LAK to CIK continuum in glioma immunotherapy: a systematic review of efficacy and safety outcomes.

Introduction

Glioma is a primary central nervous system (CNS) neoplasm arising from glial progenitor cells. An estimated 80,000 new cases of primary brain tumors occur annually in the United States, approximately 25% of which are gliomas. These tumors are generally classified based on their morphology and histopathology. According to the 2021 WHO classification, adult-type diffuse gliomas are classified based on molecular characteristics into three main categories: Isocitrate dehydrogenase(IDH)-mutant oligodendroglioma with 1p/19q deletion (grades 2–3), IDH-mutant astrocytoma (grades 2–4), and IDH-wildtype glioblastoma (GBM). GBM is the most aggressive subtype, with a 5-year survival rate of approximately 7% [ 1 – 3 ]. Headaches and seizures are the most prevalent symptoms, along with behavioral abnormalities, speech impairments, nausea, vomiting, and visual alterations. The Karnofsky Performance Status score is commonly used to evaluate patients’ functional status and overall prognosis, with lower scores indicating reduced ability to perform daily activities and poorer survival. Several factors affect the prognosis of glioma, including age, comorbidities, tumor grade, site, and the existence of hydrocephalus [ 4 ]. Head Computed tomography (CT) and brain Magnetic resonance imaging (MRI) are used to assess edema in suspected brain tumors, and further investigations, such as X-rays and positron emission tomography (PET) scans, may be required. The existing conventional therapies for glioma, such as radiation therapy, temozolomide, and surgical resection, have been considered insufficient. Moreover, treatment-related toxicokinetics have been demonstrated to have a part in the progression of low-grade to high-grade gliomas [ 5 ]. Immunotherapy is presently the dominant modality in cancer care [ 6 ].

Cancer immunotherapy synergizes innate and adaptive immune responses to improve systemic and host-specific immunity while targeting tumor cells. Immunotherapy for glioma consists of cancer vaccines, adaptive immunotherapy, and immune checkpoint inhibitors (ICIs). Dendritic cells (DCs), cytotoxic T lymphocytes (CTLs), lymphokine-activated killer cells (LAK), cytokine-induced killer (CIK) cells, and natural killer (NK) cells are among the various cells employed in cell therapy [ 7 ]. First introduced in the early 1980s, LAK cell therapy was among the first attempts to apply cell therapy in cancer treatment. LAKs are generated by incubating peripheral blood mononuclear cells (PBMCs) with interleukin-2 (IL-2). Upon activation with IL-2, NK cells and T lymphocytes may also present “self-modified” targets; the development of T-cell therapy is derived from the groundwork established by LAK therapy [ 8 ]. LAK cells effectively target and eliminate a wide range of cancer cells, including those with low or no Major Histocompatibility Complex (MHC) expression. Initial preclinical studies showed significant antitumor activity, and subsequently, LAK was used in clinical trials for patients with treatment-resistant solid tumors, such as gliomas. Despite the obstacles LAK therapy faced, LAK therapy laid the groundwork for future developments in activated killer cell therapies, such as the emergence of CIK therapies and genetically engineered NK cell platforms.

CIK cells, a diverse population of natural killer T cells and cytotoxic T cells, as well as a modest number of NK cells, have strong antitumor activity and can be rapidly expanded ex vivo because they do not require specific antigen priming. Furthermore, they have MHC-independent lytic activity [ 9 ]. CIK cell administration has minimal side effects and low toxicity, confirming CIK cell-based immunotherapy as a safe treatment option for patients, despite limitations such as the lack of a standardized procedure and inconsistent studies evaluating CIK therapy efficacy [ 10 ]. CIK therapy has shown promise in glioma treatment and other solid tumors, with both in vitro and in vivo studies highlighting its potential performance [ 11 , 12 ]. Furthermore, clinical trials evaluating the efficacy of CIK immunotherapy to improve treatment outcomes in malignant glioma (Phase III) are available, albeit with insufficient participant recruitment [ 13 ]. Long-term application inhibits malignancy recurrence and results in minimal injury to normal cells, compared to conventional treatments, with enhanced specificity. Furthermore, it can effectively cross the blood-brain barrier (BBB) without toxicity, which supports systemic use [ 14 ].

Despite the potential of CIK and LAK-based immunotherapy, no systematic review has evaluated their efficacy and safety specifically for glioma patients, their similarities and differences, or a comparison between them. Consequently, this systematic review aims to evaluate clinical evolution from LAK to CIK therapies in glioma patients and to compare these therapies across various dimensions.

Methods and materials

We performed the systematic literature review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline [ 15 ].

Search strategy

This systematic review was developed using the PICO framework to provide an organized and targeted literature search. The population (P) consisted of patients with histologically confirmed GBM. The intervention (I) was CIK and LAK therapy and the comparator (C) was standard-of-care therapies, as appropriate. The key outcomes (O) were overall survival (OS) and progression-free survival (PFS). Secondary outcomes included treatment-related adverse events and, when applicable, objective response rates.

We identified relevant studies through a comprehensive and systematic search of PubMed, Scopus, Embase, and Web of Science databases from inception to 6 August 2025, focusing on the interaction between cytotoxic immune cell populations and glioma-related tumors. The search strategy employed a combination of Medical Subject Headings (MeSH) and free text terms related to “Cytokine-Induced Killer Cell”, “Lymphokine-Activated Killer Cell”, “Glioma”, and related terms. The search strings were tailored to each database’s indexing system to maximize sensitivity and specificity. The specific search queries for each database are detailed in Supplementary File 1. Manual searches of references and citation tracking were performed from relevant articles and reviews to identify further studies. We also investigated into grey literature sources by manually searching reference lists, tracking citations, and screening relevant conference proceedings (if they were available).

Study selection and data extraction

After duplicate removal using EndNote 20, search results were exported into Rayyan. It was used to enhance the selection process and to keep a record of articles. Initial eligibility screening was performed on article titles and abstracts by two authors (S.H. and P.G.). As a secondary eligibility screening, full texts of the identified articles were carefully assessed for their adherence to the predefined inclusion criteria by two other authors (S.Z. and M.R.). Disagreements arising in the selection process were resolved through discussion by a third reviewer(S.M.). Initial eligibility screening was done on article titles and abstracts, yielding 57 out of 535 investigations. Full-text papers were evaluated during the secondary eligibility screening. This ultimately leads to 21 studies.

Eligibility criteria

This review comprised original research papers. Clinical studies that evaluate either the outcome, efficacy, or safety of CIK and LAK therapies in patients affected by different types of glioma, including GBM, astrocytoma, and oligodendroglioma. Non-clinical studies, such as animal models and in vitro experiments, non-original research such as review articles, meeting abstracts, editorials, letters, perspectives, opinions, commentaries, notes, news, books, book chapters, meta-analyses, case reports, case series, retracted articles, and secondary analyses of previously published data due to non–data driven and subjective focus; and non- English studies were excluded.

Data extraction

Data was collected from identified studies using a data extraction sheet created in Microsoft Excel. The following data were extracted from the included studies: study design, glioma type and grade, prior treatments received by patients, the type of killer immune cells used, dosage, number of cell injections, and whether IL-2 or other therapies were administered as an adjunct therapy. Clinical and paraclinical indices before and after treatment, imaging assessments, and molecular characteristics of patients were included when available. All data were retrieved, focusing on changes from baseline and overall treatment outcomes, to assess the effectiveness and safety of killer cell-based immunotherapy in glioma patients. Two reviewers (M.A. and P.G.) independently extracted data, and discrepancies were resolved by consensus or involving a third reviewer (S.M.). Supplementary file 2 represents the data extraction in Excel.

There was clinical and methodological heterogeneity, including variations in study design, population characteristics, outcome definitions, and imaging assessment tools across the included studies. Consequently, conducting a meta-analysis was not feasible. Therefore, the results were summarized descriptively in our systematic review. Additionally, initial LAK studies reported outcomes at the individual patient level without cumulative survival endpoints, thereby restricting the integration of LAK data to a qualitative, narrative format. Even though CIK research produced more distinguishing group-level outcome measures, the limited availability of studies and ongoing variability in design, patient demographics, and therapies impeded the possibility of even subgroup meta-analyses. Consequently, we conducted a structured narrative analytic comparison for CIK rather than a quantitative meta-analysis.

Assessment of studies’ quality and risk of bias

The risk of bias in included studies was evaluated using “The Joanna Briggs Institute (JBI)” critical appraisal tools [ 16 , 17 ]. Each study was assessed using the appropriate tool, which consisted of a series of questions tailored to the specific study design. For randomized controlled trials (RCTs) or quasi-experimental and Cohort studies, two writers (M.A. and P.G.) established the study design, and disagreements were resolved by consulting another author (S.M.). A complete Checklist is detailed in supplementary file 3.

Ethical considerations

This study conformed to ethical standards relevant to the analysis of secondary data. No ethical approval was required since the research used data from the public domain. Where applicable, we followed guidelines for conducting and reporting research involving human participants, ensuring transparency and reproducibility in our review process.

Results

Study selection

An extensive systematic search resulted in 930 articles. After eliminating 395 of them for being duplicates, 535 studies were screened for titles and abstracts. Out of fifty-seven articles sought for retrieval, no full-text could be found for 17 articles. Forty studies were assessed for eligibility, but 19 of them were excluded for being non-relevant, the wrong type of study, conference abstracts, or non-English language. The PRISMA flow diagram of the study is presented in Fig. 1 . The figure summarizes the process of study identification, screening, eligibility, and inclusion in accordance with the PRISMA 2020 guidelines [ 15 ].

Fig. 1 PRISMA 2020 flow diagram of study selection. (Source: Page MJ, et al. BMJ 2021;372:n71. doi: 10.1136/bmj.n71. This work is licensed under CC BY 4.0. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/ )

Study characteristics

Finally, twenty-one studies were included in this systematic review. Of these, two were RCTs [ 13 , 18 ], and one study was a retrospective observational study [ 19 ]; the rest were quasi-experimental studies. Eight studies were conducted before 1990 [ 20 – 27 ], seven studies were performed between 1990 and 2000 [ 28 – 34 ], three were done in the 2000s [ 35 – 37 ], one study in 2017 [ 13 ], another in 2022 [ 18 ], and eventually the most recent study was published in 2024 [ 19 ]. Most of the studies were conducted in the United States with several 11 articles [ 20 – 22 , 24 – 26 , 30 , 33 , 35 – 37 ], five were performed in Japan [ 23 , 27 – 29 , 32 ], two studies in South Korea [ 13 , 18 ], and one study in India [ 34 ], China [ 19 ], and Italy [ 31 ]. Three studies conducted by Jacobs et al. [ 20 – 22 ] have the same settings (publication year, country, patients, and intervention). Because each publication presented an individual aspect of their findings, they were regarded as a single research in our data extraction table in supplementary file 2.

Patient demographics

A total of 692 patients were recruited in the included studies. The largest sample size was reported in the RCT conducted by Kong et al., which included an intervention group of 91 patients and a control group of 89 [ 13 ].In contrast, the smallest sample size was observed in the quasi-experimental study conducted by Kitahara et al., which involved only five patients [ 23 ]. In five studies, intervention and control groups were determined separately [ 13 , 18 , 33 , 35 , 36 ]. Details about gender distribution were present in 19 studies. Two studies did not provide data on gender distribution [ 19 , 35 ]. In the rest of the studies, the male-to-female ratio was dominant in 15 out of 19 studies.

Glioma characteristics

The predominant glioma type among enrolled patients was GBM, as reported in 17 studies. Oligodendroglioma was present in five studies [ 18 , 23 , 24 , 33 , 34 ]. In one study, a metastatic tumor was also presented [ 24 ]. Gliosarcoma was only present in one study with three patients [ 33 ]. In the study conducted by Duan et al., one of the patients which made to survive more than 20 years without recurrence was diagnosed with diffuse hemispheric glioma H3 G34-mutant (G34-DHG, WHO grade 4) [ 19 ]. Additionally, one case of malignant melanoma was among glioma patients in 1995 [ 32 ]. Also, it is essential to note that there may be some differences in diagnoses due to changes in the WHO classification over the years.

In 14 studies, the location of tumors was discussed. The most common location for tumor presence was the frontal lobe, followed by the parietal lobe, the temporal lobe, and the occipital lobe; however, some tumors were present in two lobes, resulting in overlap. Other locations for tumors were the pons and thalamus.

The tumor size was only reported in some studies. For example, in the study by Kong et al. [ 13 ], the mean tumor size was 5.7 ± 6.3 in the intervention group and 5.1 ± 10.4 in the control group.

Pre-intervention treatments

Radiotherapy, chemotherapy, gross total resection, craniotomy, biopsies, removals, and various surgical procedures were used before the interventions, making radiotherapy the most common.

Therapeutic dose of killer cells and adjunctive therapies

Dosage of administered LAK cells varied widely, ranging from 0.002 × 10^9 [ 34 ] to 32.4 × 10^9 [ 27 ]. The dosage of delivered CIK cells ranged from 4 × 10^8 in 4 injections [ 19 ] to a mean of 6.55 × 10^9 per dose in 14 injections overall [ 13 , 18 ]. In all CIK therapy studies, concurrent radiotherapy and chemotherapy have been used, and in one study, additional IL-2 was administered along with CIK therapy. In thirteen experiments using LAK therapy, supplementary IL-2 was provided simultaneously [ 20 – 22 , 24 – 27 , 30 – 36 ]. In two of the studies, bispecific antibodies accompanied the LAK therapy [ 28 , 29 ]; and in a study by Lillehei et al., autologous stimulated lymphocytes (ASL) were co-administered [ 30 ]. Dillman et al. have used non-LAK T lymphocyte additional to LAK therapy [ 37 ].

Pre- and post-intervention clinical assessment

Karnofsky performance status was taken pre-intervention in 11 studies, with the lowest score of 20 [ 32 ] and the highest score of 100 [ 30 ]. This status had dropped for six patients in the 1988 study [ 25 ], raised forty scores in a patient in the 1995 study [ 32 ], raised 30 scores for a patient but dropped 10 scores for two patients in the Hayes et al. study [ 33 ], decreased for five patients and raised for two patients in the Sankhla et al. study [ 34 ], the score decreased for 11 individuals but was increased for a patient in Merchant et al. study [ 24 ]. In the rest of the studies, the post-intervention score was either the same or unreported.

In the study by Duan et al. [ 19 ], targeted next-generation sequencing (131 glioma-related genes), RNA sequencing, and O⁶-Methylguanine-DNA Methyltransferase (MGMT) promoter methylation status were also performed pre-treatment. Tumor genome, transcriptome, and immune microenvironment profiles were examined through genomic target sequencing, RNA sequencing, electrochemiluminescence assays, and immunohistochemistry (IHC) staining. The Neurotrophic Receptor Tyrosine Kinase 1(NTRK1) mutation was exclusively found, and 353 genes showed differential expression in long-term survivors, in contrast to short-term survivors. These differentially expressed genes were strongly linked to immune function. Electrochemiluminescence assay and IHC staining demonstrated elevated levels of cytokines and reduced tumor-associated macrophage infiltrations in the tumors of long-term survivors. They also performed regular MRI after CIK therapy [ 19 ].

The pre-intervention neurologic assessment was reported in three studies [ 24 , 26 , 30 ]. In the post-intervention assessment done by Yoshida et al. [ 27 ], remarkable gait disturbance, dysphagia, vegetative or drowsy state, Mental dullness, dysarthria, or in a patient, only a headache was observed. In the investigation performed by Nakagawa et al. [ 32 ], neurological improvement was observed in one patient, but no significant change was noted in the other nine patients. Left-sided hemi-sensory neglect and moderate lethargy appeared in two patients in the Jacobs et al. studies [ 20 – 22 ]. The increased neurologic deficit was noted in a specific dosage in the Hayes et al. study [ 33 ], unlike the Kitahara et al. study, in which no neurological deficit was found [ 23 ]. Sankhla et al. [ 34 ] observed a satisfactory improvement lasting for 62 weeks in one case, but a reappearance of symptoms was noted in another patient after 18 weeks. Lethargy and headache were some neurological findings by Merchant et al. [ 24 ].

Barba et al. reported some abnormal post-intervention findings, such as significantly increased white blood cell(WBC) count, platelet count, and erythrocyte sedimentation rate in 3 patients [ 26 ]. Duan et al. also performed cytokine quantification via electrochemiluminescence and IHC staining for immune markers and cytologic analyses of CIK cell viability in the resection cavity [ 19 ]. Biochemistry findings were normal in reported studies except for the Barba et al. study [ 26 ], in which decreased serum calcium level and increased alkaline phosphatase concentration were observed in two and three patients, respectively. The change was normalized after the treatment completion.

Outcome

Although survival was a common outcome across all included studies, the specific survival metrics varied across studies. Six studies reported OS [ 13 , 18 , 19 , 30 , 34 , 36 ] along with two older studies reporting total survival [ 24 , 25 ]. Two studies assessed PFS [ 13 , 18 ]. Two studies assessed time to progression [ 30 , 34 ] and two studies reported time of progression [ 24 , 25 ]. Kong et al. also reported objective response rate [ 13 ]. Seven studies indicated the alive/dead status of patients [ 19 , 23 , 26 – 28 , 32 , 33 ], with three studies providing more information about their condition, such as alive (usefully, vegetative state), dead (for some patients, the cause of death was reported), and recurrence status [ 27 , 28 , 33 ]. Several studies reported survival time in weeks [ 23 , 33 , 35 ], months [ 20 – 22 , 26 , 28 , 32 , 37 ]. Five studies reported survival rates as in 18 months [ 31 ], 1 year [ 33 , 36 ], 1 year and 2 years [ 37 ], 1 year, 2 years and 3 years [ 29 ].

The most extended period of reported living months after the intervention was 247.5 months, related to a CIK-therapy study, and the patient was reported alive [ 19 ]. Also, 1.5 months was the shortest reported period relative to the LAK-therapy group [ 26 ]. In Kong et al. study, PFS increased from 5.4 months (95% CI: 3.3–7.9) in the control group to 8.1 months (95% CI: 5.8–8.5) in CIK therapy group, while OS improved from 16.9 months (95% CI: 13.9–21.9) to 22.5 months (95% CI: 17.2–23.9) [ 13 ]. Han et al. performed a reanalysis of the RCT dataset from Kong et al., focusing on patients with pathologically confirmed pure GBM. Kaplan–Meier analysis and Cox regression were used to look at the difference in OS and PFS between intervention and control patients. Although Kaplan–Meier curves did not demonstrate a statistically significant difference in OS, patients receiving CIK therapy showed improved survival outcomes, with mean OS and PFS increasing from 14.9 to 5.5 months in the control group to 23.1 and 8.1 months, respectively. Multivariate Cox regression indicated that CIK therapy functions as an independent prognostic factor for improved survival: the hazard ratio (HR) for OS was 0.59 (95% CI: 0.36–0.97; p = 0.038), and the HR for PFS was 0.55 (95% CI: 0.36–0.84; p = 0.001) within the pure GBM group [ 18 ].

Considering LAK-therapy studies, Dillman et al. in 2004 reported no significant relation with survival about variables like tumor location, age, gender, number of LAK cells, and use of IL-2 [ 36 ]. Dillman et al. also reported in their 2009 study that taking corticosteroids and undergoing leukopheresis had a negative impact on survival rates [ 37 ]. Additionally, Nitta et al. reported higher survival in bispecific antibodies with LAK therapy, in which 80% were alive with 18 months of follow-up. In the research by Hishi et al., the one-year survival rate for the intervention GBM group was 60.5%, while the three-year rate was 45.1%, compared to 47.4% and 14.8% in the brain tumor registry of Japan [ 28 , 29 ].

Additionally, some positive outcomes included regaining the ability to eat and walk independently, and the disappearance of headaches, diplopia, speech difficulties, and convulsions [ 33 ], as well as the complete disappearance of the lesion [ 31 ].

Tumor imaging (MRI-CT)

Regarding LAK-therapy groups, in the study conducted by Kitahara et al. [ 23 ], large tumor masses were observed postoperatively in two cases. Still, a slight regression was noted in the other two patients. Nitta et al. [ 28 ] had four partial regression cases, four high-density observance cases, and eight recurrence cases. Nakagawa et al. [ 32 ] reported two partial responses, a progressive case, four no changes, and two complete responses. Partial Cystic change was reported in two patients in Sankhla et al.‘s study [ 34 ]. A recurrent tumor in the opposite hemisphere was also noted [ 30 ]. Barba et al. [ 26 ] reported immediate and long-term changes. Increased mass effect and brain edema were pointed out in the immediate evaluation. An increase in mass effect and a decrease in tumor size were reported in 3 weeks. Reduced tumor size and contrast enhancement persisted after 6 weeks.

According to CIK-therapy groups, in Duan et al.‘s study, pretreatment imaging was used to show the extent of resection. In post-therapy imaging, long-term survivors showed signs of pseudo-progression, such as early ring enhancement and edema, which were resolved, and the resection cavity shrank. Still, persistent/enlarging and blocky enhancement showed true tumor recurrence in short-term survivors [ 19 ]. In Kong et al.’s study, partial response in MRI was seen in 27.1% of the CIK group compared to 15.9% in the control group [ 13 ].

Complications

In LAK-therapy studies, six studies reported headaches [ 25 , 26 , 30 , 33 – 35 ], one accompanied with vomiting [ 34 ]. Other complications included fever [ 19 , 25 , 29 , 30 , 33 – 35 ], two along with chill [ 13 , 27 ], infection in the location of the reservoir [ 26 , 29 , 31 , 34 ], one case of meningitis and death due to bacterial or fungal infection [ 29 ], drowsiness [ 25 ], confusion [ 30 ], pain and fatigue [ 13 ], seizures [ 31 , 34 ], crossed aphasia [ 31 ], necrosis of the skin-responsive to reservoir removal [ 31 ], hypersomnia [ 31 ], hemiparesis [ 34 ], erythema [ 13 , 30 ], urticarial, leukopenia, and neutropenia [ 13 ]. Some other adverse effects were viremia, pulmonary embolus [ 33 ], pneumonia, hydrocephalus, and subarachnoid spread [ 28 ]. Duan et al. reported CIK therapy complications such as high fever and encephalopathy [ 19 ]. Kong et al. reported complications of CIK therapy included pyrexia, chills, fatigue, pain, urticaria, erythema, leukopenia, and neutropenia [ 13 ].Han et al. didn’t report specific CIK therapy-related complications [ 18 ].No inflammatory cytokine storm and no severe allergic reaction were reported in CIK-therapy studies.

Risk of bias assessment results

Risk of bias assessment of quasi-experimental, RCT, and cohort studies was conducted using the JBI Critical Appraisal Checklist [ 16 , 17 ]. Most studies were of high quality and appropriate for inclusion, and all were considered for inclusion. Details of the assessment are present in the supplementary file 2. Among RCTs, mostly proper randomization and allocation concealment were reported. Follow-up completion was mainly a problem in studies. Among quasi-experimental studies, cause and effect were clear in nearly all studies. In many studies, patients were involved in other comparisons receiving care. Also, nearly half of the studies had numerous outcome evaluations. Follow-up completion was reported in most quasi-experimental studies. Appropriate statistical analysis was reported in a few studies.

Discussion

Overview of results

In this systematic review, we aimed to assess the LAK and CIK therapies and critically compare their results in treating glioma. Based on our knowledge, no systematic review has explicitly compared these approaches and explained how the historical timeline has influenced their usage and efficiency, and the reasons for the decline and resurgence in investigations. We evaluated 21 studies, comprising RCTs (9.52%), cohort (4.7%), and quasi-experimental studies (85.7%), which reflect the heterogeneity in designs and methodological evolutions over time. The sample sizes were reported in 17 studies, ranging from 2 to 200. The studies span from the 1980s to the 2020s, with LAK therapy mostly regarded in older studies and CIK therapy in more recent studies. The most common glioma grade was GBM, which was studied in 66.7% of the included studies, followed by grade 3 (9.5% of the studies), indicating that the studies had primarily focused on more severe forms of glioma. Diverse pre-interventions, such as radiotherapy and chemotherapy, were recruited. After receiving the treatment, neurological assessments also varied, ranging from worsening symptoms to improvement in patients, and even complete regression in some. In older studies, the survival improvement was modest, but the results were more promising in more recent studies focusing on CIK therapy. The most common adverse events in the neurological system were brain edema and increased intracranial pressure. Considering the systemic side effects, fever was the most frequent one. Post-treatment mortality was reported to be rare, and CNS toxicity was observed in 10–20% of the patients. Both LAK and CIK therapies showed potential clinical benefit; however, CIK therapy appeared to be associated with higher OS rate than LAK therapy. Nevertheless, direct comparisons remain limited by the small number of investigations.

Analytical comparison of CIK cells studies

The detailed findings of these three studies are provided in the results section. Nevertheless, we chose to perform an analytical comparison of these investigations.

This analysis integrates three significant CIK therapy studies, highlighting both the therapeutic potential and the diversity of responses in glioma. Kong et al. [ 13 ]provides the most compelling population-level evidence, demonstrating that the addition of systemic CIK therapy to standard radiotherapy and temozolomide yields a modest yet statistically significant improvement in median PFS (8.1 vs. 5.4 months; p = 0.0401), a higher disease control rate(DCR) than the control group (82.4% vs. 63.4%, P = 0.0058), and maintenance of quality of life (QOL), without a comparable enhancement in OS. The results suggest that CIK therapy may delay radiographic progression in newly diagnosed GBM; however, this initial benefit does not guarantee prolonged survival for the general population, likely due to the rapid development of resistant clones, adaptive immune evasion, or the transient persistence of the infused cells within an immunosuppressive tumor microenvironment(TME) [ 38 , 39 ].

Han et al. augment this comprehension by secondary analysis by focusing on pathologically pure GBM, hence reducing histologic heterogeneity. In this group, CIK therapy emerged as an independent predictor of improved OS and PFS in multivariate Cox regression analysis (OS: HR 0.59, 95% CI 0.36–0.97; p = 0.038; PFS: HR 0.55, 95% CI 0.36–0.84; p = 0.001). However, the Kaplan–Meier analysis shows that there is no statistically significant difference in OS. The authors propose that a potential explanation for this result in Kaplan–Meier analysis, that the overall extent of tumor resection was comparatively reduced in the CIK therapy group comparing to the control group. It has been proven that complete resection of GBM significantly enhances OS and PFS in comparison to partial resection [ 40 ]. Potential explanations include variations in prognostic factors, limited statistical power, or non-proportional hazards across time.

However, Han et al.‘s research demonstrates that, in a more physiologically homogeneous GBM population, CIK therapy may substantially influence both progression and survival [ 18 ]. CIK immunotherapy may ameliorate an immunosuppressive TME and provide an optimal setting that enhances anticancer immunity. Notably, it was observed that NK cell cytotoxicity was augmented against stem cell-like glioblastoma cells in comparison to mature glioblastoma cells [ 41 ]. Compared to GBM combined with other malignancies, isolated GBM may have a stronger association with an immunosuppressive microenvironment. Therefore, CIK therapy may demonstrate greater therapeutic benefit in patients with pathologically confirmed isolated GBM compared with control groups [ 42 ].

Duan et al.‘s [ 19 ] study shifts the focus from population averages to individual outliers. This study showed very different results when CIK cells were given locally through an Ommaya reservoir into the surgical tumor cavity. Four of the six patients died from the disease within 10 to 33.9 months, whereas two patients lived for over 20 years without recurrence of the disease. The importance of these ultra-long responses much exceeds the modest median PFS gain observed in the Kong et al. [ 13 ], making it unlikely that this phenomenon is just attributable to chance. Duan et al. provide first molecular insights, elucidating NTRK1 mutations, distinctive immune-related gene expression patterns, elevated cytokine levels, and reduced tumor-associated macrophage infiltration in long-term survivors. These findings support the idea that the way CIK is given (locally or systemically) and the molecular and microenvironmental conditions that go along with it have a big effect on how well it works as a treatment.

These findings collectively emphasize that CIK immunotherapy for glioma should not be considered a uniformly successful approach with a uniform effect size. Systemic CIK cells injection appears to provide a moderate, broadly distributed advantage in delaying progression, as demonstrated in Kong et al [ 13 ]. This may lead to a measurable survival benefit in some physiologically favorable populations after controlling for confounding variables, as revealed by Han et al [ 18 ]. At the same time, Duan et al. showed that local CIK treatment may be linked to impressive, long-lasting disease control in some patients whose tumors have good molecular and microenvironmental features [ 19 ]. Importantly, in all three studies, the safety profile of CIK therapy—both systemic and local—remains favorable, with no rise in severe treatment-related toxicities or deterioration in QOL.

LAK therapy: the early symphony of cellular immunotherapy

Immunotherapy is one of the breakthroughs for cancer treatment, in addition to traditional therapies such as radiation and chemotherapy, and has improved rapidly over the last decades [ 43 ]. LAK cells are cytotoxic lymphocytes capable of killing autologous and allogenic tumors, and the activation of these cells depends on the existence of IL-2 [ 44 ]. Based on the included trial studies detailing the process to obtain LAK cells, the procedure initially involves collecting peripheral blood from the patient, followed by leukapheresis to isolate the WBCs. These isolated cells are cultured and stimulated with IL-2 before being maintained in an incubator. After this process, the cells are washed, resuspended in a normal saline solution, and prepared for infusion. However, several methodological variations were observed, including differences in the dose and duration of IL-2 administration, culture medium and final infusion solution, the culture period, and the cell isolation techniques. Some studies compared two delivery methods for LAK cells combined with rIL-2: intralesional injection during craniotomy and intracavitary infusion via an Ommaya reservoir post-surgery. The intralesional method demonstrated better tumor-targeting capability, successfully reaching infiltrating tumor regions beyond the resection margin. However, it was associated with increased peritumoral edema and symptoms of heightened intracranial pressure. In contrast, the intracavitary method was well tolerated, causing only mild and transient symptoms. Its effectiveness, however, might be limited by challenges in penetrating the glial scarring at resection margins [ 24 , 26 ]. Early phase studies demonstrated that while IL-2 is essential for the proliferation and cytotoxic activity of LAK cells, its administration—particularly at high doses—induces significant adverse effects on the central nervous system, most notably cerebral edema and neurological deterioration. The pathophysiology is mainly attributed to IL-2–mediated vascular permeability and disruption of the blood–brain barrier, which exacerbate peritumoral swelling and intracranial pressure [ 26 , 45 ]. While LAK/IL-2 therapy demonstrated proof-of-concept for activated cell immunotherapy in glioma, its broader application has been limited by the neurotoxicity associated with IL-2. Combining LAK with bispecific antibodies offers improved tumor targeting in glioma treatment compared to traditional LAK therapy. Bispecific antibodies can bind to two different antigens simultaneously, specifically targeting CD3 on LAK cells and glioma-specific antigens. This dual-binding capability enhances the cytotoxic effects on cancer cells. Studies indicate that this method leads to higher rates of tumor regression and reduced recurrence. Additionally, this approach may decrease the reliance on high-dose systemic IL-2, which can minimize associated toxicity. Overall, this strategy exemplifies a successful integration of cellular and molecular targeting in targeted immunotherapy, resulting in greater effectiveness and fewer side effects [ 28 , 29 ]. LAK cells and IL-2 are beneficial in recurrent GBM, as evidenced by increased long-term survival [ 33 ]. In a phase II trial on utilizing intralesional LAK in GBM, patients receiving higher doses had a longer survival time [ 37 , 46 ].

CIK therapy as the future face of immunotherapy

In 1991, a protocol for utilizing LAK therapy was amended, resulting in the recognition of CIK cells, which had a better proliferation capacity than LAK cells [ 47 ]. CIKs are exceptional lymphoid cells derived from PBMCs and depend on Anti-CD3 antibody, IFN-γ, and IL-2 to complete their maturation, exhibiting anti-tumor effects [ 48 ]. CIK therapy has shown promising effectiveness in treating hematologic and solid tumors when delivered systemically. However, there is limited information in the current literature regarding the use of intratumoral or intralesional delivery of CIK cells in human patients. Preclinical research and recent reviews suggest that CIK cells possess beneficial migratory and invasive properties that allow them to target tumor areas effectively. Nevertheless, the physical and immunological challenges posed by solid tumors may hinder the complete infiltration of these cells [ 49 ]. Furthermore, most clinical trials have focused on the systemic administration of CIK cells, often combined with other treatment methods. While these trials have reported favorable safety profiles, the effectiveness of this approach in specifically targeting infiltrative or residual tumor cells remains unclear. The mechanisms for cytotoxicity in CIK cells include binding NK-cell receptors to their ligands and the Fas signaling pathway, which conducts apoptosis in tumor cells [ 50 , 51 ]. CIK cells have superior proliferation capacity compared to LAK cells, primarily due to enhanced proliferation rate and more cytotoxic activity of CD3 + CD56+ cells [ 52 ]. The exceptional characteristics of CIK cells compared to LAK cells have led to a notable increase in the utilization of this approach, as evidenced by our results, with higher survival rates. With fewer adverse effects, the interest in CIK therapy has increased significantly, making it one of the best potential candidates for immunotherapy in hematopoietic and solid tumors.

Immunobiological differences between LAK and CIK cells and their clinical relevance

LAK and CIK cells’ immunobiological structures differ significantly. This might cause the different treatment outcomes in clinical trials. These different characteristics in NK-like differentiation, TME resilience, exhaustion kinetics, and trafficking capacity provide a possible molecular explanation for the often more advantageous results shown in CIK therapies for glioma in preclinical models and some clinical research, despite the absence of direct comparable trials with LAK therapies.

From a functional and phenotypic point of view, LAK cells are a temporary and diverse group of IL-2–activated NK cells and T lymphocytes. They are characterized by short-lived cytotoxic activity and a lack of long-term lineage commitment. On the other hand, CIK cells have a stable CD3⁺CD56⁺ population with a mixed T–NK phenotype. This means that they have high rates of proliferation and cytotoxicity, mostly by using ways that don’t depend on MHC to find tumors. This stable NK-like structure allows CIK cells to maintain a constant cytotoxic pressure on tumor cells, whereas LAK cells only produce a temporary effector burst. As we see in clinical trials, this mechanistic difference matches the fact that CIK therapy has more disease stabilization [ 52 , 53 ].

The TME is pivotal in determining the varying effectiveness of these two immunotherapies. In gliomas, the TME is characterized by elevated levels of immunosuppressive mediators, including transforming growth factor-β (TGF-β) and IL-10, as well as hypoxia-driven signaling pathways that collectively impair effective anti-tumor immune responses [ 54 ]. These factors promote the expansion of suppressive immune cell populations, thereby limiting cytotoxic activity and contributing to immune evasion. LAK cells are particularly susceptible to these suppressive conditions, as TGF-β- and IL-10–rich environments can attenuate their cytotoxic function and reduce their proliferative capacity, ultimately diminishing their anti-tumor activity within the glioma niche [ 55 ].In contrast, CIK therapy may demonstrate partial resistance to TME-mediated immunosuppression, supported by their enhanced migratory capacity and sustained antitumor activity in a suppressive tumor setting [ 49 ]. A potential explanation is their sustained production of pro-inflammatory cytokines such as IFN-γ and tumor necrosis factor-α (TNF-α), which may enhance antigen presentation and support the reactivation of endogenous immune responses within the TME. These functional properties may partly account for the more favorable trends in PFS observed in clinical studies of CIK therapies compared to LAK therapies [ 48 ].

The perforin–granzyme pathway directly helps kill tumor cells. After IL-2 activation, LAK cells show a quick but short-lived rise in perforin and granzyme B (GzmB). This cytotoxic response is short-lived and can start to lose its effectiveness because of activation-induced exhaustion. This causes an early rise in cytotoxic activity that doesn’t last, which makes it hard to control the tumor in the long term. On the other hand, CIK cells make perforin and granzyme B more steadily and for longer periods of time, especially in the CD3⁺CD56⁺ NK-like population, which is functionally enriched for natural killer group 2 member D (NKG2D)-mediated identification and subsequent cytolytic signaling. This long-lasting effector profile makes it easier to destroy tumor cells over time and have repeated cytotoxic interactions, which is more like the long-term tumor control seen in preclinical glioma models [ 52 , 56 , 57 ]. CIK cells have also shown beneficial effects for a cisplatin-resistant glioma cell line, via reversing the drug resistance. The mechanistic pathway is explained by the inhibition of Akt/nuclear factor-ĸB, suggesting that CIK therapy is capable of increasing the chemotherapy efficacy [ 58 ]. MIC-A/B are the stress-induced ligands that mediate NKG2D-dependant tumor cell killing, and the inhibition of Ubiquitin-Specific Protease 14(USP14) could restore the MIC-A/B-mediated T cell activation and resolve the immune exhaustion, which serves as a suitable candidate for treating glioma [ 59 ].

Immune fatigue is a key functional differential between LAK and CIK cells. Overstimulation with IL-2 in LAK cells causes fatigue, halts proliferation, and decreases the production of cytotoxic effector molecules such as perforin and IFN-γ. This process begins shortly after activation. Early clinical experiments using LAK cells showed only temporary and non-durable responses, since their anti-tumor activities rapidly diminish [ 60 , 61 ]. On the other hand, CIK cells display delayed exhaustion kinetics reminiscent of memory-like responses, which enables long-lasting activation and sustained anti-tumor activity [ 62 ].

Finally, trafficking and tumor infiltration make glioma immunotherapy very hard because the BBB and the tumor stroma stop the immune system from working. LAK cells express lower levels of adhesion molecules (e.g., lymphocyte function-associated antigen 1 (LFA-1)) and certain chemokine receptors, which impair their tumor-homing capacity [ 63 ]. CIK cells, on the other hand, express more adhesion molecules, such as LFA-1, and they still express chemokine receptors such as chemokine receptor 7 (CCR7), enabling chemotaxis toward CCL19/CCL21. This helps them stick to endothelial cells and get into tumors. This increased mobility is linked to better tumor control in glioma models before implementing on patients [ 64 ].

In summary, LAK cells are limited by temporary activation, quick depletion, and poor targeting of tumors, which leads to small and short-lived clinical results. In contrast, CIK cells have stable NK-like cytotoxicity, are partially resistant to tumor-induced immunosuppression, have delayed functional exhaustion, and have better trafficking abilities. While these mechanisms have been documented, they represent potential contributing factors rather than proven determinants. Therefore, they may help explain why CIK immunotherapy has shown promise in glioma, though confirmatory studies are needed. Figure 2 summarizes the biological comparison between these two approaches.

Fig. 2 A comparative figure between LAK and CIK cells (LAK: lymphokine-activated killer; CIK: cytokine-activated killer; IL-2: Interleukin-2; NK: natural killer; PFN: Perforin; GzmB: Granzyme B; TNF-α: tumor necrosis factor-α ; IFN-γ: Interferon gamma

Limitations in isolating the independent effect of killer-cell therapy

The assessment of concomitant therapy in the studies reviewed has been limited by significant variations in treatment protocols and concurrent therapies. In all CIK therapy studies, therapy was given along with standard-of-care treatments, which were mostly chemotherapy and/or radiation based on temozolomide. LAK cell methodologies were often integrated with IL-2 injection, either in the ex vivo expansion technique or as an in vivo adjunct, highlighting the recognized cytokine dependency of this therapeutic approach.

The frequent simultaneous use of chemotherapy, radiation, and cytokine support in many trials creates major confounding factors that make it hard to figure out what the independent effects of adoptive cellular immunotherapy are. Prior to or during the study, nearly all of the patients had received standard treatment. This is particularly significant as agents such as temozolomide and radiation can alter the immune system and influence lymphocyte proliferation, tumor antigen presentation, and the tumor microenvironment [ 65 , 66 ]. The combined chemotherapy-CIK approach results in higher tumor volume reduction (95%) compared to monotherapy (72%), which underlines the synergism [ 11 ].

There are also other methods that have been reported in LAK therapy studies. Lillehei et al. clarified the application of ASL in patients with recurrent malignant gliomas, signifying a non-standardized lymphocyte activation technique that differs from traditional LAK or CIK therapies [ 30 ]. Dillman et al. also wrote about adoptive immunotherapy that uses activated autologous T-lymphocyte populations that are not LAK cells. This indicates their preference for traditional T-cell subsets rather than lymphokine-activated non-specific effector populations [ 37 ].

The results should be interpreted as indicative of the comprehensive effects of multimodal treatment, rather than solely the efficacy of LAK or CIK therapy. This emphasizes the imperative for upcoming controlled studies to elucidate the unique effects of cellular immunotherapy compared to conventional standard treatments.

Insights into immunotherapeutic approaches in glioma and other malignancies

Beyond CIK and LAK therapies, several other immunotherapeutic strategies have been explored in glioma, aiming to enhance anti-tumor immune responses within the highly immunosuppressive TME.

The cytotoxicity of Chimeric Antigen Receptor (CAR)-T cell therapy has improved significantly and is being considered for various diseases [ 67 ]. Several CAR-T cell clinical trials have been held, which have shown mainly promising survival improvements in glioma patients. For instance, the HER2 trial has shown a median OS of 11.1 months, alongside other trials showing median OS ranged from 2.9 to 11.8 months [ 68 ].

Vaccines are another candidate, consisting of mRNA, DNA, peptides, or cells, which have been developed for years, but three have shown considerable effects, including Rindopepimut, DCvax, and personalized peptide vaccination [ 69 – 72 ]. Also, the tumor-infiltrating lymphocytes (TIL) are reported to be great tumor regressors in metastatic melanoma, and due to their possible capability of crossing the BBB, they could be considered for gliomas [ 73 ].To cure GBM, the precision medicine approach focuses on the underlying mechanisms, such as immune checkpoints, confounding immunotolerance, and inducing an antigen response in tumor cells [ 74 ].

On the other hand, ICISs targets such as Cytotoxic T-Lymphocyte-Associated Antigen 4(CTLA-4), Programmed Cell Death Protein 1(PD-1), and Programmed Death-Ligand (PD-L1) are under further investigation, as Iplimumab and anti-CTLA-4 ICIs are approved by Food and Drug Administration [ 75 ]. Neoadjuvant anti-PD1 immunotherapy has been investigated for recurrent GBM. Pembrolizumab, despite its potential to modulate tumor cell proliferation, has not demonstrated substantial survival benefit in recurrent GBM, with a 6-month PFS rate of only 19.5 [ 76 ]. Indicating that some gliomas poorly respond to the ICIs, and could benefit from other immunotherapeutic approaches, such as CIK therapy. As ICIs have restricted access to GBM due to the TME suppression, other treatments such as tumor treating fields (TTFields) may have a synergistic effect and improve the potency, which is favorably mentioned in a recent clinical trial. TTFields plus pembrolizumab showed a median PFS of 12.0, compared to 5.8 months in control groups (consisting of temzolomide or TTFields alone), and the median OS was 24.8 vs. 14.6 months [ 77 ] .

Additionally, the combined immunotherapy with DCs and CIK cells appears promising for solid tumors, as they increase patients’ OS and PFS [ 78 ]. Combination therapy with CIK cells could improve the survival in melanoma patients, especially in early stages [ 79 ]. Using genetic engineering, CIKs with CAR target, which serves as a tumor antigen in melanoma, and the results are promising for this creative approach [ 80 ]. In a preclinical study, the mechanism of targeting GBM cells by DC-CIK was the release of more IFN-γ and the enhancement of apoptosis [ 81 ]. Furthermore, West et al. demonstrated that co-culturing DCs with LAK cells resulted in enhanced cytotoxicity against tumor cells [ 82 ].

Considering other carcinomas, CIK therapy has demonstrated a significant efficacy for solid tumors, especially hepatocellular carcinoma (HCC), by increasing the OS, PFS, and QoL [ 83 ]. Clinical trials show that recurrence-free and survival is notably improved by HCC treatment with adjuvant including CIK therapy [ 84 ]. CIK therapy has also shown significant efficacy for esophageal and ovarian cancer [ 85 ]. Thus, it could be deduced that by finding common pathways between GBM and other solid tumors, same target therapies could contribute to glioma treatment, such as shared mechanistically pathways affected by NK cell therapy. Pan et al. [ 86 ] suggest that combining the NK and T cells would lead to outstanding potential therapy for various tumors, including gliomas. Together, by discovering the underlying mechanisms targeted by CIK therapy and the impaired pathways existing in glioma, novel treatment will emerge for target therapies.

Fan et al. have reported that the combination of all-trans retinoic acid (ATRA) and CIK could serve as a promising treatment option for lung adenocarcinoma, which is associated with the upregulation of MHC class I polypeptide-related sequence A(MICA) and IL-2 [ 87 ]. Also, MICA upregulation serves as a marker for poor prognosis in lung cancer and is a predictive factor for the response to CIK cells [ 88 ]. Their cytotoxicity has increased significantly due to the higher expression of MICA on the surface of tumor cells and the inhibition of NKG2D ligand in multiple myeloma [ 89 ]. The studies have mostly focused on lung cancers but since MICA/NKG2D is a common pathway between these tumors and glioma as mentioned, the same process could be possible in glioma tumors.

Historical transition from LAK to CIK therapy: lessons from past and present

Studies before 2000 have primarily focused on LAK therapy, reporting its limitations [ 26 , 34 ]. Due to the failure of LAK therapy to produce highly notable results, the focus on this approach declined for approximately two decades. LAK therapy demonstrated high toxicity, including intubation following respiration failure and heart diseases such as ischemia and arrhythmias [ 45 ].

The breakthroughs of novel therapeutics including CAR-T cell therapies, ICIs, vaccines, and TILs in 2010–2020 have led to a shift in focus and funding from the previous models. Despite the auspicious results of CIK therapy, especially in preclinical studies, there is a time gap for systematic and serious investigations on CIK immunotherapy, which might be due to the subsequent failures of LAK immunotherapy, as the researchers became increasingly disappointed with IL-2-based approaches and concerns about the toxicities of higher IL-2 doses emerged [ 90 ]. In the early 2000s, the roles of CIK subsets were not understood, and the mechanisms were poorly understood, resulting in less investigation into them. More research priorities, including other immunotherapeutic approaches, also appeared. Eventually, in 2010, the International Registry on CIK cells (IRCC) was launched to collect data on the efficiency of CIK in cancer treatment [ 91 ]. Ten years later, Zhang et al. assessed all the clinical trials registered in the IRCC, including 10,225 patients, of whom 4889 were treated with CIK therapy, alone or in combination, and 36 trials reported improved survival outcomes [ 92 ]. After 2015, CIK has seen huge growth and improvement, as the clinical trials resumed. The studies mentioned its potential capability of overcoming CAR-T cell therapy due to less toxicity, coverage of many tumors (since it does not require prior antigen exposure), and lower risk of graft-versus-host disease [ 93 ].

Limitations and future directions

The existing limitations of the included studies highlight the demand for better protocols, especially regarding RCTs, since many of the studies were not followed up for more than one year, small sample sizes, and blinding deficits and higher heterogeneity in LAK immunotherapy studies. Also, only three studies addressing the CIK therapy were available, recently and well-designed, but they still lack the confidence to produce a definite positive role for this immunotherapeutic approach. The paradoxical results for CIK therapy are limited but still need to be addressed for developing this method. The heterogeneity of glioma subtypes is another challenge. However, most of the studies have investigated GBM.

Increasing the OS alongside the QOL in glioma patients is the preliminary cause for exploring targeted therapies. Ideal target therapies could be those that are less dependent on pre-interventions, such as chemotherapy, have appropriate cost-effectiveness, and are eventually personalized by considering the molecular profile of the glioma for each patient. Finding solutions for dysregulated pathways that cause resistance in glioma treatment is also prioritized, such as β-catenin accumulation with Wnt/β-catenin being inhibited, leading to reduced cell differentiation in neurons and the inhibition of apoptosis in glioma stem cells [ 94 ].

Despite extraordinary advancements in immunotherapy, the unpredictability and heterogeneity of the results imply that there is still a long road to reach the destination of treating cancer [ 95 ]. The primary clinical trials have supported the possible usefulness of CIK therapy despite all the controversies, and we hope that more standardized and qualified studies will respond to our current suspicions and resolve the existing constraints to provide outstanding progress in glioma treatment and a better life for patients suffering from it after all.

Conclusion

Targeted immunotherapies showed promising outcomes in the treatment and management of glioma. CIK therapy had much greater benefits and did not present any particular adverse effects. Nonetheless, the incidence of complications including neurotoxicity, was higher in LAK therapy studies. CIK therapy may outperform CAR-T cell therapies in the management of glioma. This promotes hopes that CIK therapy may contribute to patient treatment both independently and with other concurrent therapies. Nevertheless, owing to the limited quantity of research in this domain and the heterogeneous study setting, it would be advantageous to design larger RCT studies in this area.

Supplementary Information

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Supplementary Material 1

Supplementary Material 2

Supplementary Material 3

Supplementary Material 4

Supplementary Material 5

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Sana Hamidi and Soroush Morsali contributed equally to this work and should be considered as first co-authors.

Acknowledgements

This research protocol was approved and supported by the Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran (registration code:77103). We sincerely thank Soheil Zamen Milani for his contribution in designing the graphical abstract. During the preparation of this work, the authors used Grammarly and QuillBot to refine the text and improve its fluency. Following the use of these tools/services, the authors carefully reviewed and adjusted the content as necessary and accept full responsibility for the publication’s content.

Author contributions

Systematic search; study selection, data extraction, risk of bias assessment: S.M, M.A, S.H, M.R, P.G, S.Z - Preparing the figures and writing the first draft of the manuscript; S.H, A.D, P.G, M.D - S.M, L.A: supervision and critically editing the manuscript. All authors approved the final version for submission.

Funding

This research received no external funding.

Data availability

All data from this study are included in this published article.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare any conflict of interest.

Abbreviations

Central nervous system

Isocitrate dehydrogenase

Dendritic cells

Cytotoxic T lymphocyte

Cytotoxic T-Lymphocyte-Associated Antigen 4

Lymphokine-activated killer cells

Cytokine-induced killer cells

Natural killer cell

Interleukin-2

Tumor-infiltrating lymphocytes

Interferon gamma

Glioblastoma multiform

Blood-brain barrier

Neurotrophic Receptor Tyrosine Kinase

Randomized controlled trials

Preferred Reporting Items for Systematic Reviews and Meta-Analyses

Medical Subject Headings

Joanna Briggs Institute

Patient’s peripheral blood mononuclear cells

Disease control rate

Quality of life

Autologous stimulated lymphocytes

Transforming growth factor-β

International Registry on CIK cells

Chimeric Antigen Receptor

Immunohistochemistry

Major Histocompatibility Complex

World Health Organization

Computed tomography

Magnetic resonance imaging

Positron emission tomography

O⁶-Methylguanine-DNA Methyltransferase

Chondroitin Sulfate Proteoglycan 4

Tumor microenviroment

Natural killer group 2 member D

Ubiquitin-Specific Protease 14

MHC class I polypeptide-related sequence A

Lymphocyte function-associated antigen 1

Chemokine receptor/ligand

Immune checkpoint inhibitors

Programmed Cell Death Protein 1

Programmed Death-Ligand 1

Tumor treating fields

Hepatocellular carcinoma

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