Chimeric antigen receptors (CARs) are fusion proteins with an extracellular antigen recognition domain and numerous intracellular signaling domains that have been genetically modified. CAR-engineered T lymphocyte-based therapies have shown great success against blood cancers; however, potential fatal toxicity, such as in cytokine release syndrome, and high costs are some shortcomings that limit the clinical application of CAR-engineered T lymphocytes and remain to overcome. Natural killer (NK) cells are the focal point of current immunological research owing to their receptors that prove to be promising immunotherapeutic candidates for treating cancer. However, to date, manipulation of NK cells to treat malignancies has been moderately successful. Recent progress in the biology of NK cell receptors has greatly transformed our understanding of how NK cells recognize and kill tumor and infected cells. CAR-NK cells may serve as an alternative candidate for retargeting cancer because of their unique recognition mechanisms, powerful cytotoxic effects especially on cancer cells in both CAR-dependent and CAR-independent manners and clinical safety. Moreover, NK cells can serve as an ‘off-the-shelf product’ because NK cells from allogeneic sources can also be used in immunotherapies owing to their reduced risk of alloreactivity. Although ongoing fundamental research is in the beginning stages, this review provides an overview of recent developments implemented to design CAR constructs to stimulate NK activation and manipulate NK receptors for improving the efficiency of immunotherapy against cancer, summarizes the preclinical and clinical advances of CAR-NK cells against both hematological malignancies and solid tumors and confronts current challenges and obstacles of their applications. In addition, this review provides insights into prospective novel approaches that further enhance the efficiency of CAR-NK therapies and highlights potential questions that require to be addressed in the future.

Ultrasound, computed tomography, magnetic resonance, and gamma scintigraphy-based detection and bio-imaging technologies have achieved outstanding breakthroughs in recent years. However, these technologies still encounter several limitations such as insufficient sensitivity, specificity and security that limit their applications in cancer detection and bio-imaging. The semiconductor quantum dots (QDs) are a kind of newly developed fluorescent nanoparticles that have superior fluorescence intensity, strong resistance to photo-bleaching, size-tunable light emission and could produce multiple fluorescent colors under single-source excitation. Furthermore, QDs have optimal surface to link with multiple targets such as antibodies, peptides, and several other small molecules. Thus, QDs might serve as potential, more sensitive and specific methods of detection than conventional methods applied in cancer molecular targeting and bio-imaging. However, many challenges such as cytotoxicity and nonspecific uptake still exist limiting their wider applications. In the present review, we aim to summarize the current applications and challenges of QDs in cancer research mainly focusing on tumor detection, bio-imaging, and provides opinions on how to address these challenges.

Chimeric antigen receptor (CAR) T cell therapy for solid tumors shows promise, but several hurdles remain. Strategies to overcome barriers such as CAR T therapy-related toxicities (CTT), immunosuppression, and immune checkpoints through research and technology are needed to put the last nail to the coffin and offer hope for previously incurable malignancies. Herein we review current literature and infer novel strategies for the mitigation of CTT while impeding immune suppression, stromal barriers, tumor heterogeneity, on-target/off-tumor toxicities, and better transfection strategies with an emphasis on clinical research and prospects.

Background: Ewing sarcoma (ES) is a rare and aggressive pediatric bone malignancy with poor prognosis, driven by therapy-resistant tumor microenvironments (TME). The TME plays a critical role in tumor progression through a complex and dynamic network of reciprocal interactions among immune cells (dysfunctional T cells, immunosuppressive macrophages), stromal components (cancer-associated fibroblasts), and tumor cells. These interactions collectively shape the immune landscape, promote immune evasion, and contribute to therapeutic resistance. Identifying reliable prognostic markers remains a critical challenge.Methods: Here we performed an integrated single-cell RNA sequencing, WGCNA, and bulk RNA-seq analyses to investigate tumor-immune interactions. Differentially expressed genes (DEGs) intersected with T cell markers identified a total of 174 T cell-associated genes. Functional enrichment analysis and molecular subtyping were performed to explore immune-related pathways. A prognostic model based on CLEC11A, BDP1, and ID3 was constructed using Cox regression and validated in external datasets. Immune infiltration was assessed using the CIBERSORT algorithm.Results: T cell marker analyses revealed key roles in pathways such as PI3K-Akt signaling and immune modulation. Molecular subtyping identified two clusters with distinct immune microenvironments: Cluster C1 (immunosuppressive phenotype and poorer prognosis) and Cluster C2 (functionally active immune profile associated with better prognosis). The prognostic model demonstrated high predictive accuracy for 1-, 3-, and 5-year survival (AUC: 0.85, 0.82, 0.78). Additionally, a higher tumor mutation burden (TMB) with low survival rate has been observed in High-risk group. Immune infiltration analysis showed higher CD8+ T cell and dendritic cell activity and immune checkpoint expression in low-risk groups. Experimental validation demonstrated that ID3 silencing inhibited tumor cell proliferation and induced cell cycle arrest in ES cell lines.Conclusion: Together, our study identified CLEC11A, BDP1, and ID3 as key T cell associated prognostic markers and developed a validated model to predict survival outcomes in ES. Insights into T cell markers and tumor-immune dynamics offer promising advances in prognostic assessment and immunotherapy for ES. Furthermore, the role of ID3 in immune evasion and tumor proliferation underscores its potential as a therapeutic target, providing new avenues for immune checkpoint regulation and personalized treatment strategies.

Hepatocellular carcinoma, the most common primary liver cancer and a leading cause of death, is a difficult disease to treat due to its heterogeneous nature. Traditional models, such as 2D culture and patient-derived xenografts, have not proven effective. However, the development of 3D culture techniques, such as organoids, which can mimic the tumor microenvironment (TME) and preserve heterogeneity and pathophysiological properties of tumor cells, offers new opportunities for treatment and research. Organoids also have the potential for biomarker detection and personalized medication, as well as genome editing using CRISPR/Cas9 to study the behavior of certain genes and therapeutic interventions. This review explores to-the-date development of organoids with a focus on TME modeling in 3D organoid cultures. Further, it discusses gene editing using CRISPR/Cas9 in organoids, the challenges faced, and the prospects in the field of organoids.

Immunotherapy has become an important treatment strategy for cancer patients nowadays. Targeting cancer neoantigens presented by major histocompatibility complex (MHC) molecules, which emerge as a result of non-synonymous somatic mutations with high immunogenicity, is one of the most promising cancer immunotherapy strategies. Currently, several therapeutic options based on the personalized or shared neoantigens have been developed, including neoantigen vaccine and adoptive T-cell therapy, both of which are now being tested in clinical trials for various malignancies. The goal of this review is to outline the use of neoantigens as cancer therapy targets, with an emphasis on neoantigen identification, clinical usage of personalized neoantigen-based cancer therapy agents, and the development of off-the-shelf products based on shared neoantigens. In addition, we introduce and discuss the potential impact of the neoantigen–MHC complex on natural killer (NK) cell antitumor function, which could be a novel way to boost immune response-induced cytotoxicity against malignancies.