Hepatocellular carcinoma (HCC) remains one of the major threats to human health worldwide. The emergence of systemic therapeutic options has greatly improved the prognosis of patients with HCC, particularly those with advanced stages of the disease. In this review, we discussed the pathogenesis of HCC, genetic alterations associated with the development of HCC, and alterations in the tumor immune microenvironment. Then, important indicators and emerging technologies related to the diagnosis of HCC are summarized. Also, we reviewed the major advances in treatments for HCC, offering insights into future prospects for next-generation managements.

Despite current technological advancements in the treatment of glioma, immediate alleviation of symptoms can be catered by therapeutic modalities, including surgery, chemotherapy, and combinatorial radiotherapy that exploit aberrations of glioma. Additionally, a small number of target antigens, their heterogeneity, and immune evasion are the potential reasons for developing targeted therapies. This oncologic milestone has catalyzed interest in developing immunotherapies against Glioblastoma to improve overall survival and cure patients with high-grade glioma. The next-gen CAR-T Cell therapy is one of the effective immunotherapeutic strategies in which autologous T cells have been modified to express receptors against GBM and it modulates cytotoxicity.

In this review article, we examine preclinical and clinical outcomes, and limitations as well as present cutting-edge techniques to improve the function of CAR-T cell therapy and explore the possibility of combination therapy.

To date, several CAR T-cell therapies are being evaluated in clinical trials for GBM and other brain malignancies and multiple preclinical studies have demonstrated encouraging outcomes.

CAR-T cell therapy represents a promising therapeutic paradigm in the treatment of solid tumors but a few limitations include, the blood-brain barrier (BBB), antigen escape, tumor microenvironment (TME), tumor heterogeneity, and its plasticity that suppresses immune responses weakens the ability of this therapy. Additional investigation is required that can accurately identify the targets and reflect the similar architecture of glioblastoma, thus optimizing the efficiency of CAR-T cell therapy; allowing for the selection of patients most likely to benefit from immuno-based treatments.

Chimeric antigen receptor (CAR)-modified NK (CAR-NK) cells are candidates for next-generation cancer immunotherapies. Here we generated CD19-specific CAR-NK cells with 4-1BB and CD3ζ signaling endo-domains (CD19-BBz CAR-NK) by transduction of cord blood-derived NK cells using baboon envelope pseudotyped lentiviral vectors and demonstrated their antitumor activity in preclinical B cell lymphoma models in female mice. We next conducted a phase 1 dose-escalation trial involving repetitive administration of CAR-NK cells in 8 patients with relapsed/refractory large B cell lymphoma (NCT05472558). Primary end points were safety, maximum tolerated dose, and overall response rate. Secondary end points included duration of response, overall survival, and progression-free survival. No dose-limiting toxicities occurred, and the maximum tolerated dose was not reached. No cases of cytokine release syndrome, neurotoxicity, or graft-versus-host disease were observed. Results showed an overall response rate of 62.5% at day 30, with 4 patients (50%) achieving complete response. The median progression-free survival was 9.5 months, and the median overall survival was not reached. A post hoc exploratory single-cell RNA sequencing analysis revealed molecular features of CAR-NK cells associated with therapeutic efficacy and efficacy-related immune cell interaction networks. This study met the pre-specified end points. In conclusion, CD19-BBz CAR-NK cells were feasible and therapeutically safe, capable of inducing durable response in patients with B cell lymphoma.

Hepatocellular Carcinoma (HCC), a highly prevalent malignancy, poses a significant global health challenge. Its pathogenesis is intricate and multifactorial, involving a complex interplay of environmental and genetic factors. Viral hepatitis, excessive alcohol consumption, and cirrhosis are known to significantly elevate the risk of developing HCC. The underlying biological processes driving HCC are equally complex, encompassing aberrant activation of molecular signaling pathways, dysregulation of hepatocellular differentiation and angiogenesis, and immune dysfunction. This review delves into the multifaceted nature of HCC, exploring its etiology and the intricate molecular signaling pathways involved in its development. We examine the role of immune dysregulation in HCC progression and discuss the potential of emerging therapeutic strategies, including immune-targeted therapy and tumor-associated macrophage interventions. Additionally, we explore the potential of traditional Chinese medicine (TCM) monomers in inhibiting tumor growth. By elucidating the complex interplay of factors contributing to HCC, this review aims to provide a comprehensive understanding of the disease and highlight promising avenues for future research and therapeutic development.

Hepatocellular carcinoma (HCC), accounting for 90% of primary liver cancers, is a high-mortality malignancy and the third leading cause of cancer-related deaths globally, with major risk factors like hepatitis B/C, aflatoxin exposure, and obesity. Most patients are diagnosed at advanced stages, with a 5-year survival rate below 10%. Therefore, HCC treatment and research still face significant challenges, and more effective treatments need to be further explored.

We searched PubMed, Scopus, Web of Science and Embase from the time of repository construction to March 1, 2025, preliminary included studies involving animal experiments on the therapeutic effects of Chimeric Antigen Receptor T-cell (CAR-T cell) therapy on HCC. After exclusion and evaluation of literature, the random/fixed effects model was employed to perform meta-analysis and obtain Weighted Mean Difference (WMD) and 95% confidence interval (CI) of tumor volume and mass. We then verify the robustness of the results through subgroup analysis and sensitivity analysis. Use Q-test to evaluate heterogeneity and quantify it based on I² value.

We included a total of 16 studies. Multiple independent sets of data were extracted from the experiments of these studies, of which 25 were used for volume-based meta-analysis and 16 were used for mass-based meta-analysis. Regarding volume, The combined mean CAR-T treatment group/control group resulted in an WMD of -515.77 (95% CI: -634.78 to -396.76; I² =90.8%). Meanwhile, based on mass, the combined mean CAR-T treatment group/control group resulted in an WMD of -0.30 (95% CI: -0.38 to -0.22; I² = 94.4%). The results of the bias analysis further validated the reliability of the research conclusions.

Based on the dual-index meta-analysis, the CAR-T therapy have been proved to possess significant therapeutic effect in HCC. However, the funnel plot of tumor mass and the Egger's regression suggest the potential presence of publication bias. Thus, it warrants further research to evaluate the potential of CAR-T therapy alone or as an adjuvant for HCC treatment.

Adoptive cell therapy (ACT) is a type of immunotherapy in which autologous or allogeneic immune cells, such as tumor-infiltrating lymphocytes or engineered lymphocytes, are infused into patients with cancer to eliminate malignant cells. Recently, autologous T cells modified to express a chimeric antigen receptor (CAR) targeting CD19 showed a positive response in clinical studies for hematologic malignancies and have begun to be used in clinical practice. This article discusses the current status and promise of ACT research in hepatocellular carcinoma (HCC), focusing on challenges in off-the-shelf ACT using primary cells or induced pluripotent stem cells (iPSCs) with or without genetic engineering. Early clinical trials of autologous GPC-3-, MUC1-, or CEA-targeted CAR-T cell therapies are underway for HCC. There is a growing demand for the development of off-the-shelf therapies due to the high cost and manufacturing issues associated with autologous CAR-T. The development of ACT from various cell sources, such as NK cells, NKT cells, macrophages, and γδ T cells without MHC restriction other than T cells has been proposed. Advances in genome editing, including HLA gene knockout to avoid GvHD, and strategies to enhance efficacy in overcoming the suppressive tumor microenvironment, are used to create universal 'off-the-shelf' CAR-T cells which can be used immediately as therapeutic products from healthy donors or iPSC-derived immune cells. Despite several limitations, cell-based immunotherapy is expected to become a key cancer treatment modality for both hematologic malignancies and solid tumors including HCC, thanks to technological advancements overcoming these challenges.

The toxicity of chimeric antigen receptor-natural killer (CAR-NK) therapy has not been tested in solid tumors, compared with CAR-T therapy side by side. To address this, we investigated the CD147-CAR-NK "on-target/off-tumor" toxicity and neurotoxicity in human CD147-transgenic (hCD147TG) mice with hepatocellular carcinoma (HCC). We first tested the in vitro cytotoxicity of CD147-CAR-NK against CD147+ tumor and CD147+ healthy cells. Both CD147-CAR-NK cells and CD147-IL15-CAR-NK (autocrine expressing interleukin [IL]-15) can kill tumor cells specifically but not CD147+ healthy lung and spleen tissue from hCD147TG mice. In vivo assays show minimal systemic toxicities against CD147+ healthy tissues but 1-week-longer persistence times in tumor than non-tumor tissues. To evaluate neurotoxicity, we compared the expression of ionized calcium-binding adaptor protein 1 (IBA1), glial fibrillary acidic protein (GFAP), and inducible nitric oxide synthase (iNOS) between CD147-CAR-T- and CD147-CAR-NK-treated hCD147TG mice with HCC. Both CD147-CAR-T- and CD147-CAR-NK-treated mice exhibited higher GFAP and IBA1 expression than control groups. CD147-CAR-T-treated mice showed an increase in iNOS compared to the control groups. The behavioral studies testing spatial memory showed that mice treated with CD147-CAR-NK exhibit better memory function than CD147-CAR-T-treated mice. This study provides a deeper understanding of the CD147-CAR-NK systemic toxicities and neurotoxicity of CD147-CAR-NK relative to CD147-CAR-T therapy.

Innovative therapeutic strategies are urgently needed to address the ongoing global health concern of hepatobiliary pancreatic malignancies. This review summarizes the latest and most comprehensive research of chimeric antigen receptor (CAR-T) cell engineering immunotherapy for treating hepatobiliary pancreatic cancers. Commencing with an exploration of the distinct anatomical location and the immunosuppressive, hypoxic tumor microenvironment (TME), this review critically assesses the limitations of current CAR-T therapy in hepatobiliary pancreatic cancers and proposes corresponding solutions. Various studies aim at enhancing CAR-T cell efficacy in these cancers through improving T cell persistence, enhancing antigen specificity and reducing tumor heterogeneity, also modulating the immunosuppressive and hypoxic TME. Additionally, the review examines the application of emerging nanoparticles and biotechnologies utilized in CAR-T therapy for these cancers. The results suggest that constructing optimized CAR-T cells to overcome physical barrier, manipulating the TME to relieve immunosuppression and hypoxia, designing CAR-T combination therapies, and selecting the most suitable delivery strategies, all together could collectively enhance the safety of CAR-T engineering and advance the effectiveness of adaptive cell therapy for hepatobiliary pancreatic cancers.

Renal cell carcinoma (RCC) is a malignancy that makes up 3% of adult cancers and 20%-30% of patients were diagnosed with metastatic RCC in the beginning, while the median overall survival (OS) of metastatic RCC systemic therapy ranges from 16 months to 50 months. Immunotherapy, a novel therapy that relies on the specific binding of immune cells and tumor cells, may be a potential therapy for advanced renal cell carcinoma. While chimeric antigen receptor NK-cell (CAR-NK) therapy has been investigated in a variety of solid tumors, specific research on its application to RCC has also been reported by several teams. In this review, we introduced the cytotoxicity mechanisms of NK cells, summarized the connections between RCC and NK cells, and posted new insights into renal cell carcinoma CAR-NK therapy. To date, most researches focusing on renal cell carcinoma and NK cells only claimed the mechanisms of NK cell cytotoxicity and NK cell immune suppression and even immune escape, yet the molecules involved could also be interesting targets for renal cell carcinoma CAR-NK therapy.

Hepatocellular carcinoma (HCC) remains one of the most challenging malignancies globally, characterized by significant heterogeneity, late-stage diagnosis, and resistance to treatment. In recent years, the advent of immune-checkpoint blockades (ICBs) and targeted immune cell therapies has marked a substantial advancement in HCC treatment. However, the clinical efficacy of these existing therapies is still limited, highlighting the urgent need for new breakthroughs. Natural killer (NK) cells, a subset of the innate lymphoid cell family, have shown unique advantages in the anti-tumour response. With increasing evidence suggesting the crucial role of dysfunctional NK cells in the pathogenesis and progression of HCC, considerable efforts have been directed toward exploring NK cells as a potential therapeutic target for HCC. In this review, we will provide an overview of the role of NK cells in normal liver immunity and in HCC, followed by a detailed discussion of various NK cell-based immunotherapies and their potential applications in HCC treatment.

The liver is one of the most frequent sites of primary malignancies in humans. Hepatocellular carcinoma (HCC) is one of the most prevalent solid tumors with poor prognosis. Current treatments showed limited efficacy in some patients, and, therefore, alternative strategies, such as immunotherapy, cancer vaccines, adoptive cell therapy (ACT), and recently chimeric antigen receptors (CAR)-T cells, are developed to offer better efficacy and safety profile in patients with HCC. Unlike other ACTs like tumor-infiltrating lymphocytes (TILs), CAR-T cells are equipped with engineered CAR receptors that effectively identify tumor antigens and eliminate cancer cells without major histocompatibility complex (MHC) restriction. This process induces intracellular signaling, leading to T lymphocyte recruitment and subsequent activation of other effector cells in the tumor microenvironment (TME). Until today, novel approaches have been used to develop more potent CAR-T cells with robust persistence, specificity, trafficking, and safety. However, the clinical application of CAR-T cells in solid tumors is still challenging. Therefore, this study aims to review the advancement, prospects, and possible avenues of CAR-T cell application in HCC following an outline of the CAR structure and function.

Hepatocellular carcinoma (HCC) remains a global health challenge owing to its widespread incidence and high mortality. HCC has a specific immune tolerance function because of its unique physiological structure, which limits the efficacy of chemotherapy, radiotherapy, and molecular targeting. In recent years, new immune approaches, including adoptive cell therapy, tumor vaccines, and oncolytic virus therapy, have shown great potential. As the efficacy of immunotherapy mainly depends on the spatial heterogeneity of the tumor immune microenvironment, it is necessary to elucidate the crosstalk between the composition of the liver cancer immune environment, from which potential therapeutic targets can be selected to provide more appropriate individualized treatment programs. The role of spatial heterogeneity of immune cells in the microenvironment of HCC in the progression and influence of immunotherapy on improving the treatment and prognosis of HCC were comprehensively analyzed, providing new inspiration for the subsequent clinical treatment of liver cancer.

Treatment for malignant primary brain tumors, including glioblastoma, remains a significant challenge despite advances in therapy. CAR-T cell immunotherapy represents a promising alternative to conventional treatments. This review discusses the landscape of clinical trials for CAR-T cell therapy targeting brain tumors, highlighting key advancements like novel target antigens and combinatorial strategies designed to address tumor heterogeneity and immunosuppression, with the goal of improving outcomes for patients with these aggressive cancers.

Immunotherapy has transformed the landscape of cancer treatment, with chimeric antigen receptor (CAR)-engineered T (CAR-T) cell therapy emerging as a front runner in addressing some hematological malignancies. Despite its considerable efficacy, the occurrence of severe adverse effects associated with CAR-T cell therapy has limited their scope and prompted the exploration of alternative therapeutic strategies. Natural killer (NK) cells, characterized by both their innate cytotoxicity and ability to lyse target cells without the constraint of peptide specificity conferred by a major histocompatibility complex (MHC), have similarly garnered attention as a viable immunotherapy. As such, another therapeutic approach has recently emerged that seeks to combine the continued success of CAR-T cell therapy with the flexibility of NK cells. Clinical trials involving CAR-engineered NK (CAR-NK) cell therapy have exhibited promising efficacy with fewer deleterious side effects. This review aims to provide a concise overview of the cellular and molecular basis of NK cell biology, facilitating a better understanding of advancements in CAR design and manufacturing. The focus is on current approaches and strategies employed in CAR-NK cell development, exploring at both preclinical and clinical settings. We will reflect upon the achievements, advantages, and challenges intrinsic to CAR-NK cell therapy. Anticipating the maturation of CAR-NK cell therapy technology, we foresee its encouraging prospects for a broader range of cancer patients and other conditions. It is our belief that this CAR-NK progress will bring us closer to making significant strides in the treatment of refractory and recurrent cancers, as well as other immune-mediated disorders.

Hepatocellular carcinoma (HCC), a major subtype of liver cancer, poses significant therapeutic challenges due to its late diagnosis and rapid progression. The evolving landscape of immunotherapy offers a beacon of hope, with natural killer (NK) cells emerging as pivotal players in combating HCC. NK cells are unique cytotoxic lymphocytes that are essential in the fight against infections and malignancies. Phenotypic and functional NK cell abnormalities have been shown in HCC patients, indicating their significance as a component of the innate immune system against cancer. This review elucidates the critical role of NK cells in combating HCC, focusing on their interaction with the tumor microenvironment, the development of NK cell-based therapies, and the innovative strategies to enhance their efficacy in the immunosuppressive milieu of HCC. The review delves into the various therapeutic strategies, including autologous and allogeneic NK cell therapies, genetic engineering to improve NK cell resilience and targeting, and the integration of NK cells with other immunotherapeutic approaches like checkpoint inhibitors and oncolytic virotherapy. By highlighting recent advancements and the ongoing challenges in the field, this review sets the stage for future research directions that could unlock the full potential of NK cell-based immunotherapy for HCC, offering a beacon of hope for patients battling this formidable cancer.

Hepatocellular carcinoma (HCC) is one of the most common cancers and a worldwide health concern that requires novel treatment approaches. Tyrosine kinase inhibitors (TKIs) and immune checkpoint blockades (ICBs) are the current standard of care; however, their clinical benefits are limited in some advanced and metastatic patients. With the help of gene engineering techniques, a novel adoptive cellular therapy (ACT) called chimeric antigen receptor (CAR)-T cells was recently introduced for treating HCC. A plethora of current clinical and preclinical studies are attempting to improve the efficacy of CAR-T cells by dominating the immunosuppressive environment of HCC and finding the best tumor-specific antigens (TSAs). The future of care for HCC patients might be drastically improved due to the convergence of novel therapeutic methods and the continuous progress in ACT research. However, the clinical application of CAR-T cells in solid tumors is still facing several challenges. In this study, we provide an overview of the advancement and prospects of CAR-T cell immunotherapy in HCC, as well as an investigation of how cutting-edge engineering could improve CAR-T cell efficacy and safety profile.

Retinoblastoma is the most common type of eye tumor in infants and children. Current treatments for retinoblastoma include intravenous chemotherapy, intra-arterial chemotherapy, intravitreal chemotherapy, cryotherapy, radiotherapy, and surgery. However, these treatments come accompanied by adverse effects such as the toxic side effects of chemotherapeutic drugs, post-operative complications including blindness after surgery, or other complications caused by radiotherapy. Immunotherapy is more promising for its low toxicity on normal cells and effectively improves the quality of life of patients. Disialoganglioside (GD2), a sphingolipid expressed on the surface of retinoblastoma, is a potential therapeutic target for retinoblastoma. We summarized immunotherapeutic approaches for both preclinical studies and clinical trials of GD2. An anti-GD2 monoclonal antibody (Dinutuximab), which has been approved for the treatment of high-risk neuroblastomas, has shown promising efficacy in improving patients' prognosis. Additionally, chimeric antigen receptors (CAR)-T therapy, GD2 vaccines and nanoparticles are also potential therapeutics. Finally, we discuss the prospects and current limitations of these immunotherapeutic approaches for treating retinoblastoma, as well as how to address these problems.

Drug resistance resulting from diverse mechanisms including the presence of cancer stem cells (CSCs) is the main obstacle for improving therapeutic efficacy of lenvatinib in hepatocellular carcinoma (HCC). Herein, a nanomedicine (siCD24-Len-MnO@PLAP) is developed by incorporating manganese oxide (MnO), lenvatinib (Len), and siRNA against CD24 (siCD24) into micelles composed of methoxypolyethylene glycol (mPEG), poly-L-lysine (PLLys), and polyasparagyl(N-(2-Aminoethyl)piperidine) (PAsp(PIP)) triblock copolymer. The nanomedicine can respond to the tumor microenvironment (TME) to release lenvatinib, and produce Mn2+ and O2, accompanied by changes in nanoparticle charge, which facilitates cellular endocytosis of siCD24-loaded nanoparticles. The released siCD24 and lenvatinib synergistically reduces CD24 expression, resulting in a more pronounced inhibition of stemness of CSCs. In the mouse models of HCC using Huh7-derived CSCs and Hepa1-6-derived CSCs, the nanomedicine shows remarkable anti-cancer effect by enhancing the therapeutic effects of lenvatinib against HCC via reducing the expression level of CD24 and decreasing the expression of hypoxia inducible factor-1α (HIF-1α). Moreover, in situ production of paramagnetic Mn2+ from the nanomedicine serves as an excellent contrast agent for magnetic resonance imaging (MRI) to monitor the therapeutic process. This study demonstrates that this multifunctional MRI-visible siCD24- and lenvatinib-loaded nanodrug holds great potential in enhancing therapeutic sensitivity for HCC lenvatinib therapy.

A new fate of cell surface receptors, cleaved activation in the nucleus, is summarized. The intracellular domain (ICD) of cell surface receptors, cleaved by enzymes like γ-secretase, translocates to the nucleus to form transcriptional complexes participating in the onset and development of tumors. The fate is clinically significant, as inhibitors of cleavage enzymes have shown effectiveness in treating advanced tumors by reducing tumorigenic ICDs. Additionally, the construction of synthetic receptors also conforms with the fate mechanism. This review details each step of cleaved activation in the nucleus, elucidates tumorigenic mechanisms, explores application in antitumor therapy, and scrutinizes possible limitations.

Cancer research has become increasingly complex over the past few decades as knowledge of the heterogeneity of cancer cells, their proliferative ability, and their tumor microenvironments has become available. Although conventional therapies remain the most compelling option for cancer treatment to date, immunotherapy is a promising way to harness natural immune defenses to target and kill cancer cells. Cell-mediated drug delivery systems (CDDSs) have been an active line of research for enhancing the therapeutic efficacy and specificity of cancer immunotherapy. These systems can be tailored to different types of immune cells, allowing immune evasion and accumulation in the tumor microenvironment. By enabling the targeted delivery of therapeutic agents such as immune stimulants, cytokines, antibodies, and antigens, CDDSs have improved the survival of some patients with cancer. This review summarizes the research status of CDDSs, with a focus on their underlying mechanisms of action, biology, and clinical applications. We also discuss opportunities and challenges for implementation of CDDSs into mainstream cancer immunotherapy.

Gastrointestinal (GI) cancers represent a significant health burden worldwide. Their incidence continues to increase, and their management remains a clinical challenge. Chimeric antigen receptor (CAR) natural killer (NK) cells have emerged as a promising alternative to CAR-T cells for immunotherapy of GI cancers. Notably, CAR-NK cells offer several advantages, including reduced risk of graft-versus-host disease, lower cytokine release syndrome, and the ability to target cancer cells through both CAR-dependent and natural cytotoxic mechanisms.

This review comprehensively discusses the development and applications of CAR-NK cells in the treatment of GI cancers. We explored various sources of NK cells, CAR design strategies, and the current state of CAR-NK cell therapy for GI cancers, highlighting recent preclinical and clinical trials. Additionally, we addressed existing challenges and propose potential strategies to enhance the efficacy and safety of CAR-NK cell therapy.

Our findings highlight the potential of CAR-NK cells to revolutionize GI cancer treatment and pave the way for future clinical applications.

Cancer is a leading cause of fatality worldwide. Due to the heterogeneity of cancer cells the effectiveness of various conventional cancer treatment techniques is constrained. Thus, researchers are diligently investigating therapeutic approaches like immunotherapy for effective tumor managements. Immunotherapy harnesses the inherent potential of patient's immune system to achieve desired outcomes. Within the realm of immunotherapy, CAR-T (Chimeric Antigen Receptor T) cells, emerges as a revolutionary innovation for cancer therapy. The process of CAR-T cell therapy entails extracting the patient's T cells, altering them with customized receptors designed to specifically recognize and eradicate the tumor cells, and then reinfusing the altered cells into the patient's body. Although there has been significant progress with CAR-T cell therapy in certain cases of specific B-cell leukemia and lymphoma, its effectiveness is hindered in hematological and solid tumors due to the challenges such as severe toxicities, restricted tumor infiltration, cytokine release syndrome and antigen escape. Overcoming these obstacles requires innovative approaches to design more effective CAR-T cells, which require a competent and diverse team to develop and implement. This comprehensive review addresses numerous therapeutic issues and provides a strategic solution while providing a deep understanding of the structural intricacies and production processes of CAR-T cells. In addition, this review explores the practical aspects of CAR-T cell therapy in clinical settings.

In hepatocellular carcinoma (HCC), CD147 expression contributes to tumor malignancy; however, its relationship with the tumor-immune microenvironment (TIME) remains unclear. This study aimed to elucidate the clinicopathological characteristics associated with CD147 expression in HCC and investigate its association with the TIME, specifically its association with tumor-infiltrating lymphocytes (TILs) and oncostatin M (OSM). Using 397 HCC specimens from patients undergoing curative-intent resection, we assessed CD147 expression in tumor cells and quantified OSM-positive cells and various TILs (CD8+, CD4+, FOXP3+, and CD20+ cells) in the TIME. Using tissue microarrays, these assessments were performed through immunohistochemical analysis. We investigated the associations between CD147 expression status, the density of OSM-positive cells, and the densities of various TILs. High CD147 expression, found in 332 specimens (83.6%), was associated with advanced clinical stage (P = 0.029), fibrosis (P = 0.036), and higher densities of FOXP3+ cells (P = 0.0039), CD4+ cells (P = 0.0012), and OSM-positive cells (P = 0.0017). In CD147-high tumors, OSM-positive cell density was associated with all assessed TIL subsets (CD8+, CD4+, FOXP3+, and CD20+ cells; all Ps < 0.001), whereas in CD147-low tumors, OSM-positive cell density was associated only with FOXP3+ cells (P = 0.0004). In HCC, CD147 expression is associated with an immunosuppressive TIME, characterized by increased FOXP3+ regulatory T cells and a correlation with OSM-positive cells. These results elucidate the potential mechanisms through which CD147 facilitates tumor-immune evasion, suggesting the CD147 - OSM axis as a promising target for therapeutic intervention in HCC.

As a solid tumor with high glycolytic activity, hepatocellular carcinoma (HCC) produces excess lactic acid and increases extracellular acidity, thus forming a unique immunosuppressive microenvironment. L-lactate dehydrogenase (LDH) and monocarboxylate transporters (MCTs) play a very important role in glycolysis. LDH is the key enzyme for lactic acid (LA) production, and MCT is responsible for the cellular import and export of LA. The synergistic effect of the two promotes the formation of an extracellular acidic microenvironment. In the acidic microenvironment of HCC, LA can not only promote the proliferation, survival, transport and angiogenesis of tumor cells but also have a strong impact on immune cells, ultimately leading to an inhibitory immune microenvironment. This article reviews the role of LA in HCC, especially its effect on immune cells, summarizes the progress of LDH and MCT-related drugs, and highlights the potential of immunotherapy targeting lactate combined with HCC.

HER2 amplification occurs in approximately 5% of colorectal cancer (CRC) cases and is associated only partially with clinical response to combined human epidermal growth factor receptor 2 (HER2)/epidermal growth factor receptor (EGFR)-targeted treatment. An alternative approach based on adoptive cell therapy using T cells engineered with anti-HER2 chimeric antigen receptor (CAR) proved to be toxic due to on-target/off-tumor activity. Here we describe a combinatorial strategy to safely target HER2 amplification and carcinoembryonic antigen (CEA) expression in CRC using a synNotch-CAR-based artificial regulatory network. The natural killer (NK) cell line NK-92 was engineered with an anti-HER2 synNotch receptor driving the expression of a CAR against CEA only when engaged. After being transduced and sorted for HER2-driven CAR expression, cells were cloned. The clone with optimal performances in terms of specificity and amplitude of CAR induction demonstrated significant activity in vitro and in vivo specifically against HER2-amplified (HER2amp)/CEA+ CRC models, with no effects on cells with physiological HER2 levels. The HER2-synNotch/CEA-CAR-NK system provides an innovative, scalable, and safe off-the-shelf cell therapy approach with potential against HER2amp CRC resistant or partially responsive to HER2/EGFR blockade.

Production of large amounts of functional NK and CAR-NK cells represents one of the bottlenecks for NK-based immunotherapy. In this study, we developed a large-scale, reliable, and practicable NK and CAR-NK production using G-Rex 100M bioreactors, which depend on a gas-permeable membrane technology. This system holds large volumes of medium with enhanced oxygen delivery, creating conditions conducive to large-scale PBNK and CAR-NK expansions for cancer therapy. Both peripheral blood NK cells (PBNKs) and CAR-NKs expanded in these bioreactors retained similar immunophenotypes and exhibited comparable cytotoxicity towards hepatocellular carcinoma (HCC) cells akin to that of NK and CAR-NK cells expanded in G-Rex 6 well bioreactors. Importantly, cryopreservation minimally affected the cytotoxicity of NK cells expanded using the G-Rex 100M bioreactors, establishing a robust platform for scaled-up NK and CAR-NK cell production. This method is promising for the development of "off-the-shelf" NK cells, supporting the future clinical implementation of NK cell immunotherapy.

Hepatocellular carcinoma (HCC), the predominant primary liver tumor, remains one of the most lethal cancers worldwide, despite the advances in therapy in recent years. In addition to the traditional chemically and dietary-induced HCC models, a broad spectrum of novel preclinical tools have been generated following the advent of transgenic, transposon, organoid, and in silico technologies to overcome this gloomy scenario. These models have become rapidly robust preclinical instruments to unravel the molecular pathogenesis of liver cancer and establish new therapeutic approaches against this deadly disease. The present review article aims to summarize and discuss the commonly used preclinical models for HCC, evaluating their strengths and weaknesses.

Cancer immunotherapy harnesses the body's immune system to combat malignancies, building upon an understanding of tumor immunosurveillance and immune evasion mechanisms. This therapeutic approach reactivates anti-tumor immune responses and can be categorized into active, passive, and combined immunization strategies. Active immunotherapy engages the immune system to recognize and attack tumor cells by leveraging host immunity with cytokine supplementation or vaccination. Conversely, passive immunotherapy employs exogenous agents, such as monoclonal antibodies (anti-CTLA4, anti-PD1, anti-PD-L1) or adoptive cell transfers (ACT) with genetically engineered chimeric antigen receptor (CAR) T or NK cells, to exert anti-tumor effects. Over the past decades, CAR-T cell therapies have gained significant traction in oncological treatment, offering hope through their targeted approach. However, the potential adverse effects associated with CAR-T cells, including cytokine release syndrome (CRS), off-tumor toxicity, and neurotoxicity, warrant careful consideration. Recently, CAR-NK cell therapy has emerged as a promising alternative in the landscape of tumor immunotherapy, distinguished by its innate advantages over CAR-T cell modalities. In this review, we will synthesize the latest research and clinical advancements in CAR-NK cell therapies. We will elucidate the therapeutic benefits of employing CAR-NK cells in oncology and critically examine the developmental bottlenecks impeding their broader application. Our discussion aims to provide a comprehensive overview of the current status and future potential of CAR-NK cells in cancer immunotherapy.

Chimeric antigen receptor (CAR) T cell therapy has shown promising results in hematologic malignancies, but its effectiveness in solid cancers remains challenging. Macrophages are immune cells residing within the tumor microenvironment. They can phagocytose tumor cells. Recently, CAR macrophages (CAR-M) have been a promising candidate for treating solid cancers. One of the common cancer antigens overexpressed in various types of cancer is CD147. CAR-T and NK cells targeting CD147 antigen have shown significant efficacy against hepatocellular carcinoma. Nevertheless, CAR-M targeting the CD147 molecule has not been investigated. In this study, we generated CAR targeting the CD147 molecule using the THP-1 monocytic cell line (CD147 CAR-M). The CD147 CAR-M exhibited typical macrophage characteristics, including phagocytosis of zymosan bioparticles and polarization ability toward M1 and M2 phenotypes. Furthermore, the CD147 CAR-M demonstrated enhanced anti-tumor activity against K562 and MDA-MB-231 cells without exhibiting off-target cytotoxicity against normal cells. Our research provides valuable insights into the potential of CD147 CAR-M as a promising platform for cancer immunotherapy, with applications in both hematologic malignancies and solid cancers.

This study aimed to develop synthetic Claudin18.2 (CLDN18.2) chimeric antigen receptor (CAR)-T (CAR-T) cells as a treatment for advanced gastric cancer using lentiviral vector genetic engineering technology that targets the CLDN18.2 antigen and simultaneously overcomes the immunosuppressive environment caused by programmed cell death protein 1 (PD-1). Synthetic CAR T cells are a promising approach in cancer immunotherapy but face many challenges in solid tumors. One of the major problems is immunosuppression caused by PD-1. CLDN18.2, a gastric-specific membrane protein, is considered a potential therapeutic target for gastric and other cancers. In our study, CLDN18.2 CAR was a second-generation CAR with inducible T-cell costimulatory (CD278), and CLDN18.2-PD1/CD28 CAR was a third-generation CAR, wherein the synthetic PD1/CD28 chimeric-switch receptor (CSR) was added to the second-generation CAR. In vitro, we detected the secretion levels of different cytokines and the killing ability of CAR-T cells. We found that the secretion of cytokines such as interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) secreted by three types of CAR-T cells was increased, and the killing ability against CLDN18.2-positive GC cells was enhanced. In vivo, we established a xenograft GC model and observed the antitumor effects and off-target toxicity of CAR-T cells. These results support that synthetic anti-CLDN18.2 CAR-T cells have antitumor effect and anti-CLDN18.2-PD1/CD28 CAR could provide a promising design strategy to improve the efficacy of CAR-T cells in advanced gastric cancer.

The basigin (BSG) gene, also known as CD147, has been implicated in the progression and prognosis of various cancers, including liver cancer. This study aimed to comprehensively evaluate the prognostic value of total BSG expression and its specific transcript variants, ENST00000353555 and ENST00000545507, in a large cohort of patients with primary liver cancer.

The prognostic values of total BSG, ENST00000353555, and ENST00000545507 expression in overall survival (OS) and progression-free interval (PFI) of patients with primary liver cancer were assessed using The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) dataset. Survival analysis, receiver operating characteristic (ROC) analysis, and validation of an extracellular matrix (ECM)-related prognostic signature were performed.

In univariate and multivariate analyses, total BSG, ENST00000353555, and ENST00000545507 expression were associated with poor OS in liver cancer patients. ENST00000353555 showed the highest hazard ratio among the three prognostic indicators. ROC analysis revealed that ENST00000353555 had better prognostic performance than total BSG expression. Replacing total BSG with ENST00000353555 in an existing ECM-related prognostic signature marginally increased the area under the curve values for one year from 0.79 to 0.80, and five-year OS from 0.72 to 0.73. ENST00000353555 showed isoform-specific positive correlations with EDNRB, IL10, C10orf54, and VEGFA.

ENST00000353555 serves as a better prognostic biomarker than total BSG expression in liver cancer, either as an individual marker or as a component of an ECM-related gene signature. Additionally, ENST00000353555 exhibited isoform-specific positive correlations with several immunosuppressive genes, suggesting a potential role in regulating the tumor microenvironment.

Liver cancer (LC) is the sixth most common disease and the third most common cause of cancer-related mortality. The WHO predicts that more than 1 million deaths will occur from LC by 2030. Hepatocellular carcinoma (HCC) is a common form of primary LC. Today, the management of LC involves multiple disciplines, and multimodal therapy is typically selected on an individual basis, considering the intricate interactions between the patient's overall health, the stage of the tumor, and the degree of underlying liver disease. Currently, the treatment of cancers, including LC, has undergone a paradigm shift in the last ten years because of immuno-oncology. To treat HCC, immune therapy approaches have been developed to enhance or cause the body's natural immune response to specifically target tumor cells. In this context, immune checkpoint pathway inhibitors, engineered cytokines, adoptive cell therapy, immune cells modified with chimeric antigen receptors, and therapeutic cancer vaccines have advanced to clinical trials and offered new hope to cancer patients. The outcomes of these treatments are encouraging. Additionally, treatment using stem cells is a new approach for restoring deteriorated tissues because of their strong differentiation potential and capacity to release cytokines that encourage cell division and the formation of blood vessels. Although there is no proof that stem cell therapy works for many types of cancer, preclinical research on stem cells has shown promise in treating HCC. This review provides a recent update regarding the impact of immunotherapy and stem cells in HCC and promising outcomes.

Immunotherapy has shown robust efficacy in treating a broad spectrum of hematological and solid cancers. Despite the transformative impact of immunotherapy on cancer treatment, several outstanding challenges remain. These challenges include on-target off-tumor toxicity, systemic toxicity, and the complexity of achieving potent and sustainable therapeutic efficacy. Synthetic biology has emerged as a promising approach to overcome these obstacles, offering innovative tools for engineering living cells with customized functions. This review provides an overview of the current landscape and future prospects of cancer immunotherapy, particularly emphasizing the role of synthetic biology in augmenting its specificity, controllability, and efficacy. We delineate and discuss two principal synthetic biology strategies: those targeting tumor surface antigens with engineered immune cells and those detecting intratumoral disease signatures with engineered gene circuits. This review concludes with a forward-looking perspective on the enduring challenges in cancer immunotherapy and the potential breakthroughs that synthetic biology may contribute to the field.

Radiation therapy (RT) has been shown to effectively induce the expression of intercellular adhesion molecule-1 (ICAM-1), which is recognized by lymphocyte function-associated antigen 1 (LFA-1) expressed on natural killer (NK) cells. However, the potential synergistic antitumor immune response of tumor irradiation and administered NK cells has not been explored in intractable human liver cancers. Furthermore, NK cell targeting against both parental and cancer stemness has never been investigated.

Highly activated ex vivo NK cells were administered into the human liver tumor-bearing mice. Tumor direct RT was optimized according to tumor bearing site. HepG2 and Hep3B ICAM-1 knockout cells were generated using CRISPR/CAS9. Stemness tumor spheres were generated. NK cell cytolysis against parental and tumor sphere was evaluated using flow cytometry and real-time cytotoxicity assay.

A combination of adoptive NK cell therapy with RT significantly improved therapeutic efficacy over monotherapies against subcutaneous, orthotopic, and metastatic human liver tumor models. Direct tumor irradiation potentiated NK cell recognition and conjugation against liver cancer through the LFA-1/ICAM-1 axis. Suppression of immune synapse formation on NK cells using high-affinity LFA-1 inhibitors or ICAM-1 knockout liver cancer induced "outside-in" signal blocking in NK cells, resulting in failure to eliminate liver tumor despite the combination therapy. NK cells effectively recognized and targeted triple-high epithelial cell adhesion molecule+CD133+CD24+ liver cancer expressing upregulated ICAM-1 in the irradiated tumor microenvironment, which led to prevention of the initiation of metastasis, improving survival in a metastatic model. In addition, the LFA-1/ICAM-1 axis interruption between NK cells and stemness liver tumor spheres significantly diminished NK cell cytolysis. Consistent with our preclinical data, the LFA-1/ICAM-1 axis correlated with survival outcomes in patients with metastatic cancer from the The Cancer Genome Atlas databases.

NK cells in combination with tumor irradiation can provide synergistic therapeutic effects for NK cell recognition and elimination against both parental and stemlike liver cancer through LFA-1/ICAM-1.

Hepatocellular carcinoma (HCC) is a major health concern worldwide, with limited therapeutic options and poor prognosis. In recent years, immunotherapies such as immune checkpoint inhibitors (ICIs) have made great progress in the systemic treatment of HCC. The combination treatments based on ICIs have been the major trend in this area. Recently, dual immune checkpoint blockade with durvalumab plus tremelimumab has also emerged as an effective treatment for advanced HCC. However, the majority of HCC patients obtain limited benefits. Understanding the immunological rationale and exploring novel ways to improve the efficacy of immunotherapy has drawn much attention. In this review, we summarize the latest progress in this area, the ongoing clinical trials of immune-based combination therapies, as well as novel immunotherapy strategies such as chimeric antigen receptor T cells, personalized neoantigen vaccines, oncolytic viruses, and bispecific antibodies.

Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 in B-cell non-Hodgkin lymphoma (NHL) validates the utility of CAR-based therapy for lymphomatous malignancies. Despite the success, treatment failure due to CD19 antigen loss, mutation, or down-regulation remains the main obstacle to cure. On-target, off-tumor effect of CD19-CAR T leads to side effects such as prolonged B-cell aplasia, limiting the application of therapy in indolent diseases such as chronic lymphocytic leukemia (CLL). Alternative CAR targets and multi-specific CAR are potential solutions to improving cellular therapy outcomes in B-NHL. For Hodgkin lymphoma and T-cell lymphoma, several cell surface antigens have been studied as CAR targets, some of which already showed promising results in clinical trials. Some antigens are expressed by different lymphomas and could be used for designing tumor-agnostic CAR. Here, we reviewed the antigens that have been studied for novel CAR-based therapies, as well as CARs designed to target two or more antigens in the treatment of lymphoma.

Recent advancements in genetic engineering have made it possible to modify Natural Killer (NK) cells to enhance their ability to fight against various cancers, including solid tumors. This comprehensive overview discusses the current status of genetically engineered chimeric antigen receptor NK-cell therapies and their potential for treating solid tumors. We explore the inherent characteristics of NK cells and their role in immune regulation and tumor surveillance. Moreover, we examine the strategies used to genetically engineer NK cells in terms of efficacy, safety profile, and potential clinical applications. Our investigation suggests CAR-NK cells can effectively target and regress non-hematological malignancies, demonstrating enhanced antitumor efficacy. This implies excellent promise for treating tumors using genetically modified NK cells. Notably, NK cells exhibit low graft versus host disease (GvHD) potential and rarely induce significant toxicities, making them an ideal platform for CAR engineering. The adoptive transfer of allogeneic NK cells into patients further emphasizes the versatility of NK cells for various applications. We also address challenges and limitations associated with the clinical translation of genetically engineered NK-cell therapies, such as off-target effects, immune escape mechanisms, and manufacturing scalability. We provide strategies to overcome these obstacles through combination therapies and delivery optimization. Overall, we believe this review contributes to advancing NK-cell-based immunotherapy as a promising approach for cancer treatment by elucidating the underlying mechanisms, evaluating preclinical and clinical evidence, and addressing remaining challenges.

Natural killer (NK) cell-based immunotherapies are attracting increasing interest in the field of cancer treatment. Early clinical trials have shown promising outcomes, alongside satisfactory product efficacy and safety. Recent developments have greatly increased the therapeutic potential of NK cells by endowing them with enhanced recognition and cytotoxic capacities. This review focuses on surface receptor engineering in NK cell therapy and discusses its impact, challenges, and future directions.Most approaches are based on engineering with chimeric antigen receptors to allow NK cells to target specific tumor antigens independent of human leukocyte antigen restriction. This approach has increased the precision and potency of NK-mediated recognition and elimination of cancer cells. In addition, engineering NK cells with T-cell receptors also mediates the recognition of intracellular epitopes, which broadens the range of target peptides. Indirect tumor peptide recognition by NK cells has also been improved by optimizing immunoglobulin constant fragment receptor expression and signaling. Indeed, engineered NK cells have an improved ability to recognize and destroy target cells coated with specific antibodies, thereby increasing their antibody-dependent cellular cytotoxicity. The ability of NK cell receptor engineering to promote the expansion, persistence, and infiltration of transferred cells in the tumor microenvironment has also been explored. Receptor-based strategies for sustained NK cell functionality within the tumor environment have also been discussed, and these strategies providing perspectives to counteract tumor-induced immunosuppression.Overall, receptor engineering has led to significant advances in NK cell-based cancer immunotherapies. As technical challenges are addressed, these innovative treatments will likely reshape cancer immunotherapy.

Hepatocellular carcinoma (HCC) remains a global health challenge that urgently calls for innovative therapeutic strategies. Chimeric antigen receptor T cell (CAR T) therapy has emerged as a promising avenue for HCC treatment. However, the therapeutic efficacy of CAR T immunotherapy in HCC patients is significantly compromised by some major issues including the immunosuppressive environment within the tumor, antigen heterogeneity, CAR T cell exhaustion, and the advanced risk for on-target/off-tumor toxicity. To overcome these challenges, many ongoing preclinical and clinical trials are underway focusing on the identification of optimal target antigens and the decryption of the immunosuppressive milieu of HCC. Moreover, limited tumor infiltration constitutes a significant obstacle of CAR T cell therapy that should be addressed. The continuous effort to design molecular targets for CAR cells highlights the importance for a more practical approach for CAR-modified cell manufacturing. This review critically examines the current landscape of CAR T cell therapy for HCC, shedding light on the changes in innate and adaptive immune responses in the context of HCC, identifying potential CAR T cell targets, and exploring approaches to overcome inherent challenges. Ongoing advancements in scientific research and convergence of diverse treatment modalities offer the potential to greatly enhance HCC patients' care in the future.

Liver cancer, predominantly hepatocellular carcinoma (HCC), globally ranks sixth in incidence and third in cancer-related deaths. HCC risk factors include non-viral hepatitis, alcohol abuse, environmental exposures, and genetic factors. No specific genetic alterations are unequivocally linked to HCC tumorigenesis. Current standard therapies include surgical options, systemic chemotherapy, and kinase inhibitors, like sorafenib and regorafenib. Immunotherapy, targeting immune checkpoints, represents a promising avenue. FDA-approved checkpoint inhibitors, such as atezolizumab and pembrolizumab, show efficacy, and combination therapies enhance clinical responses. Despite this, the treatment of hepatocellular carcinoma (HCC) remains a challenge, as the complex tumor ecosystem and the immunosuppressive microenvironment associated with it hamper the efficacy of the available therapeutic approaches. This review explores current and advanced approaches to treat HCC, considering both known and new potential targets, especially derived from proteomic analysis, which is today considered as the most promising approach. Exploring novel strategies, this review discusses antibody drug conjugates (ADCs), chimeric antigen receptor T-cell therapy (CAR-T), and engineered antibodies. It then reports a systematic analysis of the main ligand/receptor pairs and molecular pathways reported to be overexpressed in tumor cells, highlighting their potential and limitations. Finally, it discusses TGFβ, one of the most promising targets of the HCC microenvironment.

Innate lymphoid cells (ILCs) have been identified as potent regulators of inflammation, cell death and wound healing, which are the main biological processes involved in the progression of chronic liver disease. Obesity and chronic alcohol consumption are the leading contributors to chronic liver diseases in developed countries, due to inappropriate lifestyles. In particular, inflammation is a key factor in these liver abnormalities and promotes the development of more severe lesions such as fibrosis, cirrhosis and hepatocellular carcinoma. Opposite roles of ILC subsets have been described in the development of chronic liver disease, depending on the stage and aetiology of the disease. The heterogeneous family of ILCs encompasses cytotoxic natural killer cells, the cytokine-producing type 1, 2 and 3 ILCs and lymphoid tissue inducer cells. Dysfunction of these immune cells provokes uncontrolled inflammation and tissue damage, which are the basis for tumour development. In this review, we provide an overview of the recent and putative roles of ILC subsets in obesity and alcohol-associated liver diseases, which are currently the major contributors to end-stage liver complications such as fibrosis/cirrhosis and hepatocellular carcinoma.

Extracellular matrix metalloproteinase inducer CD147 is a glycoprotein on the cell surface. There is minimal expression of CD147 in normal epithelial and fetal tissues, but it is highly expressed in a number of aggressive tumors. CD147 has been implicated in pan-cancer immunity and progression. With the development of CD147-targeting therapeutic strategy, accurate detection of CD147 expression in tumors and its changes during the therapy is necessary. In this study we constructed a novel radiotracer by labeling the anti-CD147 mAb with radionuclide 124/125I (124/125I-anti-CD147) for noninvasive detection of CD147 expression in pan-cancers, and characterized its physicochemical properties, affinity, metabolic characteristics, biodistribution and immunoPET imaging with 124I-IgG and 18F-FDG as controls. By examining the expression of CD147 in cancer cell lines, we found high CD147 expression in colon cancer cells LS174T, FADU human pharyngeal squamous cancer cells and 22RV1 human prostate cancer cells, and low expression of CD147 in human pancreatic cancer cells ASPC1 and human gastric cancer cells BGC823. 124/125I-anti-CD147 was prepared using N-bromine succinimide (NBS) as oxidant and purified by PD-10 column. Its radiochemical purity (RCP) was over 99% and maintained over 85% in saline or 5% human serum albumin (HSA) for more than 7 d; the RCP of 125I-anti-CD147 in blood was over 90% at 3 h post injection (p.i.) in healthy mice. The Kd value of 125I-anti-CD147 to CD147 protein was 6.344 nM, while that of 125I-IgG was over 100 nM. 125I-anti-CD147 showed much greater uptake in CD147 high-expression cancer cells compared to CD147 low-expression cancer cells. After intravenous injection in healthy mice, 125I-anti-CD147 showed high initial uptake in blood pool and liver, the uptake was decreased with time. The biological half-life of distribution and clearance phases in healthy mice were 0.63 h and 19.60 h, respectively. The effective dose of 124I-anti-CD147 was estimated as 0.104 mSv/MBq. We conducted immunoPET imaging in tumor-bearing mice, and demonstrated a significantly higher tumor-to-muscle ratio of 124I-anti-CD147 compared to that of 124I-IgG and 18F-FDG in CD147 (+) tumors. The expression levels of CD147 in cells and tumors were positively correlated with the maximum standardized uptake value (SUVmax) (P < 0.01). In conclusion, 124/125I-anti-CD147 displays high affinity to CD147, and represents potential for the imaging of CD147-positive tumors. The development of 124I-anti-CD147 may provide new insights into the regulation of tumor microenvironment and formulation of precision diagnosis and treatment programs for tumors.

Equipping cancer-fighting immune cells with chimeric antigen receptor (CAR) has gained immense attention for cancer treatment. CAR-engineered T cells (CAR T cells) are the first immune-engineered cells that have achieved brilliant results in anti-cancer therapy. Despite promising anti-cancer features, CAR T cells could also cause fatal side effects and have shown inadequate efficacy in some studies. This has led to the introduction of other candidates for CAR transduction, e.g., Natural killer cells (NK cells). Regarding the better safety profile and anti-cancer properties, CAR-armored NK cells (CAR NK cells) could be a beneficial and suitable alternative to CAR T cells. Since introducing these two cells as anti-cancer structures, several studies have investigated their efficacy and safety, and most of them have focused on hematological malignancies. Solid tumors have unique properties that make them more resistant and less curable cancers than hematological malignancies. In this review article, we conduct a comprehensive review of the structure and properties of CAR NK and CAR T cells, compare the recent experience of immunotherapy with CAR T and CAR NK cells in various solid cancers, and overview current challenges and future solutions to battle solid cancers using CARNK cells.