Clinical application of cytokine-induced killer cells in cancer immunotherapy.

Introduction

Cancer immunotherapy has transformed modern oncology, offering a way to precisely and persistently attack tumors by harnessing the body’s immune defenses [ 1 ]. Within adoptive cell therapies (ACTs), cytokine-induced killer (CIK) cells stand out because they merge the tumor-killing capabilities of T cells and natural killer (NK) cells, exhibiting antitumor activity that does not require strict human leukocyte antigen (HLA) matching and reflects both T-cell receptor (TCR)-dependent adaptive recognition and NK-like, less HLA-restricted cytotoxic mechanisms [ 2 , 3 ]. This major histocompatibility complex (MHC)-unrestricted killing, combined with their excellent safety profile characterized by minimal toxicity, carves out a distinct and clinically valuable niche for CIK cells in the competitive landscape of ACTs, which includes complex and toxic options such as chimeric antigen receptor (CAR)-T cells and tumor-infiltrating lymphocytes (TILs) [ 4 , 5 ]. CIK cells are ex vivo-expanded peripheral blood mononuclear cells (PBMCs) activated with interferon-gamma (IFN-γ), anti-CD3 antibodies, and interleukin-2 (IL-2), resulting in a heterogeneous population of CD3 + CD56+ effector cells that can kill tumor cells through perforin/granzyme-mediated cytotoxicity and death receptor pathways [ 6 ].

Preclinical research has demonstrated that CIK cells can effectively target a wide range of cancers, paving the way for clinical trials [ 7 ]. Early clinical trials confirmed that CIK cell therapy is generally safe, with side effects typically limited to mild fever or occasional allergic reactions. However, researchers have had to overcome hurdles, including the cells’ short-lived activity in the body and the immune-dampening effects of the tumor microenvironment (TME) [ 8 – 11 ]. Recent breakthroughs directly address these limitations through next-generation strategies. These include advanced genetic engineering, such as CAR-CIK and CRISPR-mediated gene editing; refined combinations with immune checkpoint inhibitors (ICIs) and epigenetic modulators; and the development of biomarker-driven protocols. These novel approaches aim to enhance CIK cell effectiveness by increasing their potency, durability, and capacity to overcome the TME [ 12 , 13 ]. In clinical practice, CIK cells have shown encouraging results, whether used after surgery to prevent recurrence or in advanced metastatic disease, especially when paired with standard treatments such as chemotherapy, radiation, or surgery [ 14 ].

Even though these results are promising, many important questions remain. This is why this review is so important. One of the main problems is that it is very hard to standardize CIK cell production because differences in cytokine cocktail protocols, culture duration, and product characterization make it difficult to compare results across trials and reproduce them in the clinic. Also, it’s still unclear what the best way to choose patients is, especially regarding which disease stages and tumor types respond best and how previous treatments affect outcomes. The absence of dependable predictive biomarkers significantly hinders the identification of patients likely to respond, the real-time monitoring of treatment efficacy, and the intelligent design of combination therapies. To advance CIK cells as a standard, reliable, and accessible component of precision oncology, we need to address these unresolved problems.

In this review, we summarize what we know about CIK cells, including how they work, how to enhance their therapeutic effects, and how well they perform in real-world settings across different cancer types. We want to help CIK cell therapy reach its full potential in personalized cancer treatment by analyzing data from randomized clinical trials, discussing current challenges, and highlighting promising new approaches.

Methodology

A literature review was conducted (Fig. 1 ) to ensure that the current evidence on CIK cell therapy was synthesized in a comprehensive and fair manner. This review encompasses clinical studies assessing the efficacy of autologous or allogeneic CIK cell therapy for solid tumors and hematological malignancies, administered either as monotherapy or in combination with other treatment modalities. We used the keywords and index terms we identified to search MEDLINE via PubMed for articles published between January 2014 and December 2025. Appendix I has all the information you need about the PubMed search strategies. Eligible study designs included randomized controlled trials (RCTs), non-randomized trials, and prospective or retrospective cohort studies that reported clinical outcomes, including survival, response rates, and safety. Cancer stage did not limit eligibility. We looked at publications in English or other languages that had an English abstract. To ensure thoroughness, the reference lists of all retrieved articles were manually examined to identify any additional pertinent studies not included in the initial database search.

CIK cell phenotype

CIK cells exhibit a unique immunophenotypic profile, harnessing the potent MHC-unrestricted cytotoxicity of NK cells alongside the antigen-specific proliferative capacity and memory of T cells, thereby constituting a singular and potent therapeutic platform. This hybrid approach confers unique advantages in cancer treatment. Their defining characteristic is this dual nature, which underpins their favorable safety profile and broad, off-the-shelf potential compared with more restricted antigen-specific therapies.

CIK cell products exhibit a heterogeneous phenotypic and functional profile, comprising various lymphocyte subsets that are expanded via standardized cytokine stimulation. The primary effector population, comprising CD3 + CD56+ cells, exhibits features of both T cells and NK cells and is considered the primary mediator of MHC-unrestricted antitumor cytotoxicity. Nonetheless, CIK cultures also include conventional CD3 + CD56− T cells, which may contribute to antigen-specific recognition and immunological memory, as well as CD3 − CD56+ NK cells, which facilitate innate cytotoxic activity [ 3 , 15 ].

The potent antitumor efficacy of CIK cell therapy is primarily mediated by a distinct subset of CD3 + CD56+ cells that bridges our adaptive and innate immune defenses. These dual-action cells make up 15–30% of the final cell product. They combine the targeted memory of T cells with the ability of NK cells to attack quickly without needing specific antigen matching [ 16 ]. This synergistic function enables CIK cells to recognize and eliminate malignant cells through multiple mechanisms. One of their best features is that they can perform T-cell-like effector functions, such as strong cytotoxicity and cytokine release, without recognizing MHC-presented antigens [ 16 ].

Specialized receptors on the surface of CIK cells give them a lot of their ability to fight cancer. These include powerful activating molecules such as NKG2D and DNAM-1, which recognize ‘stress signals,’ particularly the MICA/B and PVR proteins that cancer cells often overexpress when they become genetically unstable or metabolically distressed [ 17 ]. CIK cells have a key advantage over regular T cells. They naturally express low levels of immune checkpoints, such as PD-1 and CTLA-4. This makes them more resistant to tumors’ immunosuppressive tricks. This inherent resistance to exhaustion is a critical feature that underpins their efficacy and differentiates them from conventional, often exhausted, TILs. With their effector memory profile (CD45RO+, CD62L−), CIK cells can rapidly travel to tumor sites and attack cancer cells in multiple ways, including by releasing perforin and granzymes, triggering Fas/FasL-mediated death signals, and activating the immune system via IFN-γ (Fig. 2 ) [ 18 ]. With these versatile attack methods and a low risk of attacking healthy tissue or causing dangerous immune reactions, it’s clear why CIK cells are becoming such promising cancer fighters [ 19 ].

Circumventing HLA/MHC matching requirements: the strategic advantage of CIK cells

Traditional adoptive T cell immunotherapies face substantial clinical limitations due to stringent HLA-restriction requirements that significantly limit patient eligibility and treatment accessibility. Conventional T cell-based approaches necessitate precise HLA haplotype matching between donors and recipients, fundamentally limiting the number of patients who can benefit from such therapeutic interventions [ 20 ]. This restriction creates considerable logistical barriers, including prolonged donor identification processes, treatment delays, and the exclusion of patients with rare HLA phenotypes from potentially curative therapies.

CIK cells represent a paradigmatic shift in adoptive immunotherapy through their unique ability to mediate cytotoxicity via both MHC and non-MHC restricted recognition mechanisms, termed “dual-functional capability,” while displaying minimal alloreactivity [ 21 ]. CIK cells recognize and destroy tumor cells in an HLA-independent manner via NKG2D engagement, eliminating the need for antigen-specific stimuli for activation and proliferation [ 22 ]. This MHC-unrestricted antitumor activity is primarily mediated by the interaction between NKG2D molecules on CIK cells and MIC A/B or ULBP molecules expressed on tumor cells [ 23 ].

Recent clinical evidence has shown that CIK cells made from full-donor chimeric patients can be successfully expanded and maintain their strong anti-leukemic activity without increasing alloreactivity across major HLA barriers [ 24 ]. These results provide translational evidence supporting the clinical use of CIK cells as a substitute for traditional donor lymphocyte infusions after hematopoietic cell transplantation. Moreover, CIK cells exhibit diminished alloreactivity relative to standard T cells, even when confronted with HLA barriers, resulting in only mild graft-versus-host disease (GVHD) in a limited number of patients post-allogeneic CIK cell therapy [ 23 ].

The clinical implications of this HLA-independent function are significant, particularly in enhancing graft-versus-leukemia effects while reducing the risk of GVHD. CIK cells have shown good response rates, especially in cases of minimal residual disease, and the rate of GVHD is less than 25% [ 21 ]. This feature designates CIK cells as an appropriate option for enhancing anti-tumor immune responses while reducing adverse effects, establishing a feasible new avenue in cancer immunotherapy with considerable clinical potential [ 23 ].

The removal of HLA matching requirements facilitates the development of standardized cellular therapies, significantly decreasing treatment preparation time and associated costs. It also makes it possible to start treatment immediately for patients who need it. This MHC-unrestricted approach expands the pool of patients eligible for adoptive immunotherapy, a major challenge that has made it hard to successfully use conventional T cell-based strategies in the clinic.

Manufacturing, standardization, and regulatory challenges of CIK cell therapy

For CIK cell therapy to be used in clinical settings, it must be produced using reliable, consistent methods that follow Good Manufacturing Practice (GMP) standards to ensure it is safe, effective, and scalable. Although the first protocols differed, recent progress has focused on standardizing them to reduce batch variability, improve quality control, and lower costs. This will make them more widely used [ 25 , 26 ].

CIK cells are typically derived from autologous or allogeneic PBMCs collected via leukapheresis or venipuncture (30–100 mL of blood). The GMP-compliant expansion process involves culturing cells for 14 to 21 days in serum-free medium, such as X-VIVO 15, supplemented with IFN-γ, an anti-CD3 monoclonal antibody (mAb), and IL-2. Recent protocols replace fetal bovine serum (FBS) with human AB serum or fully synthetic alternatives to reduce contamination risks, achieving higher expansion rates while meeting regulatory standards. Closed-system bioreactors, such as WAVE or G-Rex, have been validated for automation, which minimizes manual handling and contamination. Additionally, replacing IL-2 with IL-15 improves memory phenotypes and persistence [ 27 – 29 ].

GMP requires rigorous testing for identity, purity, potency, and safety. Identity is confirmed via flow cytometry (CD3 + > 90%, CD3 + CD56 + > 20%, low PD-1/CTLA-4). Purity is assessed by contaminants, such as 50% lysis against K562 targets, and cytokine secretion (IFN-γ > 1,000 pg/mL). Sterility (bacterial/fungal/mycoplasma-free) and endotoxin (80–90% by trypan blue/7-AAD) are mandatory. Cryopreservation stability programs show CIK cells retain > 80% viability and potency after 9–12 months in DMSO-based media, enabling off-the-shelf logistics [ 25 ].

Cost is a key factor to consider. Although CIK cell therapy tends to be more cost-effective than CAR-T cell therapy, mainly because it does not involve viral vectors or genetic modifications, it still demands specialized GMP facilities, skilled staff, and lengthy culture processes [ 30 ].

Comparative analysis of CIK cells with other ACTs (NK, CAR-T, CAR-NK)

ACTs include various effectors such as CIK cells, NK cells, CAR-T cells, and CAR-NK cells. Although all aim to eliminate tumors, they vary in their mechanisms, effectiveness, safety profiles, production methods, and uses. CIK cells stand out with their hybrid phenotype, providing distinct benefits [ 31 ].

CAR-T cells currently represent the most clinically advanced ACT, particularly in B-cell malignancies, where they achieve high complete response rates [ 32 , 33 ]. However, CAR-T therapy faces notable challenges, such as serious toxicities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). It also involves complex, expensive manufacturing processes and has limited success in solid tumors because of antigen heterogeneity and immunosuppressive TME. Also, CAR-T cells need to target antigens very carefully, which makes it more likely that antigens will escape and the disease will come back [ 34 – 37 ].

NK cells are innate immune cells that can recognize and eliminate cancer cells without prior sensitization. They present an alternative strategy characterized by MHC-independent tumor recognition, diminished incidence of GVHD, and a favorable safety profile [ 38 , 39 ]. Nevertheless, a major obstacle in NK cell therapy is improving their survival and effectiveness within the immunosuppressive TME [ 40 ]. Approaches to address this include genetically modifying NK cells to boost their activity, providing cytokine support such as IL-15, and integrating NK cell therapy with other immunotherapies, such as ICIs [ 41 , 42 ]. The clinical effectiveness has generally been limited across numerous solid tumor cases, leading to the exploration of CAR-NK cell therapies to enhance targeting precision and long-term persistence.

CAR-NK cells combine the antigen-targeting precision of CAR engineering with NK cells’ natural ability to kill and safety benefits. Early-phase clinical trials suggest that CAR-NK cells can achieve meaningful antitumor responses with minimal CRS, neurotoxicity, or GVHD, even in allogeneic settings [ 43 – 45 ]. This is mainly due to the inherent characteristics of NK cells, which are transient in the body and exhibit different cytokine profiles compared to T cells. Typically, NK cells produce fewer pro-inflammatory cytokines, such as IL-6, greatly reducing the risk of CRS and neurotoxic effects [ 46 ]. Moreover, the reduced lifespan of NK cells in vivo implies that they do not endure sufficiently to elicit the sustained cytokine-mediated inflammation observed with CAR-T cell therapies [ 43 ].

CIK cells represent an intermediate and complementary category within ACTs. They phenotypically and functionally connect innate and adaptive immunity by expressing T cell proliferation capabilities alongside NK-like cytotoxicity that does not rely on MHC, primarily mediated through NKG2D signaling [ 47 ].

In contrast to CAR-T cells, CIK cells do not rely on predefined tumor antigens, thereby diminishing the risk of antigen escape and allowing activity against heterogeneous tumors [ 20 ]. When compared with NK cells, CIK cells demonstrate superior ex vivo expansion, extended persistence, and enhanced cytotoxicity, all while maintaining an advantageous safety profile characterized by a low incidence of severe CRS and GVHD [ 48 ].

Modifications of CIK cells to improve their function

Recent developments in cell-based engineering and immunotherapeutic approaches have facilitated novel methods to augment the tumor-targeting efficacy, durability, and precision of CIK cells. In the subsequent section, we analyze principal modifications assessed in both experimental and clinical research, focusing on their biological mechanisms and translational applications.

Cytokines

Cytokines are essential for the growth, survival, and functional activation of CIK cells. While traditional culture methods use IL-2 and IFN-γ to make cells grow, new research has been looking at ways to make cytokine cocktails better so that they work better as treatments. Significantly, replacing IL-2 with IL-15 has shown considerable benefits, reducing cell exhaustion and promoting a beneficial memory-like phenotype. IL-15-primed CIK cells show higher mitochondrial oxidative phosphorylation (OXPHOS), which is a metabolic change that helps them live longer in the low-oxygen TME [ 50 , 51 ]. In addition, adding IL-21 has been shown to greatly increase the expression of granzyme B while also encouraging the growth of the CD3 + CD56+ effector population, which is a group of cells that is especially good at fighting tumors [ 49 ].

Immune checkpoint inhibitors

Combining CIK cells with ICIs is a promising way to get around the immune-suppressing mechanisms in the TME. New evidence shows that CIK cells usually have low levels of PD-1 at rest, but these levels are still high enough to make them respond to PD-1/PD-L1 blockade. A 2025 phase II trial in non-small cell lung cancer (NSCLC) provided clinical validation, showing that combining anti-PD-1 therapy with CIK cells had synergistic effects by reversing T-cell exhaustion. This led to a two-fold improvement in progression-free survival (PFS) compared to CIK cell monotherapy [ 50 ]. Preclinical studies corroborate this strategy, demonstrating that CTLA-4 inhibition enhances CIK cell therapy by increasing tumor infiltration, especially in immunologically quiescent “cold” tumor models [ 51 ].

Dendritic cells

Combining CIK cells with tumor-antigen-loaded dendritic cells (DCs) strengthens antigen-specific antitumor responses. A 2022 trial of hepatocellular carcinoma (HCC) showed that administering DC-CIK in addition to CIK increased the number of tumor-reactive CD8 + T cells by 3-fold compared with CIK alone. This immune boost led to a clinically significant 50% reduction in tumor recurrence. Recent methodological advancements use mRNA-electroporated dendritic cells expressing tumor neoantigens, enabling CIK cells to target diverse cancer cell populations more efficiently. A 2025 study showed that this method has great clinical potential. It found that 30% of colorectal cancer patients with microsatellite instability-high (MSI-H) who received neoantigen-primed DC-CIK therapy had complete tumor regression [ 52 , 53 ].

Chimeric antigen receptor

The advent of CAR engineering has elevated CIK cells to precision-targeted therapeutics with remarkable clinical efficacy. In B-cell malignancies, CD19-directed CAR-CIK cells induced impressive 85% complete response rates among patients with relapsed/refractory disease, while notably avoiding severe CRS, a frequent limitation of conventional CAR-T therapies [ 54 ]. In solid tumor applications, HER2-specific CAR-CIK cells have shown significant potential in gastric carcinoma, as their intrinsic NKG2D signaling pathway enhances TME infiltration. The most innovative clinical advance in 2025 used bispecific CAR constructs (targeting both EGFRvIII and IL-13Rα2) against glioblastoma multiforme. This led to a durable 6-month PFS in 60% of patients treated [ 55 ].

Antibodies

Bispecific antibodies (BsAbs) are powerful molecular bridges that selectively bring CIK cells to cancer cells by binding to both CIK surface markers (CD3 or NKG2D) and tumor-associated antigens at the same time. A 2021 study showed that EpCAM/CD3-BsAbs increased CIK-mediated killing of pancreatic adenocarcinoma cells by 70% in vitro, which was a preclinical validation of this method. After that, there was a clinical trial in 2024 that showed that CEAxNKG2D BsAbs made CIK cells move to metastatic colorectal cancer lesions much better. This led to a two-fold increase in disease control rates (DCR) compared to regular CIK therapy. Researchers are now working on more advanced trispecific constructs, like CD3/NKG2D/PD-L1, that can engage CIK cell effectors, stop PD-L1-mediated immunosuppression, and keep tumor antigen specificity. This is a next-generation approach that is currently being studied [ 56 , 57 ].

CIK cell efficacy in relation to tumor immune phenotype and antigen landscape

The efficacy of CIK cells concerning tumor immune phenotype delineates a complex clinical scenario, wherein the NK-like component offers limited but inadequate solutions for “cold” tumors characterized by low neoantigen burden and minimal immune infiltration. “Cold” tumors, commonly observed in pancreatic and prostate cancers, exhibit sparse immune infiltrates, lack interferon signatures, and show poor responsiveness to ICIs. This contrasts markedly with “hot” tumors such as melanoma and lung cancer, which demonstrate substantial immune infiltration [ 58 ]. CIK cells inherently possess advantageous qualities owing to their CD3 + CD56+ phenotype, which facilitates MHC-unrestricted tumor cytotoxicity through interactions between the NKG2D receptor and MIC A/B or ULBPs molecules on tumor cells. This mechanism potentially enables them to circumvent certain immune evasion strategies typical of cold tumors [ 20 ].

Clinical trials have shown that CIK therapy is effective even in difficult tumor environments. Lee et al. reported in a Phase I trial ( NCT00699816 ) that patients treated with CIK after curative therapy for HCC experienced a median recurrence-free survival of 14 months, along with improved overall and cancer-specific survival rates compared to controls [ 59 ].

Wu et al. demonstrated in clinical trials that the combination of CIK cells with chemotherapy (docetaxel and cisplatin) markedly extended both PFS and OS in patients with advanced NSCLC [ 60 ]. Niu et al. showed that adding cord blood-derived CIK cells to second-line chemotherapy improves PFS and OS rates in patients with advanced solid tumors who have failed first-line chemotherapy [ 61 ]. Chen and colleagues reported that MICA expression correlated with clinical outcomes in gastric cancer patients undergoing CIK cell therapy, with higher MICA levels associated with better outcomes. An expression being linked to better therapeutic effectiveness [ 62 ].

Nonetheless, the accumulation of clinical data underscores the significance of combinatorial strategies to attain optimal efficacy in immunologically cold tumors. Dai and his team found that blocking the PD-1/PD-L1 axis made CIK cells more effective at killing gastric and colorectal cancer cells. In preclinical studies, the combination treatment slowed tumor growth and improved survival [ 63 ]. Numerous clinical studies have confirmed improved efficacy when CIK cells are combined with DCs, ICIs, or engineered with CARs [ 64 ]. To turn cold tumors into hot ones, you need to use a lot of different methods, like making tumor cells die in a way that makes the immune system attack them, targeting immunosuppressive microenvironments, and making antigen presentation better [ 65 ]. Consequently, although the NK-like aspect of CIK cells offers significant benefits via MHC-independent tumor recognition and exhibits clinical effectiveness across diverse cancer types, the intricate immunosuppressive mechanisms inherent in cold tumors require multi-modal therapeutic approaches that integrate CIK cell therapy with priming agents, checkpoint blockade, and additional immunomodulatory treatments to attain optimal clinical outcomes in these demanding tumor contexts.

Clinical studies on CIK cell therapy

Clinical studies have shown that CIK cells are a safe and effective new immunotherapy for cancer. The International Registry of CIK Cells (IRCC) has gathered extensive clinical data from various treatment modalities, encompassing standalone neoadjuvant/adjuvant therapy, combination regimens with conventional chemotherapy, and integrated strategies with other immunotherapies. These results demonstrate that CIK cells constitute a secure and efficacious therapeutic strategy for cancer patients [ 66 ].Data from multiple randomized clinical trials regarding CIK cell-based therapy were extracted from PubMed and subjected to analysis. Table 1 summarizes clinical studies on CIK cell therapy alone or in combination with conventional therapy in solid tumors. Moreover, Table 2 presents the efficiency of CIK cell therapy, combined with immunotherapy and engineered CIK cells, in treating solid tumors. CIK cell therapy for the treatment of hematological malignancies is also shown in Table 3 .

Hepatocellular carcinoma

The effectiveness of CIK cells in treating HCC likely results from the common upregulation of NKG2D ligands (such as MICA/B and ULBP) on cancerous hepatocytes, rendering them particularly vulnerable to CIK’s MHC-unrestricted cytotoxicity [ 67 ]. Furthermore, the liver’s intrinsic immunotolerant microenvironment may be positively influenced by locoregional therapies such as transcatheter arterial chemoembolization (TACE) or RFA, which induce immunogenic cell death and facilitate the release of tumor-associated antigens. This synergistic effect enhances the recruitment and activation of CIK cells within the TME, thereby elucidating the notable improvements in PFS and immune restoration observed in combination treatment regimens. These effects are especially significant in cases of intermediate-stage disease, where the tumor burden is manageable, and the immunogenic potential persists [ 68 , 69 ].

The combination of DC-CIK immunotherapy with locoregional therapies has emerged as a promising strategy for HCC management. A clinical comparison (non-randomized study, n = 68) demonstrated that adding DC-CIK cells to TACE significantly extended median PFS (16 vs. 7 months) and improved quality of life compared to TACE alone, while maintaining an excellent safety profile with only transient fever and allergic reactions observed. Although overall survival (OS) did not reach statistical significance (24 vs. 13 months), the near doubling of median OS highlights the potential clinical benefit of this combination approach. It should be noted that this was a relatively small, non-randomized study, which may introduce selection bias. Furthermore, multivariate analysis identified BCLC stage and pre-treatment AFP level as independent risk factors affecting outcomes, suggesting that patient selection significantly influences the results. The study further establishes that CIK-based combinations can safely potentiate standard HCC interventions without compromising tolerability, offering meaningful disease control, particularly for patients with intermediate-stage disease [ 70 ].

A 2015 multicenter, randomized, open-label, phase III study by Lee et al. ( NCT00699816 ) showed that adjuvant CIK cell therapy, produced by stimulating patients’ PBMCs with IL-2 and anti-CD3 antibody, improved recurrence-free and OS in 230 HCC patients after curative treatment (median 44.0 vs. 30.0 months). Although associated with mostly mild-to-moderate side effects, such as fever and fatigue, this immunotherapy proved safe and effective, particularly for intermediate-stage HCC, offering a promising post-resection treatment option. These promising results are tempered by certain limitations. The use of a one-sided test for the primary analysis and the wide confidence intervals around the survival estimates indicate a need for cautious interpretation. Furthermore, recruiting patients solely from Korean tertiary centers may affect the generalizability of the findings. These findings support the use of CIK cells as a valuable addition to HCC management strategies [ 71 ].

A retrospective, single-center cohort study evaluated the addition of adjuvant autologous CIK cell therapy to RFA and TACE in 156 HCC patients (research group: n = 93; control group: n = 63). While OS rates (1-, 3-, 5-year) did not differ significantly between all patients receiving RFA+TACE + CIK versus RFA+TACE alone (e.g., 75.3% vs. 71.4% at 1 year), a significant survival advantage was observed in the high-risk subgroup with tumors ≤ 5 cm (5-year survival: 37.5% vs. 23.5%). The principal limitations of this study are its non-randomized, retrospective design, which introduces the possibility of selection bias, particularly given the unequal group sizes. Additionally, the extended recruitment period (2006–2012) may affect the consistency of supportive care standards. The findings suggest that CIK cell therapy can effectively complement standard locoregional treatments for a defined HCC subgroup, offering improved survival in high-risk patients with smaller tumors and an added virological benefit, all without introducing substantial new toxicity [ 72 ].

Long et al. conducted a single-center, prospective cohort study ( n = 60) to evaluate an integrative approach for advanced HCC, comparing the combination of Jianpi Liqi Yiliu Formula (JLYF) with CIK cell therapy versus a traditional syndrome-typed TCM decoction plus CIK cells. The combination regimen with JLYF yielded superior clinical outcomes, significantly prolonging the median time to progression (TTP) compared to the control group (3.5 vs. 2.5 months) and showing a trend toward improved OS (5.2 vs. 4.6 months). The treatment was also associated with a better performance status post-therapy. However, the interpretation of these results is limited by the study’s non-randomized design, small sample size, and the comparison of two active TCM-based regimens rather than a placebo control. The findings suggest a potential benefit of this specific integrative approach, particularly for patients with better baseline liver function (Child-Pugh A) and performance status [ 73 ].

A prospective, randomized phase II trial ( n = 132, treatment-naïve BCLC A-C HCC patients) indicated that CIK cell augmentation of standard therapy markedly enhanced survival outcomes, attaining an 81% three-year survival rate when combined with RFA. The study showed how to combine post-locoregional adjuvant therapy with TACE and RFA. Adverse events related to treatment were limited to mild, temporary reactions, such as fever and allergic reactions, which are consistent with CIK’s known safety record. The study’s conclusions are constrained by the variability in the standard treatments administered to the control group, which diminishes the precision of comparisons. Also, the often-cited 81% survival rate comes from a subgroup of patients who had RFA after the fact, not from the whole trial population. Still, effectiveness remained the same across all BCLC stages, which means it could be used alongside other therapies as well. These findings establish CIK cells as a flexible immunotherapeutic element suitable for both curative and palliative treatment approaches in HCC [ 74 ].

The evidence as a whole indicates that CIK cell therapy is a promising adjunctive treatment for HCC. Its main job seems to be to enhance the efficacy of curative-intent procedures such as resection, RFA, and TACE, where it greatly reduces the risk of recurrence and, in some trials, increases survival. This benefit is most pronounced and well documented in patients with intermediate-stage disease after initial treatment, and the therapy is distinguished by its consistent, manageable safety record.

Renal cell carcinoma

Renal cell carcinoma (RCC) has historically been recognized as an immunogenic cancer, characterized by substantial lymphocyte infiltration and the common expression of tumor-associated antigens [ 75 ]. RCC also exhibits significant immune escape features, including the expansion of regulatory T cells (Tregs) and activation of immune checkpoints [ 76 ]. This immunologically “hot” profile provides a favorable landscape for CIK cell therapy, which can exploit both innate (NKG2D) and adaptive (antigen-loaded DC) recognition pathways [ 77 ]. These features explain why CIK monotherapy provides only modest benefits, whereas combination strategies, particularly those involving DCs, optimized cytokine priming, or PD-1 blockade, result in markedly improved clinical outcomes by enhancing antigen presentation and mitigating immune suppression [ 78 ].

Wang et al. (2015) did a retrospective study on 82 advanced RCC patients. They found that Ag-DC-CIK cells improved immune markers in patients compared to CIK monotherapy and increased immune cell activation and proliferation in vitro, with no severe side effects. The conclusions about the treatment’s effectiveness, on the other hand, are not very strong because the study was not randomized, there was no standard therapy control group, and there was no key clinical outcome data, like survival rates. The study backs up the biological potential of this method, but it also shows that more prospective randomized trials are needed to prove its clinical benefit [ 79 ].

Zhao et al. (2015) conducted a randomized clinical trial that evaluated CIK-based therapies in RCC patients stratified by disease stage. In postoperative patients, adjuvant treatment with autologous Ag-DC-CIK significantly improved 3-year disease-free survival (96.7% vs. 57.7% in controls), lowering the risk of progression and relapse. For inoperable patients, CIK monotherapy significantly extended both 3-year OS and PFS compared to the control group. Immunological analysis confirmed enhanced immune function, with a marked increase in the CD4+/CD8 + T cell ratio post-treatment, most pronounced in the Ag-DC-CIK group. The regimens maintained an excellent safety profile with no severe toxicity. However, the study’s limitations include a lack of detailed reporting on the nature of the control intervention, which is critical for assessing the robustness of the comparisons. These findings position Ag-DC-CIK as a promising personalized adjuvant therapy for resected RCC, while CIK alone benefits inoperable patients, highlighting a stage-specific application of cellular immunotherapy [ 80 ].

A significant single-center, single-arm study (Zhao et al., 2021) examined the combination of a PD-1 inhibitor with autologous CIK cells in 29 patients with metastatic RCC resistant to previous targeted therapy. The treatment had a very high objective response rate of 41.4% (12 out of 29 patients), with 7 complete responses (24% CR rate) and a median PFS of 15.0 months. These results are better than the historical benchmark of 25% objective response rate (ORR) for nivolumab monotherapy in a similar setting. The treatment had a very good safety record, with no deaths related to it. Nonetheless, being a single-arm study conducted at a single center without a concurrent control group, the reported efficacy cannot be directly ascribed to the combination rather than PD-1 inhibition alone, and the results may be affected by selection bias. The small number of people in the sample also makes the survival estimates less accurate. Despite this, this strong synergy gives new hope for cases that don’t respond to targeted therapy, as complete responders show long-lasting remissions even after treatment stops. This suggests that the combination could be a potential cure for some patients [ 81 ].

A single-arm, single-center clinical trial evaluating genetically modified DC-CIK (gmDCs-CIK) in 28 patients with advanced RCC demonstrated an ORR of 39% and a DCR of 75%, while maintaining CIK therapy’s favorable safety profile with no significant treatment-related side effects. Key findings revealed that DCR was significantly associated with receiving multiple treatment cycles, and benefits were consistent regardless of metastatic status. Immunological monitoring in a subset of 11 patients showed preserved Th1 responses without expansion of Tregs. Major limitations of this study include its small sample size, the absence of a control group, and the lack of detailed reporting on critical survival endpoints such as PFS or OS. These results highlight how genetic engineering can leverage RCC’s immunogenicity while showing CIK therapy’s dependence on sustained treatment rather than single interventions. The gmDCs-CIK approach represents a promising proof-of-concept for overcoming RCC’s immunosuppressive barriers, providing a foundation for future optimized cellular therapies in this immunoresponsive malignancy, pending validation in larger, controlled trials [ 82 ].

RCC, clinical evidence suggests that CIK cell therapy demonstrates variable efficacy depending on the stage of the disease. In the adjuvant context, antigen-loaded DC-CIK immunotherapy markedly diminishes postoperative recurrence. For advanced, metastatic renal cell carcinoma (RCC), CIK cells, whether administered as monotherapy or in conjunction with immune checkpoint inhibitors (ICIs) like PD-1 blockers, exhibit encouraging antitumor efficacy in refractory instances. The best results come from using CIK cells with other immunomodulatory agents, like antigen-primed DCs or PD-1 inhibitors, to fight the immunosuppressive TME.

Lung cancer

The efficacy of CIK cell therapy for lung cancer is predominantly influenced by the disease stage and the immune environment. In early-stage or resected NSCLC, immune responsiveness is usually maintained, and tumor burden is lower. This situation allows CIK cells to promote Th1 polarization and activate cytotoxic T cells. In contrast, advanced NSCLC exhibits a profoundly immunosuppressive microenvironment dominated by VEGF signaling, Th2 cytokines, and expression of immune checkpoints, which limits CIK activity when used alone [ 83 , 84 ]. These biological distinctions clarify why CIK cells are most effective against lung cancer when used alongside chemotherapy, radiotherapy, or ICIs that modify the TME and revive effector functions.

A mechanistic, prospective observational study of 50 NSCLC patients (tumor-bearing vs. resected) revealed that tumor-bearing individuals exhibited significantly elevated baseline serum levels of Th2 cytokines (IL-4, IL-10) compared to resected patients. While DC-CIK therapy successfully enhanced Th1 responses, significantly increasing IFN-γ production and the frequency of IFN-γ + CD8 + T cells in resected patients, tumor-bearing patients paradoxically showed further Th2 polarization post-treatment. Critically, tumor burden was associated with VEGF overproduction, which showed a statistically positive correlation with IL-4 levels, suggesting VEGF-mediated maintenance of the immunosuppressive Th2 milieu. The primary limitations of this study are its observational nature, which cannot establish causality, and the relatively small sample size within each patient subgroup, which limits the generalizability of the finding. These findings demonstrate how established tumors create a Th2-skewed microenvironment that resists DC-CIK-driven immune reprogramming, explaining the limited clinical efficacy in advanced NSCLC and highlighting the need for strategies, such as VEGF blockade, to overcome this immunosuppressive barrier [ 85 ].

A randomized clinical trial involving 63 stage IIIB NSCLC patients (30 in the DC-CIK + chemoradiotherapy group; 33 in the chemoradiotherapy-only control group) demonstrated that combining DC-CIK immunotherapy with concurrent docetaxel-cisplatin chemotherapy and radiotherapy yielded superior clinical outcomes. The combination therapy significantly improved the response rate (83.3% vs. 54.5%), Karnofsky performance status (KPS), 12-month survival rate, and T-cell subset profiles compared to chemoradiotherapy alone, while maintaining a comparable safety profile with no significant difference in adverse reactions. However, this study’s limitations include a relatively small sample size and the absence of reported long-term survival metrics (e.g., median OS or PFS), which are critical for fully assessing the treatment’s impact on locally advanced disease. These findings support this integrated approach as a promising therapeutic strategy for stage IIIB NSCLC, warranting validation in larger trials with extended follow-up and standardized survival endpoints (Fig. 3 ) [ 86 ].

A non-randomized feasibility study evaluating DC-CIK therapy combined with thoracic radiotherapy (TRT) in 82 patients with locally advanced or metastatic NSCLC (21 in the combination group, 61 in the TRT-only control group) demonstrated a favorable safety profile, with no severe immunotherapy-related adverse events. Patients receiving the combined treatment exhibited enhanced immune responses, and the regimen significantly improved median PFS (330 vs. 233 days) and the ORR (47.6% vs. 24.6%) compared to radiotherapy alone. However, the study’s major limitations include its non-randomized design, the highly unequal group sizes, which suggest potential selection bias, and the lack of a significant OS benefit between groups. These findings support the potential of DC-CIK immunotherapy as an adjunct to radiotherapy in advanced NSCLC, warranting further investigation in larger RCTs to confirm efficacy and define its role in the treatment paradigm [ 87 ].

Research has identified CD4 + T cells within CIK populations as critical mediators of antitumor activity through IL-17 A-dependent AKT pathway activation in cytotoxic subsets (CD3 + CD56+/CD8 + T cells) and simultaneous reversal of T-cell exhaustion via T-bet/Eomes-mediated PD-1 + Tim-3 + downregulation. These findings explain the enhanced Th1 responses observed in resected NSCLC patients receiving CIK therapy versus Th2-dominant resistance in tumor-bearing cases, while providing mechanistic support for ongoing phase II investigations of CIK/PD-1 combinations ( NCT04836728 ) in stage IV NSCLC and previous clinical successes combining DC-CIK with chemoradiotherapy in stage IIIB disease. The data establish that maximal CIK efficacy requires both intrinsic T-cell subset coordination, particularly CD4 + helper functions, and extrinsic microenvironment modulation, informing rational combination strategies with ICIs for advanced malignancies where monotherapy shows limited efficacy [ 88 ].

A phase Ib, single-arm trial ( n = 34) in treatment-naïve stage IIIB-IV NSCLC patients demonstrated that combining autologous CIK cells with sintilimab, an anti-PD-1 mAb, and platinum-based chemotherapy achieved unprecedented efficacy (82.4% ORR, 19.3-month median PFS), with a 93.3% response rate in non-squamous histology, surpassing conventional chemoimmunotherapy benchmarks. However, these impressive efficacy results must be interpreted with caution due to the trial’s small sample size, single-arm design (lacking a direct comparator group), and the potential for selection bias inherent in early-phase trials. While grade ≥ 3 adverse events occurred in 64.7% of patients, which were primarily chemotherapy-related, the regimen maintained manageable toxicity (one treatment-related mortality), validating preclinical insights that CIK cells synergize with checkpoint inhibition by leveraging CD4 + T-cell-mediated immune activation and reversing T-cell exhaustion. These results establish triple therapy as a transformative approach, with ongoing studies refining patient selection through CD4 + subset analysis and exhaustion marker profiling to optimize the risk-benefit ratio in advanced disease [ 89 ].

A large-scale, retrospective cohort analysis involving 943 lung cancer patients with immune dysfunction (411 received CIK therapy after standard treatment, and 532 received conventional therapy alone) revealed that CIK cell therapy significantly improved cellular immune function. The study found that the rates of recurrence (56.2% vs. 78.6%) and metastasis (49.1% vs. 70.3%) were much lower, and the long-term survival rates were much better than those of conventional treatments alone. The median OS times were 48 months compared to 36 months, and the survival rates were higher at 60 months (27.7% vs. 9.2%). However, the study’s principal limitations are its non-randomized, retrospective design over an extended accrual period (2002–2010), which presents considerable risks for selection bias and confounding variables. The “conventional therapy” control group is made up of people with different types of cancer, and there isn’t enough detailed staging or histology data for subgroup analysis. This makes the conclusions less specific and less applicable to other situations. This extensive analysis corroborates the correlation of CIK therapy with enhanced immune and clinical outcomes in a diverse lung cancer cohort; however, the evidence remains observational in nature. It underscores the potential of CIK therapy as an effective immunotherapeutic intervention but highlights the necessity for prospective, randomized validation in defined patient subsets [ 90 ].

A randomized study involving 60 patients with stage IIIB-IV non-small cell lung cancer (NSCLC) indicated that undergoing more than two cycles of DC-CIK immunotherapy subsequent to navelbine-platinum (NP) chemotherapy significantly enhanced outcomes in comparison to receiving only two cycles. In this group with a poor prognosis, the group that got more immunotherapies almost doubled the 3-year survival rate (23.3% vs. 6.7%, P = 0.037) and had a 60% 1-year survival rate. Furthermore, their TTP was significantly longer (7.3 vs. 6.2 months; P = 0.034). However, the study’s conclusions are limited by its small sample size and the fact that the comparator was a lower dose of the same immunotherapy rather than a standard-of-care or placebo control, which restricts the interpretation of the absolute benefit of the DC-CIK approach itself. The results suggest key clinical parameters, including a potential minimum threshold of immunotherapy cycles for optimal benefit and maintained compatibility with chemotherapy. The observed dose-dependent survival improvement mirrors observations in other cancers, hinting at a possible universal principle for CIK therapy. This study provides preliminary protocol standardization guidelines, but its findings require validation in larger trials with a more conventional control arm to definitively establish DC-CIK’s ability to overcome chemotherapy limitations [ 91 ].

A pivotal randomized, multicenter, open-label phase II trial ( NCT01631357 ) provided high-level evidence for CIK cell therapy in squamous NSCLC, a subtype with limited targeted options. This study evaluated the addition of autologous CIK cell immunotherapy to first-line platinum-based gemcitabine-cisplatin chemotherapy in patients with previously untreated, advanced squamous NSCLC ( n = 90). The combination therapy significantly improved both median PFS (8.7 vs. 4.0 months; HR 0.26) and OS (21.0 vs. 10.3 months; HR 0.22) compared to chemotherapy alone. The ORR was also a lot higher in the combination group (62.2% vs. 31.1%). Patients did not have any serious side effects that were worse than those in the chemotherapy-only group. As one of the first multicenter randomized trials in this setting, these strong results show that combining CIK cell therapy with chemotherapy is a safe and effective way to treat advanced squamous NSCLC. More research is needed to confirm these findings in larger phase III studies [ 92 ].

A 2025 randomized phase II trial ( n = 40) in PD-L1-positive advanced NSCLC provides comparative evidence for integrating CIK cells with ICIs, demonstrating that the triple combination of CIK cells, the anti-PD-1 antibody toripalimab, and platinum-based chemotherapy significantly extended median progression-free survival (20 vs. 6 months) and improved overall survival compared to the doublet of CIK cells and toripalimab alone. The study also found a dose-response relationship, with patients who got four or more cycles of CIK cells doing better no matter which treatment arm they were in. The safety profile was also manageable. Although constrained by its sample size, these findings indicate that incorporating chemotherapy into a CIK/anti-PD-1 backbone may provide a clinically significant survival benefit, enhancing first-line combination immunotherapy strategies for this population [ 93 ].

CIK cell therapy works best for NSCLC when it is used along with other treatments. Important uses include being a consolidative adjuvant therapy after chemoradiotherapy for stage IIIB disease and being used with PD-1 inhibitors for advanced or metastatic cancer. These combinations help the immune system fight tumors and increase survival, especially in squamous cell carcinoma. Multiple treatment cycles improve effectiveness.

Gastrointestinal cancers

Gastrointestinal cancers exhibit heterogeneous immunogenicity, with the outcomes of CIK therapy being closely associated with tumor burden, inflammatory status, and baseline immune competence. Tumors such as gastric and colorectal cancers frequently express stress ligands recognized by NKG2D, thereby facilitating CIK-mediated cytotoxicity, especially in postoperative or adjuvant settings [ 94 – 96 ].

A phase II randomized study of first-line chemotherapy with or without autologous CIK cell therapy in 33 patients with stage IV gastrointestinal cancer found that the combination arm had significant clinical benefits. The CIK-chemotherapy group had a better overall response rate (ORR) and disease control rate (DCR), as well as a longer median progression-free survival (PFS) (5.6 months vs. 3.83 months) and a positive trend in overall survival (OS). The combination showed that it was very well tolerated and did not cause any serious immunotherapy-related side effects. Immunological tests showed that CIK therapy improved the body’s immune system by increasing the number of CD3 + CD8+ T-cells and NK cells and counteracting the immunosuppression caused by chemotherapy. The small sample size of this study is one of its biggest problems. This makes the results less statistically powerful and may explain why the PFS improvement was only borderline significant. The fact that it was done at only one center may also affect how generalizable the results are. These promising results are the first signs that CIK-chemotherapy combinations work better together in advanced gastrointestinal cancers. This shows that a phase III study is needed to confirm these results [ 97 ].

A randomized trial in metastatic colorectal cancer with 122 patients (61 in the CIK + FOLFOX4 group and 61 in the FOLFOX4 alone group) demonstrated that the addition of autologous CIK cells to FOLFOX4 chemotherapy significantly enhanced overall survival compared to chemotherapy alone, resulting in superior long-term outcomes. The combination worked well and only had mild side effects [ 98 ].

A matched-control retrospective analysis of 92 gastric cancer patients following resection demonstrated that adjuvant CIK therapy significantly prolonged disease-free survival (DFS) and indicated a notable trend in overall survival (OS). The neutrophil-to-lymphocyte ratio (NLR) became an important predictive biomarker. Patients with NLR < 2.995 had significant DFS benefits, while patients with high NLR needed more treatment. These results make it possible to tailor CIK therapy to each patient, with the immune status before treatment being a major factor in how well the treatment works. One of the main problems with this study is that it was retrospective and not randomized, which could lead to selection bias even though the groups were matched. The statistical trend for OS was not significant, and the biomarker cutoff (NLR = 2.995) came from this specific group of people, so it needs to be checked by an outside source. Moreover, the biological mechanisms that connect low NLR to CIK efficacy are still not fully understood [ 99 ].

A two-arm, single-center, exploratory RCT in locally advanced/metastatic gastric cancer involving 59 patients demonstrated that autologous CIK cell therapy combined with SOX chemotherapy (S-1 + oxaliplatin) significantly improved ORR (55.2% vs. 32.0%) and extended median OS by 8 months (17.8 vs. 9.75 months) compared to chemotherapy alone, while exhibiting a favorable safety profile with reduced hematologic toxicity. Major limitations include the small sample size, which likely caused the trial to be underpowered to detect a statistically significant survival benefit, and its exploratory, single-center nature, which limits the generalizability of the findings. These findings complement two key clinical observations, including the NLR-predicted survival benefits of adjuvant CIK therapy in resected gastric cancer and the remarkable 24% complete response rate achieved with PD-1/CIK combinations in refractory cases. Collectively, this evidence establishes CIK cells as a multifaceted therapeutic tool throughout the gastric cancer treatment continuum, potentiating first-line chemotherapy efficacy, synergizing with ICIs in resistant disease, and enabling precision application through NLR-based patient selection and optimized dosing regimens [ 100 ].

A pivotal single-arm, single-center clinical trial evaluating tumor lysate-pulsed DC and CIK cell combination therapy in 54 postoperative gastric and colorectal cancer patients demonstrated superior survival outcomes. With an extended 98-month follow-up, the DC-CIK group showed both significantly improved OS and reduced disease progression risk compared to conventional treatments. This antigen-specific immunotherapy achieved robust cellular dosing (mean 58.8 × 10⁸ CIK cells/cycle) while enhancing critical antitumor immune responses, as evidenced by sustained elevation of IFN-γ and IL-12. However, as a non-randomized, single-arm study without a concurrent control group, the observed survival benefits cannot be definitively attributed to the DC-CIK therapy and may be influenced by selection bias. The heterogeneous patient population also complicates the interpretation of the results. The DC-CIK platform’s unique ability to integrate innate and adaptive immunity was reflected in its durable clinical benefits, particularly its effectiveness against residual micrometastases, a key therapeutic challenge in postoperative settings. These results establish an important efficacy benchmark for cellular immunotherapy in gastrointestinal malignancies [ 101 ].

A retrospective analysis revealed that autologous CIK cell therapy combined with chemotherapy significantly improved clinical outcomes in metastatic colorectal cancer. The combination almost doubled the median PFS (8.2 vs. 4.3 months) and added 10.5 months to the OS compared to chemotherapy alone. These clinical benefits were linked to strong immune activation, such as an 82% rise in CD8 + T cells, a 51% rise in CD3 + CD56+ CIK cells, and a 14-fold rise in NK cell (CD3-CD56+) populations. The median OS of over 40 months sets a new standard for cellular immunotherapy in metastatic CRC. This strongly supports its inclusion in current treatment protocols [ 102 ].

A comparative, non-randomized cohort study involving 351 colorectal cancer patients demonstrated that DC-CIK therapy significantly enhanced overall survival (OS) while delivering clinically relevant improvements in quality of life. Patients showed measurable improvements in their physical strength (68%), appetite (72%), and sleep quality (65%). The treatment produced strong antitumor immunity, as evidenced by 62% of participants exhibiting positive delayed-type hypersensitivity (DTH) responses. This immunotherapy method had an excellent safety record, with no extra toxic effects beyond what is normal for standard care. The main problems with this study are that it wasn’t randomized and used a matched-control design, which makes it very likely that there will be selection bias even though the researchers tried to match patient characteristics. Also, the median follow-up period of about 16 months is not very long, so it may not be enough to fully capture long-term survival outcomes. These findings position DC-CIK therapy as a compelling integrative strategy for advanced CRC, simultaneously addressing both oncological outcomes and palliative care needs while providing immunological verification of treatment efficacy through objective DTH measures [ 103 ].

CIK cell therapy works well with standard chemotherapy for gastrointestinal cancers. Combining autologous CIK cells with first-line treatments like FOLFOX improves response rates, PFS, and OS for metastatic colorectal and gastric cancers. In the postoperative adjuvant setting for gastric cancer, CIK therapy extends disease-free survival. Biomarkers like the neutrophil-to-lymphocyte ratio help choose the right patients. The best results are seen when CIK cells are used with chemotherapy to control the whole body and with antigen-loaded DC-CIK to get long-lasting immune responses against micrometastases.

Pancreatic cancers

Pancreatic carcinoma ranks among the most immunologically resistant neoplasms, characterized by a dense desmoplastic stroma, a low neoantigen load, and substantial immune suppression. These features restrict immune cell infiltration and limit the efficacy of most immunotherapies [ 104 ]. CIK therapy in pancreatic cancer offers limited DCR and improvements in quality of life, rather than sustained responses, thus highlighting the importance of employing multi-modal combination strategies.

A prospective cohort study in advanced pancreatic cancer involving 47 patients demonstrated that DC-CIK immunotherapy combined with S-1 chemotherapy was feasible and clinically active. The study, which included four non-randomized treatment groups (DC-CIK + S-1, DC-CIK alone, S-1 alone, and best supportive care), found that the combination produced significantly longer median OS (212 days vs. 141 days for CT alone) and PFS (136 days vs. 92 days). Similar advantages were noted in stage IV gastrointestinal cancers, where CIK-chemotherapy combinations enhanced treatment response and disease control rate (DCR). The study’s non-randomized design and the limited patient population in each treatment arm represent significant limitations, heightening the risk of selection bias and constraining the reliability of the comparative survival analyses. Even though the absolute survival benefit is statistically significant, it is still small in this aggressive cancer. The treatment showed a good safety profile, with no grade 3 or 4 toxicities reported [ 105 ].

A phase II clinical trial with only one arm and one center looked at adoptive CIK cell therapy in 20 advanced pancreatic adenocarcinoma patients who were not responding to gemcitabine. It found that the treatment had a 25% DCR and a median OS of 6.7 months. These results were similar to those of standard chemotherapy regimens, but they had some clear benefits, such as much better quality of life measures and a toxicity profile that was only grade 3 or lower. The key limitations of this study are its single-arm design without a control group, which prevents a direct comparison of efficacy against other salvage therapies, and its tiny sample size, which limits the precision of the survival estimates as indicated by the wide confidence intervals. The study provides evidence for CIK cell immunotherapy as a well-tolerated therapeutic alternative in this treatment-resistant population [ 106 ].

In advanced pancreatic cancer, CIK cell therapy serves as a well-tolerated adjunct to chemotherapy. The most promising method is to combine DC-CIK immunotherapy with drugs, such as S-1, which have shown small but important improvements in survival rates. This regimen offers a favorable toxicity profile and enhanced quality of life, presenting a viable alternative, particularly for patients with gemcitabine-refractory disease, where it maintains comparable efficacy with potentially better tolerability.

Gynecological cancers

A randomized, non-blinded trial’s clinical evidence shows that autologous CIK cell therapy works well with standard treatments for aggressive gynecologic cancers. The study involved 89 patients with advanced cervical cancer (44 receiving CIK plus radiochemotherapy and 45 receiving radiochemotherapy alone), demonstrating that the CIK combination significantly enhanced short-term therapeutic efficacy relative to the control group. This method kept the immune system strong during intensive treatment, which is a major flaw in current regimens. One major problem with this study is that there was no significant difference in the 1-, 2-, and 3-year survival rates between the two groups. This means that the short-term benefits did not lead to a long-term survival advantage. These results establish CIK immunotherapy as an effective approach to address treatment resistance in pelvic malignancies, especially for tumors unresponsive to conventional therapies [ 107 ].

In a first-in-human, early-phase pilot study of 6B11-OCIK therapy, which combines antibody-activated T cells with DC/cytokine stimulation, 3 patients with platinum-resistant ovarian cancer were treated. The disease was stable in 33% of the patients. Immune monitoring showed that the treatment activated cytotoxic CD8 + T cells and CD3 + CD56+ CIK populations, which was linked to how well the treatment worked. These results add to what is already known about CIK therapies for cervical cancer. They show two different strategic approaches: molecularly targeted 6B11-OCIK therapy and combinations of chemo- and radiotherapy. The study also found that circulating tumor cells could be used as a new response biomarker along with the usual CA125 and immunophenotypic monitoring. The main problems with this study are that it has a very small sample size, which makes it impossible to draw any conclusions about effectiveness, and that it is a single-arm, non-randomized design with no control group. Though preliminary, these results establish critical safety data for the future development of engineered CIK therapies in treatment-refractory gynecologic malignancies [ 108 ].

For gynecological cancers, CIK cell therapy is a promising supportive strategy, particularly in advanced or refractory cases. In cervical cancer, the combination of autologous CIK cells with standard chemoradiation enhances short-term tumor response and aids in the preservation of immune function; however, a conclusive long-term survival advantage necessitates further validation. For platinum-resistant ovarian cancer, early engineered approaches, such as 6B11-OCIK, show initial safety and biological activity. The most effective current application is the integration of conventional CIK therapy with frontline chemoradiotherapy for advanced cervical cancer, as it enhances immediate treatment efficacy and mitigates therapy-induced immunosuppression.

Other solid tumors

A large retrospective cohort study by Li et al. ( n = 222) demonstrated that adding CIK cell therapy to gemcitabine-cisplatin chemotherapy significantly improved PFS and OS rates in metastatic NPC patients’ post-radiotherapy. The study showed that adding CIK cell therapy made both PFS and OS much better. Some of the main problems with the retrospective design are that it may have selection bias, it doesn’t use randomization, and it can’t control for other factors that may have affected treatment assignment and outcomes. The GC + CIK combination worked better than chemotherapy alone, which suggests that CIK cells may make standard treatment work better. These results endorse CIK immunotherapy as a promising adjunctive treatment for advanced NPC, necessitating further prospective clinical evaluation [ 109 ].

Recent research highlights CIK cell therapy’s ability to overcome immune evasion in head and neck malignancies. A single-arm, translational study in 13 patients with tongue squamous cell carcinoma demonstrated that improved CIK (iCIK) transfer reverses PD-1/PD-L1-mediated immunosuppression post-resection/chemotherapy, restoring CD8 + T cells and Th cytokine production while improving survival. The iCIKs showed intrinsic resistance to PD-1 suppression, with enhanced cytotoxicity following checkpoint blockade in vitro. Clinically, 12 of the 13 patients were long-term survivors (follow-up > 83 months). However, the study’s conclusions are constrained by its very small sample size, the absence of a control group, and its single-arm design, which prevents direct attribution of the survival outcomes to the iCIK therapy itself. Furthermore, the specific survival analysis was not formally reported. These findings support CIK therapy for addressing treatment-induced immunosuppression and ICIs resistance [ 110 ].

A randomized controlled study investigated the effectiveness of DC-CIK immunotherapy with intensity-modulated radiation therapy (IMRT) in 68 elderly patients with EC, assigning 34 patients to each group. The results showed that patients who received both DC-CIK immunotherapy and IMRT had superior short-term outcomes, improved quality of life, and enhanced immune function compared to those treated with radiation alone. A key limitation is the lack of reported quantitative survival data and statistical metrics for the claimed survival benefit, making the magnitude of the “increased OS” difficult to assess. Furthermore, the definition of “short-term outcomes” and “efficacy rate” was not specified [ 111 ].

A single-arm, phase II clinical trial assessed high-dose chemotherapy (cyclophosphamide, thiotepa, carboplatin) followed by DC-CIK immunotherapy and maintenance cyclophosphamide in 23 young metastatic TNBC patients (< 45 years). The regimen resulted in a median PFS of 13.5 months and OS of 15.2 months, with a partial response rate of 13.0% and stable disease in 56.5% of patients. Treatment was associated with significant hematologic toxicity, though no severe DC-CIK-related toxicity or treatment-related mortality occurred. Major limitations include the single-arm design without a concurrent control group, preventing a direct comparison of efficacy, and the small sample size, which limits the robustness of the survival estimates. This intensive combination may represent a salvage option for younger patients with aggressive, pretreated TNBC, but its definitive role requires evaluation in RCTs [ 112 ].

Clinical trials have validated CIK cell immunotherapy’s role in neuro-oncology. A Phase III multicenter, randomized, open-label trial showed that adding autologous CIK cells to standard temozolomide chemoradiotherapy enhanced PFS in 180 newly diagnosed glioblastoma patients versus chemoradiotherapy alone (median PFS: 8.1 vs. 5.4 months). Although OS remained unchanged, the CIK combination exhibited similar safety and quality-of-life outcomes to standard treatment. It is important to note that the PFS benefit was analyzed using a one-sided statistical test, which increases the risk of false positives, and the reported confidence intervals for PFS were wide and overlapping, indicating uncertainty in the magnitude of effect. These findings indicate that CIK therapy, when combined with conventional regimens, may provide clinical advantages for both primary and metastatic brain tumors [ 113 ].

A study employing a single-arm, retrospective design assessed RetroNectin-activated CIK cell therapy in 20 patients with metastatic brain cancer subsequent to standard treatment. The group was made up of people with different types of cancer: 4 breast cancer patients (2 survivors and 2 who died) and 14 NSCLC patients (all adenocarcinoma). In the NSCLC subgroup, three patients experienced a partial response, eight exhibited stable disease, and three progressed following treatment, resulting in an overall response rate of 21.4% and a disease control rate (DCR) of 78.6%. The median progression-free survival (PFS) for the whole group was 7.7 months, and the median overall survival (OS) was 12.6 months. The principal limitations comprise the exceedingly small and heterogeneous sample size, the lack of a control group for comparative analysis, and the retrospective design of the study, which engenders the possibility of selection bias and constrains causal inference. The wide confidence intervals around the survival estimates show that there is a lot of uncertainty. These results suggest that RetroNectin-activated CIK therapy may improve outcomes in metastatic brain tumors, particularly for lung adenocarcinoma patients [ 114 ].

Another retrospective clinical trial (April 2012-August 2014) evaluated CB-CIK immunotherapy in 15 cancer patients using varying cycle regimens. One HCC patient and one EC patient had complete responses to treatment. Two ovarian cancer patients had partial remissions, and ten patients had stable disease. Disease progression occurred in one HCC case. The therapy demonstrated excellent tolerability, with only mild acute toxicities post-infusion. Immunological analysis showed a significant post-treatment increase in CD3 + CD4+ T cells and CD3-CD56 + NK cells. Key limitations of this study are its very small, heterogeneous sample size, the absence of a control group, and its retrospective, non-comparative design, which precludes any definitive conclusions about therapeutic efficacy. The varying treatment cycles and cancer types further complicate the interpretation of outcomes. These results confirm the clinical feasibility and safety of CB-CIK cell therapy for malignant diseases, suggesting its potential as a treatment option for medically fragile or elderly patients who cannot undergo repeated phlebotomy [ 115 ].

A phase II/III, parallel assignment, open-label, non-randomized clinical trial evaluated combined RFA and CIK cell immunotherapy in 60 colorectal cancer patients with liver metastases. The RFA + CIK group achieved superior median PFS (23.0 vs. 18.5 months), higher 3-year PFS (20.3% vs. 13.3%), and survival rates (81.0% vs. 64.6%), with a median OS of 43 months (not reached in the RFA-only group). Immunological tests showed stronger CEA-specific T cell responses. All 8 patients who were tested had significant T cell expansion after CIK therapy (7 of them had higher levels than after RFA therapy), including 6 patients who had only responded to RFA therapy at first. One big problem with the study is that it wasn’t randomized, which means there is a high risk of selection bias when putting patients into treatment groups. Furthermore, the statistical significance for the key 3-year survival benefit was not achieved. These findings provide the first clinical evidence that RFA-CIK combination therapy boosts tumor-specific immunity while offering survival benefits and favorable tolerability for colorectal liver metastases [ 116 ].

A small, non-randomized clinical study assessed DC-CIK immunotherapy for malignant pericardial effusion (MPE) in 31 patients (16 in the DC-CIK treatment group; 15 in a control group receiving cisplatin + IL-2) using pericardial drainage followed by intrapericardial DC-CIK infusion. Compared to standard drainage, the combination therapy demonstrated significantly reduced effusion recurrence and improved the patients’ quality of life. The treatment showed an excellent safety profile, with only transient fever reported. Key limitations include the small sample size, the non-randomized design, and the use of an intrapericardial cisplatin control rather than a placebo or best supportive care, which complicates the interpretation of both efficacy and safety comparisons. These results suggest locoregional DC-CIK therapy may be particularly beneficial for advanced cancer patients with MPE [ 117 ].

A single-center phase Ib/II study ( n = 45) of decitabine-primed chemotherapy plus CIK cells in refractory esophageal, gastric, and colorectal cancers showed promising outcomes: 28% ORR, 92% DCR, and two durable complete responses. These findings align with prior evidence of adjuvant CIK therapy’s effectiveness in locally advanced gastric cancer, particularly for intestinal-type tumors with improved 5-year survival. The study further correlates with predictive biomarkers and survival benefits observed in metastatic colorectal cancer. However, the study’s non-randomized design and the lack of a direct comparator arm for the CIK component limit definitive conclusions about the specific additive benefit of CIK cells versus the epigenetic priming effect alone. Collectively, these results underscore CIK therapy’s versatility across alimentary tract cancers, from adjuvant treatment to salvage therapy, while demonstrating the potential of epigenetic priming with agents such as decitabine to address treatment resistance [ 118 ].

Multiple myeloma (MM)

Multiple myeloma arises within the bone marrow microenvironment, a compartment distinguished by intricate immune suppression facilitated by TGF-β, IL-6, IL-17, and Tregs [ 119 ]. CIK cells are notably efficacious in this context due to their ability to combine direct cytotoxic effects on malignant plasma cells with immune-modulatory properties that recalibrate Th1/Th2 responses and diminish immunosuppressive cytokine networks [ 120 ]. Nevertheless, the highly protected marrow microenvironment requires combination strategies, most often with chemotherapy or DC therapy, to disrupt immune tolerance and promote sustained CIK cell activity.

A randomized trial of 56 MM patients showed that combining DC-CIK adoptive immunotherapy with chemotherapy led to better clinical outcomes than chemotherapy alone. This was shown by significant improvements in quality of life, survival rates, and disease biomarkers. Immunological profiling revealed the combination therapy group exhibited favorable Th1/Th2 cytokine polarization, characterized by elevated IL-2 and IFN-γ levels alongside reduced IL-4 and IL-10 concentrations. However, significant limitations of this study encompass its relatively small sample size, which may constrain the statistical power to identify differences in long-term survival endpoints, and the possibility of heterogeneity in the chemotherapy regimens employed within the control group. These results furnish both clinical and mechanistic evidence endorsing DC-CIK as an efficacious complement to standard chemotherapy in the treatment of MM [ 121 ].

A clinical study of 50 MM patients showed that combining DC-CIK adoptive immunotherapy with chemotherapy effectively changed the tumor immunosuppressive microenvironment in several ways. For example, it stopped CD8 + T cell-mediated immunosuppression, lowered TGF-β secretion by both tumor cells and Tregs, and restored the Th1/Th2 balance by lowering CD4 + CD25+ Treg activation and increasing NKG2D expression. Nevertheless, the study’s constraints encompass a limited sample size, a brief post-treatment evaluation duration (3 weeks for initial immune markers), and an absence of long-term clinical outcome data directly associated with the noted immunological alterations. These results show that this combined approach has a lot of potential as a treatment, but the immunomodulatory pathways involved are very complicated, so more studies are needed to fully prove its clinical usefulness [ 120 ].

Qin et al. (2016) executed a randomized clinical trial involving 60 elderly multiple myeloma patients to assess the immunomodulatory effects and safety profile of CIK cell therapy. The treatment group (CIK + VAD chemotherapy) showed much bigger drops in immunosuppressive cytokines (IL-17, IL-6, TGF-β) and T cell subsets (CD3 + CD4+, CD3 + CD8+, and their ratio) than the control group (VAD chemotherapy alone), even though both groups had the same number of side effects. It is interesting to note that these strong changes in the immune system were linked to better treatment outcomes in the CIK-treated group. Nonetheless, the study failed to disclose essential clinical endpoints such as progression-free survival (PFS) or overall survival (OS), and the precise criteria for “curative efficiency” were not established. The results suggest that targeted immune modulation may be what makes CIK therapy work for these patients [ 122 ]. In the microenvironment of multiple myeloma (MM), these cytokines mostly suppress the immune system and promote tumors. For example, IL-17 and IL-6 make myeloma cells grow and Th17 cells skew, which stops Th1 cells from fighting tumors. TGF-β makes Treg cells grow and become resistant to drugs [ 123 – 125 ]. Their reduction under CIK therapy helps restore immune balance and boost the activity against myeloma.

Clinical studies show that using DC-CIK immunotherapy along with chemotherapy changes important immune system parameters. A randomized study of 42 newly diagnosed MM patients (22 in the combined DC-CIK + chemo group vs. 20 in the chemo-only group) found that this method lowers CD4 + CD25+ Tregs (with CD4 + CD25+/CD4 + and CD4 + CD25+FoxP3+/CD4 + CD25+ ratios that are much lower) and rebalances immune responses. These immunologic effects were associated with better clinical results compared to chemotherapy alone, such as better quality of life, better disease biomarkers, and longer survival rates. Nonetheless, the study’s limited sample size and insufficient reporting on specific survival metrics undermine the robustness of its conclusions. Additional research in elderly multiple myeloma patients corroborate these findings, demonstrating that CIK therapy significantly decreases immunosuppressive cytokines (IL-17, IL-6, TGF-β) while preserving a favorable safety profile. The fact that DC-CIK combination therapy has consistently shown therapeutic benefits in studies, including immune restoration and clinical efficacy, makes it a promising treatment option for multiple myeloma that targets cancer cells and reverses tumor-induced immunosuppression at the same time [ 126 ].

CIK-based therapy, typically administered as DC-CIK cell infusions, shows consistent benefits as an adjunct to standard chemotherapy in MM. Its principal mechanism involves remodeling the immunosuppressive TME by rebalancing Th1/Th2 cytokines, reducing factors, including IL-6 and TGF-β, and diminishing Tregs. This immunomodulation enhances anti-tumor immunity and is associated with improved survival and quality of life, especially in elderly or newly diagnosed patients. The best way to treat cancer is to use both DC-CIK immunotherapy and frontline chemotherapy. This kills cancer cells directly and reverses immune suppression.

Hematological malignancies

Hematological cancers are well-suited for CIK cell therapy because they are directly accessible within the circulation and bone marrow, bypassing the physical barriers that often hinder immune infiltration in solid tumors [ 127 ]. CIK cells retain robust graft-versus-leukemia activity while exhibiting reduced alloreactivity compared with donor lymphocyte infusions, a trait linked to their partial independence from MHC. This unique immunological characteristic underpins their improved safety profile and effectiveness in post-transplant scenarios, as well as in the management of minimal residual disease and relapse prevention, particularly when used as early consolidation or prophylactic treatment [ 21 ].

A single-arm pilot study of 15 high-risk relapsed/refractory hematologic malignancy patients demonstrated that sequential CIK cell infusion followed by allogeneic HSCT, with post-transplant CIK prophylaxis, achieved successful engraftment and complete remission in all cases. Despite theoretical GVHD concerns, only two patients developed aggravated GVHD, establishing the approach’s favorable safety profile. With a median follow-up of 1513 days, six patients remained alive while nine succumbed to their disease. However, the lack of a control group and the small, high-risk cohort limit the ability to attribute outcomes directly to CIK therapy and to generalize the findings. These findings support donor-derived CIK cell immunotherapy as a feasible and well-tolerated adjunct to HSCT, offering a potential prophylactic strategy against relapse in high-risk hematologic malignancies [ 128 ].

In a phase I/II single-arm clinical trial of 14 B-cell lymphoma patients receiving α-galactosylceramide-pulsed DC-CIK loaded with tumor membranes, objective responses were observed in 50% of cases (4 complete remissions, 3 partial remissions), with disease stabilization in 36% (5 patients) and progression in 14% (2 patients). The treatment demonstrated an exceptional safety profile, with no severe adverse events or autoimmune complications. Immunological monitoring at 90 days post-treatment revealed significant expansion of peripheral effector populations, including helper T cells (CD3 + CD4+), activated cytotoxic T lymphocytes (CD8 + CD28+), and NK cells, confirming robust cellular immune activation. Key limitations include the small sample size, the absence of a control group, and the single-arm design, which preclude definitive conclusions about efficacy relative to standard care. These results support the dual mechanism of this approach, combining direct antitumor activity with systemic immune potentiation [ 129 ].

A small, single-arm clinical study evaluating autologous CIK cells combined with IL-2 in 9 elderly B-cell malignant lymphoma patients demonstrated significant immunologic and clinical benefits, including enhanced expansion of CD3 + CD56+ effector cells and increased tumor-specific cytotoxicity. The regimen was well-tolerated with minimal adverse effects, offering a viable therapeutic alternative for older patients who are poor candidates for intensive chemotherapy. However, the extremely small sample size, absence of a control group, and non-randomized design preclude definitive conclusions about the therapy’s comparative efficacy and limit the generalizability of the findings. These findings support the potential of CIK/IL-2 immunotherapy as an adjunctive treatment capable of improving immune function while maintaining a favorable safety profile in this vulnerable population [ 130 ].

A pivotal retrospective comparative study comparing outcomes in 91 patients who received either donor lymphocyte infusions (DLI) or allogeneic CIK cell therapy after hematopoietic stem cell transplantation revealed that CIK cell therapy yielded superior results, even in a higher-risk cohort. Patients treated with CIK cells achieved higher complete remission rates (53% vs. 29%) and experienced fewer relapses (47% vs. 71%) than those receiving DLI. The 6-month cumulative incidence of relapse was significantly lower with CIK therapy (22% vs. 55%). Importantly, CIK therapy was associated with improved T-cell recovery and a lower incidence of GVHD, all while maintaining a strong safety profile, with no deaths attributed to the treatment. As a retrospective analysis, the study is subject to selection bias and confounding factors, and the groups were not matched at baseline, with the CIK group having a worse prognostic risk score. These findings suggest that CIK cell therapy could represent a breakthrough for patients with high-risk blood cancers, particularly when administered early, at the first signs of disease recurrence before full relapse occurs [ 131 ].

A phase II trial investigated the safety and feasibility of early post-transplant consolidation therapy using donor-derived CIK cells (1 × 10⁸/kg CD3+) in 31 of 44 enrolled patients with myeloid malignancies following nonmyeloablative conditioning (TLI-ATG) found that a single CIK infusion yielded two-year OS (50.6%; 95% CI, 37.5–68.2%) and cumulative grade II-IV GVHD incidence (25.1%; 95% CI, 12–38.2.2%) comparable to historical controls. Although the treatment did not hasten donor chimerism establishment, its favorable safety profile suggests potential for exploring repeated dosing regimens. Key limitations include the use of a historical control group rather than concurrent randomization, which may introduce bias, and the lack of a significant impact on the co-primary endpoint of achieving full donor chimerism. These results build upon prior evidence highlighting CIK cells’ advantages over DLI in preventing relapse after HSCT, particularly in high-risk patients with complex karyotypes. The study also reinforces CIK cells’ distinct immunologic features, primarily CD3 + CD8+NKG2D+ effector populations with expanded CD3 + CD56+ subsets, while introducing their novel use as a prophylactic consolidation strategy early in the post-transplant period [ 132 ].

A groundbreaking single-center imaging study tracking ¹⁸F-FDG-labeled CIK cells in 9 refractory APL patients revealed their dynamic migration pattern, with initial pulmonary sequestration (1 h post-infusion) followed by targeted accumulation in bone marrow and brain (4–8 h), correlating with remarkable clinical responses while explaining their superior safety profile compared to DLI. However, the study’s conclusions are constrained by the very small sample size, the limitations of ¹⁸F-FDG labeling (which reflects general metabolic activity rather than being a specific cell tracer), and the absence of a direct comparative control group (such as unlabeled CIK cells or another cell therapy). The findings address key knowledge gaps by demonstrating CIK cells’ homing capacity and establishing temporal activity parameters. The observed migration kinetics provide a mechanistic basis for their efficacy, particularly in sanctuary site involvement [ 133 ].

In hematological malignancies, CIK cell therapy has two main uses, each with its own set of benefits. Following stem cell transplantation, donor-derived CIK cells offer a potent and safer alternative to DLI for preventing relapse, as they maintain a strong anti-leukemia effect while significantly reducing the risk of severe GVHD. For the treatment of active, refractory diseases, such as B-cell lymphomas, autologous CIK cells, frequently augmented with additional immune agents, demonstrate encouraging clinical and immune-stimulating efficacy. The most effective strategy appears to be the early, prophylactic use of donor CIK cells post-transplant, which optimizes the graft-versus-leukemia effect and offers a superior risk-benefit profile compared to standard DLI.

Critical appraisal of clinical evidence: heterogeneity and risk of bias

The clinical evidence supporting CIK cell therapy comes from studies with considerable design and quality variability, which must be carefully evaluated to interpret the results accurately.

The evidence base includes large multicenter RCTs, small single-arm studies, and various retrospective analyses. Non-randomized and retrospective studies are particularly vulnerable to selection bias, as patients selected for CIK therapy may have superior performance status, lower tumor burden, or distinct prior treatment histories compared with controls. This can lead to an overestimation of effectiveness. Even within RCTs, open-label formats and differences in the control intervention can introduce performance and detection biases.

Diverse patient populations in clinical trials exhibit considerable variation in disease stage, prior treatment lines, and the standard of care, and these factors are further compounded by CIK cells. This diversity complicates comparisons across trials. For instance, the significant benefit seen with adjuvant HCC cannot be directly compared to the more restricted effects in gemcitabine-refractory pancreatic cancer, as the disease context and treatment goals are fundamentally different.

One of the most important sources of non-clinical variability lies within the CIK cell product itself. There is currently no universal standard for its manufacturing. Key variables include the cytokine mixture used (IL-2 vs. IL-15, with or without IFN-γ), culture duration, method of activation (anti-CD3 antibody or RetroNectin), and the final composition of effector cells (such as the percentage of CD3 + CD56+ cells). Additionally, clinical protocols vary significantly in terms of dosing, number of treatment cycles, and intervals between treatments. This inconsistency means that “CIK therapy” does not represent a singular, defined treatment but rather a category of therapies, which complicates the understanding of dose-response relationships and makes it difficult to determine an ideal treatment regimen.

The timing of assessments and follow-up treatments can affect the evaluation of OS and PFS endpoints, despite their frequent use. Immune monitoring endpoints are typically descriptive and frequently exhibit a lack of uniformity. Numerous studies, especially those in early phases or conducted at a single center, tend to be underpowered and report efficacy results that generate hypotheses rather than confirm them. The common lack of predefined statistical analysis plans in smaller studies raises the possibility of reporting bias.

This widespread variation significantly undermines the robustness of conclusions drawn from a straightforward aggregation of trials. The encouraging indicators RCTs offer the most dependable evidence, yet their findings are specific to the context of their unique design and CIK product. o reduce bias, the field needs to focus on prospective trials that use standardized, GMP-compliant production, well-defined patient groups, and clear, pre-established statistical methods. Future meta-analyses should thoughtfully consider these variations rather than treating all CIK studies as identical. Acknowledging these limitations does not undermine the clinical data but rather emphasizes that the existing evidence positions CIK therapy as a hopeful yet still improvable and incompletely standardized approach whose full potential depends on more uniform and stringent evaluation.

Efficacy of CIK monotherapy versus combination therapy

Although most clinical trials discussed in this review evaluate CIK cell therapy in conjunction with established treatments such as chemotherapy, radiotherapy, or ICIs, there is limited data on CIK monotherapy. This scarcity reflects both the priorities in trial design and the progressive understanding of CIK cells’ mechanisms. Such a trend raises important questions about the independent efficacy of CIK cells and their optimal therapeutic applications.

Available evidence on CIK monotherapy primarily comes from smaller or retrospective studies across select cancer types. For instance, in RCC, a study of inoperable patients receiving CIK monotherapy demonstrated improved 3-year OS and PFS compared to untreated controls, with enhanced CD4+/CD8 + ratios and a favorable safety profile limited to mild adverse events [ 80 ]. Similarly, in advanced pancreatic adenocarcinoma refractory to gemcitabine, CIK monotherapy achieved a 25% DCR and a median OS of 6.7 months, comparable to second-line chemotherapy but with superior quality of life and minimal toxicity (grade ≤ 3) [ 106 ]. In hematological malignancies, donor-derived CIK cells as post-transplant prophylaxis have shown feasibility as monotherapy, reducing relapse rates without exacerbating GVHD in high-risk patients, though long-term survival varied (e.g., 6/15 patients alive at median 1513-day follow-up) [ 128 , 132 ]. These monotherapy outcomes indicate modest but clinically meaningful benefits, particularly in adjuvant or maintenance settings, with response rates typically 20–40% and PFS/OS improvements of 3–15 months compared to controls. Safety remains a key strength, with adverse events predominantly mild (e.g., transient fever, fatigue) and no treatment-related mortalities reported.

However, direct comparisons in randomized trials suggest that CIK monotherapy may be insufficient for robust, durable responses in advanced or metastatic disease, where tumor burden and immunosuppressive microenvironments limit efficacy [ 85 , 88 ]. For example, in NSCLC, CIK monotherapy served as a comparator in trials in which combinations with ICIs or chemotherapy doubled PFS and improved ORR [ 50 , 89 ]. This aligns with preclinical insights that CIK cells’ hybrid T/NK-like activity benefits from synergistic partners to overcome resistance mechanisms, including PD-1/PD-L1 signaling or Th2 polarization [ 18 , 51 ].

CIK cells demonstrate enhanced anti-tumor efficacy when combined with other immunotherapies, leveraging complementary immune mechanisms and overcoming the limitations of individual therapies. A concrete example is Congqi Dai et al. [ 134 ], which demonstrated that inhibiting PD-L1/PD-1 pathways in conjunction with CIK cell infusion delayed tumor progression and conferred survival benefits. Ying Zhang and colleagues [ 135 ] further validated these results, demonstrating enhanced PFS and OS in several clinical trials when CIK cells were combined with either standard or innovative treatment approaches.

Given these findings, CIK therapy should primarily be developed as a combination strategy, particularly with ICIs (e.g., anti-PD-1) to reverse exhaustion, chemotherapy to reduce tumor burden, or locoregional therapies (e.g., TACE/RFA) to enhance antigen exposure and immune priming [ 70 , 74 , 81 ]. Monotherapy may still be appropriate in select settings, such as adjuvant treatment for early-stage cancers (e.g., post-resection HCC or RCC) [ 71 , 80 ], maintenance in hematological malignancies post-HSCT [ 128 , 132 ], or in frail patients where combination toxicities are prohibitive. Future trials should prioritize head-to-head comparisons to clarify these contexts, potentially guided by biomarkers, such as NLR, to identify monotherapy responders [ 99 ]. Autologous tumor lysate-pulsed DC-CIK improves survival in gastric and colorectal cancer patients.

Conclusion and future prospects

In the last 30 years, CIK cell therapy has gone from being an experimental treatment to a clinically proven one that works for many types of cancer. Extensive clinical trials have established its key advantages, most notably its excellent safety profile. Adverse events are typically mild and transient, primarily low-grade fever or minor allergic reactions, making CIK therapy particularly suitable for vulnerable populations, including elderly patients and those with organ dysfunction who may not tolerate more aggressive treatments.

Combining CIK cell therapy with locoregional therapies like TACE or RFA has shown particular efficacy in HCC, where it improves PFS and boosts immune function. CIK cell therapy has shown broad clinical applications across multiple cancer types. CIK cells efficiently lower relapse rates in hematologic malignancies, particularly in post-transplant settings, without aggravating GVHD. In gastrointestinal cancers, they work in concert with chemotherapy to enhance survival and quality of life. The therapy’s growing role in oncology has been highlighted by recent developments that have expanded its usefulness to more difficult clinical scenarios, such as tumors of the central nervous system and ICI-resistant cancers.

Precision engineering presents the next frontier for CIK cell therapy, with emerging technologies poised to enhance its clinical potential. CAR-CIK cells have already demonstrated promising results in early-phase trials for B-cell malignancies, achieving high response rates with favorable safety profiles. Further advancements using CRISPR-based gene editing to disrupt immune checkpoint molecules (such as PD-1 and TGF-β receptors) may significantly improve CIK cell persistence and effector function within immunosuppressive TME. To overcome the fundamental challenges of limited persistence and tumor infiltration, future engineering must extend beyond checkpoint disruption. Critical strategies include metabolic reprogramming of CIK cells to survive in nutrient-poor tumor niches and engineering homing receptors, such as CXCR2, to actively direct cells to tumor sites. These innovative approaches could transform CIK cells into more potent and durable therapeutic weapons against cancer.

The therapeutic potential of CIK cells may be further amplified through strategic combinations with existing modalities. Particularly promising is their synergy with ICIs, where preclinical evidence indicates CIK cells could counteract PD-1/PD-L1 resistance mechanisms. Looking ahead, the most promising combination strategies are with specific ICIs, such as anti-TIGIT or anti-LAG-3 antibodies, to target T-cell exhaustion pathways. For maximum impact, these combinations should be guided by a profound understanding of tumor-immune phenotypes. The most transformative breakthroughs are anticipated in cancers with high unmet need and a defined immunosuppressive microenvironment, such as advanced pancreatic ductal adenocarcinoma and platinum-resistant ovarian cancer, where CIK combinations can directly counteract key resistance mechanisms. Moreover, combining CIK cells with epigenetic modulators such as decitabine may enhance tumor immunogenicity and improve cancer cell recognition, while integration with radiotherapy could harness the abscopal effect to stimulate systemic antitumor immunity. These multimodal approaches offer compelling opportunities to optimize CIK cell efficacy across various cancer types.

The promising potential of next-generation CIK therapies must be interpreted in the context of ongoing safety and translational challenges. While conventional CIK cells have consistently demonstrated a favorable safety profile, engineered modalities, particularly CAR-CIK cells, and allogeneic products introduce distinct risks that necessitate careful and continuous monitoring, including cytokine release syndrome, off-target toxicity, and GVHD in donor-derived applications. Moreover, the clinical translation of these therapies is hindered by substantial regulatory and manufacturing barriers. The absence of fully standardized, GMP-compliant production protocols, the need for clearly defined release criteria and validated potency assays, and the complexity of regulatory approval pathways for cell-based therapies collectively remain significant obstacles to widespread clinical implementation and commercial scalability.

Nonetheless, considerable obstacles persist, such as the limited persistence of cells transferred via adoptive methods and their inability to penetrate solid tumors. The insufficient persistence of infused cells in vivo and their inability to infiltrate solid tumors constitute fundamental biological challenges. Future investigations should focus on methods to address these issues, including metabolic reprogramming to improve cell survival in nutrient-deficient TMEs and engineering strategies to enhance tumor targeting (e.g., via CXCR2 or CCR4 receptor expression). Furthermore, the field needs improved tools for accurately selecting patients. Progressing biomarker research is essential, with promising avenues including monitoring dynamic circulating tumor DNA, analyzing immune contexture (e.g., tertiary lymphoid structures), and evaluating the functional properties of the CIK product itself. These tools have the potential to facilitate tailored treatment plans and enable real-time assessment of responses.

A critical factor for the success of CIK therapy, and one that requires far greater attention, lies in the complex variability of both the donor and the patient. The age and sex of the cell donor, the extent of a patient’s prior treatments, their current tumor burden, and, in allogeneic transplants, the level of HLA mismatch are not merely background details. These factors profoundly shape the cells’ ability to proliferate in culture, survive and function within the patient, and ultimately, determine the clinical outcome. To make this therapy more reliable, future studies need to rigorously analyze how these variables interconnect. Building predictive models from this data is essential. Doing so will allow clinicians to intelligently select donors for ‘off-the-shelf’ products and identify which patients are the best candidates for their own reinfused cells, paving the way for a truly tailored and effective CIK cell treatment paradigm.

To enable widespread clinical adoption, CIK cell production requires standardization and scalability improvements. Implementing closed-system bioreactors and uniform culture protocols would enhance product consistency while reducing costs. The development of off-the-shelf allogeneic CIK cell products could dramatically increase treatment accessibility, potentially transforming this therapy into a readily available option across medical centers.

Future research should examine CIK cell biology and TME interactions to optimize therapeutic efficacy. Critical investigations should focus on CIK cell crosstalk with tertiary lymphoid structures and cancer stem cells.

Supplementary Information

Supplementary Material 1

Acknowledgements

Not applicable.

Abbreviations

Autologous tumor lysate-pulsed DCs

Bispecific antibodies

Cytokine release syndrome

Cytokine-induced killer

Disease control rates

Graft-versus-host disease

Gemcitabine-cisplatin

Human leukocyte antigen

Microsatellite instability-high

Multiple myeloma

Natural killer

Non-small cell lung cancer

Neutrophil-to-lymphocyte ratio

Objective response rate

Overall survival

Immune checkpoint inhibitors

International Registry of CIK Cells

Peripheral blood mononuclear cells

Progression-free survival

Transcatheter arterial chemoembolization

Radiofrequency ablation

Renal cell carcinoma

Author contributions

Farzaneh Ghorbani and Hossein Abbaszadeh contributed to the conception, design and drafted the manuscript; Yahya Yahyavi and Mehdi Talebi contributed to revising the manuscript; Karim Shamsasenjan supervised the manuscript.

Funding

This research received no specific grant from any funding agency.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

No new human or animal subjects were involved, and no original clinical data were generated by the authors.

Consent for publication

This review does not contain any individual person’s data in any form.

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.

Farzaneh Ghorbani and Hossein Abbaszadeh contributed equally to this paper.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12935-026-04318-y.

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Associated Data

Supplementary Materials

Supplementary Material 1

Data Availability Statement

No datasets were generated or analysed during the current study.