue D, Xu L, Wang L, Zhang W, Zhang Y. Cytokine induced killer cell-based immunotherapies in patients with different stages of renal cell carcinoma. Cancer Lett. 2015;362:192–8.

46. Märten A, Ziske C, Schöttker B, Renoth S, Weineck S, Buttgereit P, Schakowski F, von Rücker A, Sauerbruch T, Schmidt-Wolf IG. Interactions between dendritic cells and cytokine-induced killer cells lead to an activation of both populations. J Immunother. 2001;24:502–10.

47. Zhan HL, Gao X, Pu XY, Li W, Li ZJ, Zhou XF, Qiu JG. A randomized controlled trial of postoperative tumor lysate-pulsed dendritic cells and cytokine-induced killer cells immunotherapy in patients with localized and locally advanced renal cell carcinoma. Chin Med J (Engl). 2012;125:3771–7.

48. Zhang Y, Wang J, Wang Y, Lu XC, Fan H, Liu Y, Zhang Y, Feng KC, Zhang WY, Chen MX, Fu X, Han WD. Autologous CIK cell immunotherapy in patients with renal cell carcinoma after radical nephrectomy. Clin Dev Immunol. 2013;2013:195691.

49. Kasherman L, Siu DHW, Woodford R, Harris CA. Angiogenesis inhibitors and immunomodulation in renal cell cancers: the past, present, and future. Cancers (Basel). 2022;14:1406.

50. Zheng K, Tan JM, Wu WZ, Qiu YM, Zhang H, Xu TZ, Sun XH, Zhuo WL, Wang D, Zhang JP. Adjuvant dendritic cells vaccine combined with cytokine-induced-killer cell therapy after renal cell carcinoma surgery. J BUON. 2015;20:505–13.

51. Wang ZX, Li JL, Cao JX, Liu YS, Li D, Zhang XY, Wang M, Wu M, Xu BL, Liu JL, Wang HB. Cytokine-induced killer cells in the treatment of patients with renal cell carcinoma: a pooled meta-analysis. Immunotherapy. 2014;6:787–95.

52. Mai HX, Mei GH, Zhao FL, Li BT, Tang YY, Zhang B, Xu XJ, Chen LJ. Retrospective analysis on the efficacy of sunitinib/sorafenib in combination with dendritic cells-cytokine-induced killer in metastasis renal cell carcinoma after radical nephrectomy. J Cancer Res Ther. 2018;14:S427–32.

53. Song MJ, Pan QZ, Ding Y, Zeng J, Dong P, Zhao JJ, Tang Y, Li J, Zhang Z, He J, Yang J, Huang Y, Peng R, Wang QJ, Gu JM, He J, Li YQ, Chen SP, Huang R, Zhou ZQ, Yang C, Han Y, Chen H, Liu H, Xia S, Wan Y, Weng DS, Xia L, Zhou FJ, Xia JC. The efficacy and safety of the combination of axitinib and pembrolizumab-activated autologous DC-CIK cell immunotherapy for patients with advanced renal cell carcinoma: a phase 2 study. Clin Transl Immunol. 2021;10:e1257.

54. Zhang Z, Xiong L, Wu Z, Liu H, Ning K, Peng Y, Yu C, Ding Y, Weng D, Xia J, Jiang L, Guo S, Han H, Zhou F, Dong P. Neoadjuvant combination of pazopanib or axitinib and programmed cell death protein-1-activated dendritic cell-cytokine-induced killer cells immunotherapy may facilitate surgery in patients with renal cell carcinoma. Transl Androl Urol. 2021;10:2091–102.

55. Zhao L, Li T, Song Y, Yang Y, Ma B, Zhang Y, Shang Y, Xu B, Guo J, Qin P, Han L, Fu X, Lin H, Liu L, Ren X, Wang Z, Gao Q. High complete response rate in patients with metastatic renal cell carcinoma receiving autologous cytokine-induced killer cell therapy plus anti-programmed death-1 agent: A single-center study. Front Immunol. 2022;12:779248.

56. Chaoul N, Lauricella E, Giglio A, D’Angelo G, Ganini C, Cives M, Porta C. The future of cellular therapy for the treatment of renal cell carcinoma. Expert Opin Biol Ther. 2024;24:1245–59.

57. Hwang A, Mehra V, Chhetri J, Ali S, Tran M, Roddie C. Current treatment options for renal cell carcinoma: focus on cell-based immunotherapy. Cancers (Basel). 2024;16:1209.

58. Wang B, Xiang Y, Liu X, Pan X, Peng L, Ma J. Advances in immunotherapy and targeted therapy for advanced clear-cell renal cell carcinoma: current strategies and future directions. Front Immunol. 2025;16:1582887.

59. Wang Y, Suarez ER, Kastrunes G, de Campos NSP, Abbas R, Pivetta RS, Murugan N, Chalbatani GM, D’Andrea V, Marasco WA. Evolution of cell therapy for renal cell carcinoma. Mol Cancer. 2024;23:8.

60. Hussain M, Fizazi K, Shore ND, Heidegger I, Smith MR, Tombal B, Saad F. Metastatic Hormone-Sensitive Prostate Cancer and Combination Treatment Outcomes: A Review. JAMA Oncol. 2024;10:807–20.

61. Wilt TJ, Ullman KE, Linskens EJ, MacDonald R, Brasure M, Ester E, Nelson VA, Saha J, Sultan S, Dahm P. Therapies for clinically localized prostate cancer: a comparative effectiveness review. J Urol. 2021;205:967–76.

62. Riaz IB, Naqvi SAA, He H, Asghar N, Siddiqi R, Liu H, Singh P, Childs DS, Ravi P, Hussain SA, Murad MH, Boorjian SA, Sweeney C, Van Allen EM, Bryce AH. First-line systemic treatment options for metastatic castration-sensitive prostate cancer: a living systematic review and network meta-analysis. JAMA Oncol. 2023;9:635–45.

63. Francini E, Agarwal N, Castro E, Cheng HH, Chi KN, Clarke N, Mateo J, Rathkopf D, Saad F, Tombal B. Intensification approaches and treatment sequencing in metastatic castration-resistant prostate cancer: a systematic review. Eur Urol. 2025;87:29–46.

64. Cheever MA, Higano CS. PROVENGE (Sipuleucel-T) in prostate cancer: the first FDA-approved therapeutic cancer vaccine. Clin Cancer Res. 2011;17:3520–6.

65. Marcus L, Lemery SJ, Keegan P, Pazdur R. FDA approval summary: pembrolizumab for the treatment of microsatellite instability-high solid tumors. Clin Cancer Res. 2019;25:3753–8.

66. Wang Z, Li Y, Wang Y, Wu D, Lau AHY, Zhao P, Zou C, Dai Y, Chan FL. Targeting prostate cancer stem-like cells by an immunotherapeutic platform based on immunogenic peptide-sensitized dendritic cells-cytokine-induced killer cells. Stem Cell Res Ther. 2020;11:123.

67. Shen YC, Shih HJ, Lin CC, Huang SH, Wu SC, Hsiao CH, Chiu SC, Cho DY, Chang CP, Pan Y, Shih PH. Synergistic benefit of adoptive T cells in combination with chemoradiotherapy against metastatic prostate cancer cells. Anticancer Res. 2022;42:3427–34.

68. Li Y, Chen S, Liu S. Immune effect of co-culture of dendritic cells and cytokine-induced killer cells on prostate cancer cells. Cell Biochem Biophys. 2025;83:1593–604.

69. Pungsrinont T, Schneider MA, Baniahmad A. Androgen receptor agonist and antagonist reduce response of cytokine-induced killer cells on prostate cancer cells. J Cell Mol Med. 2023;27:2970–82.

Associated Data

Data Availability Statement

No datasets were generated or analysed during the current study.